Citation
The functional role of cholesterol in cold adaptation

Material Information

Title:
The functional role of cholesterol in cold adaptation
Creator:
Mosher, M. J
Publication Date:
Language:
English
Physical Description:
viii, 119 leaves : illustrations ; 29 cm

Subjects

Subjects / Keywords:
Cholesterol ( lcsh )
Cold adaptation ( lcsh )
Cholesterol ( fast )
Cold adaptation ( fast )
Genre:
bibliography ( marcgt )
theses ( marcgt )
non-fiction ( marcgt )

Notes

Bibliography:
Includes bibliographical references (leaves 110-119).
General Note:
Submitted in partial fulfillment of the requirements for the degree, Master of Arts, Anthropology.
Statement of Responsibility:
by M.J. Mosher.

Record Information

Source Institution:
University of Florida
Rights Management:
All applicable rights reserved by the source institution and holding location.
Resource Identifier:
31508881 ( OCLC )
ocm31508881
Classification:
LD1190.L43 1994m .M67 ( lcc )

Downloads

This item has the following downloads:


Full Text
THE FUNCTIONAL ROLE OF CHOLESTEROL IN COLD ADAPTATION
by
M. J. Mosher
A.D.N., Coastal Carolina Community College, 1981
B.S.N., Metropolitan State College of Denver, 1986
A thesis submitted to the
Faculty of the Graduate School of the
University of Colorado at Denver
in partial fulfillment
of the requirements for the degree of
Master of Arts
Anthropology
1 994


This thesis for the Master of Arts
degree by
M. J. Mosher
has been approved for the
Department of
Anthropology
by

Date


Mosher, M. J. (M.A., Anthropology)
The Functional Role of Cholesterol in Cold Adaptation
Thesis directed by Professor Linda Curran-Everett
ABSTRACT
The phenomena of seasonal variation and elevation
of serum cholesterol during exposure to cold climate
have been documented in populations since the mid-1920's.
The function of increased Serum cholesterol is neither
clearly documented, nor fully researched. With cholesterol
now implicated as a major risk factor in cardiovascular
disease, much of its documented benefit to the human
body has been de-emphasized. The intent of this thesis
is to explore the hypothesis that elevated serum
cholesterol is a functional human adaptive response to
cold and to suggest that arbitrary lowering of serum
cholesterol in all populations could be detrimental.
This thesis is a review of international and
interdisciplinary literature of cholesterol research
and of human response to cold. The specific cholesterol
function investigated is that of 'structural antioxidant'
to the cell membrane during periods of cold exposure.
iii


Evidence, primarily documented in Russian literature,
is presented. The research in this area is new and
incomplete. However, it suggests a direction for further
investigation into the relationship between cold climate
and cholesterol.
This abstract accurately represents the content of the
candidate's thesis. I recommend its publication.
Signed
Linda Curran-Everett
iv


CONTENTS
CHAPTER PAGE
1. INTRODUCTION............................. 1
2. ADAPTATION TO COLD....................... 6
Heat production....................... 7
Heat loss ..............................9
Responses to cold stress...............11
Heat conserving behaviors .............15
Physiological cold adaptations.........16
Hormonal response to cold..............21
Human Variation...................... 26
3. HOMEOVISCOUS ADAPTATION..................32
Membrane structure and function........33
Cold effects on cells..................36
Homeoviscous adaptation................37
Lipid Peroxidation.....................42
Population research....................44
Discussion.............................46
4. CHOLESTEROL..............................49
Transport and metabolism...............50
Cholesterol oxidation..................56
Other fats and lipids..................58
The structural antioxidant.............60
Discussion.............................61
v


5. ADAPTATION................................64
Factors affecting selection.............66
Coevolution.............................69
Adaptation as a multi-modal activity... 70
Models for study...................... 72
Stress responses.................... ,76
i
Physiological stress responses.........|78
The study of adaptation.................bl
Discussion..............................85
6. DISCUSSION AND PROPOSALS..................87
Review of studies..................... 87
Proposals for future study............94
Conclusion........................... 106
7. APPENDIX........................... ....108
8 . BIBLIOGRAPHY.............................110
vi


FIGURES
FIGURE PAGE
1 . Thermoregulation.............................12
2. Fluid mosaic for biological membranes........39
3. Cholesterol transport system.................51
4. Dyson-Hudson1 s inclusive model..............73
vii


TABLES
TABLES PAGE
1. Changes in non-shivering thermogenesis
during short and long term exposure.......23
2. Temperature and metabolic responses during
all night cold tests......................23
3. Transport mechanisms of vital substances.... 35
4. Apolipoproteins............................ 53
5. Cholesterol percentages.....................53
6. Serum cholesterol levels....................88
viii


ACKNOWLEDGEMENTS
Anssi Arpiainen
Liason Officer, TUKOSPAR
Helsinki, Finland
Finnish Translator
Harriet Mosher
Oberlin, Ohio
Funding
Lena Peschanskaia
Department of Economics
Graduate Student
UCD
Russian Translator
Diane Oliver
Seattle, Washington
Editor


CHAPTER 1
INTRODUCTION
Cholesterol is currently denounced for its potential
detrimental effects on the human cardiovascular system.
As early as the 1950s medical researchers documented
streaky deposits of fat and fiber in the vascular system
of young men. Epidemiologists noted that victims of
cardiovascular disease often had high serum cholesterol
levels. Health officials responded quickly by declaring
war on cholesterol. Doctors developed arbitrary numerical
parameters for serum cholesterol levels and placed
individuals into risk categories. International programs
to lower serum cholesterol were implemented, despite
documented evidence that cholesterol is so vital to cell
viability that virtually every cell in the body
manufactures the substance.
Current epidemiological research associates low
serum cholesterol with higher rates of cancer and risk
of stroke. Polyunsaturated fats, once thought to be
a beneficial exchange for high cholesterol animal fats,
are now under investigation for possible detrimental
effects on the cardiovascular system and cellular
1


structure. And, the controversy continues.
Elevated serum levels are associated with exposure
to stress, particularly exposure to cold stress. Russian
researchers now believe that cholesterol may in some
way be protective against the effects of cold on cellular
tissue. Yet, medical science still places restrictions
on acceptable levels of serum cholesterol for all humans
regardless of history, circumstances, or environment.
This thesis is a review of international research
on cholesterol and human response to cold. The intent
is to reframe the research within the hypothesis that
elevated serum cholesterol may be an adaptive human
response and may serve a functional purpose. The goal
of this thesis is to establish the framework by which
to further examine the connection between cold adaptation
and cholesterol.
The investigation begins with a review of research
addressing the effects of cold on the human body. The
information presented includes general human adaptive
responses and some population variations. It is followed
by an examination of cellular response to cold and the
adaptive response of the cell membrane's lipid bilayer.
This discussion of homeoviscous adaptation is relevant
in several ways, including an understanding of human
food sources available in cold climate.
2


Chapter four includes a general review of the
accepted knowledge base concerning cholesterol
utilization, transport system and oxidation. It includes
a look at current research concerning oxidation stress
on the cell and its membranes.
An examination into the theoretical framework for
an adaptation model follows. The discussion takes into
consideration biological, psychological, social and
cultural variables which impact adaptive processes.
The review of theoretical considerations illustrates
the difficulty in operationalizing research projects
which address the specifics of human adaptation. However
the inclusive perspective sets the stage for developing
several lines of research by which to study cold stress
and cholesterol. These will be delineated and discussed.
The final chapter is a synopsis of current research
connecting cold adaptation and cholesterol, acquired
through both literary review and interviews with
international scientists actively investigating the issue
The studies originate from a wide variety of disciplines,
each with its paradigmatic view. The research reflects
the difficulties of understanding languages, scientific
methods and explanatory models. Reinforcement of the
idea that cholesterol is involved in adaptation to cold
came from professional asides and brief comments which
3


were not directly associated with the stated goals of
the research projects themselves.
The intent of the last chapter is to discuss the
lack of consensus in explanations concerning the
relationship of cold and cholesterol. No clear
explanation as to why cholesterol levels rise with cold
exposure was found. Repeatedly scientist stated their
belief that the elevation was part of a functional or
adaptive response, however, adding that research on the
subject had not been done. No temperature-based studies
exist which correlate elevated serum cholesterol with
elevated cholesterol content in cell membranes;
documenting the mechanism by which omega-3 reduces serum
cholesterol; or examining erythrocyte behavior in high
serum cholesterol under varying temperatures. Yet, the
knowledge would be invaluable in further understanding
of the cholesterol issue.
The practical applications of research exploring
the mechanism and function of the relationship between
cold and climate are many. Russians are using their
studies to develop preventive health measures to protect
workers now migrating above the Arctic Circle. Alaskans
are searching for more information on the detrimental
human effects of dietary change versus intake of dietary
contaminants in order to rule on indigenous subsistence
4


hunting. Finns are searching for an explanation as to
why Saami (Lapp) reindeer herders have higher cholesterol
levels yet lower cardiovascular disease than the Finns.
And Americans are now questioning whether trans fat may
be more detrimental to women's cardiovascular system
than cholesterol.
Research examining cholesterol's role must be
approached by a framework which incorporates theories
of human variation, adaptation and ecology. Knowledge
gained from such studies must be applied when implementing
widespread prevention programs. This thesis represents
an examination of multi-disciplinary cholesterol research
and the initial stage of a research direction to blend
the many approaches into a single research program.
5


CHAPTER 2
ADAPTATION TO COLD
Adaptation to cold is the complex
interdependence which develops through
harmonious interdependence of various
reactions interrelated within a time-
dependent scheme ..... it is a sort of
integrated systemic potentiation of all
the heat producing and heat preserving
systems which exist in the organism.
(LeBlanc, 1975, p. 102)
Humans evolved initially in the warm climate of
Africa. They were hardly designed to function in cold
climates, but function they do. Humans are homeothermic
organisms which must maintain body temperatures within
a consistent range, independent of environment. Their
core temperatures are found between 37-38C/98.6F. A
drop of only 9F in core temperature results in
thermoregulatory system failure. While a naked human
may maintain body temperature with its basal metabolism
rate (BMR) for heat production in an ambient temperature
of 75F (Frisancho, 1981), death will occur within 15
minutes in the common conditions of the Arctic, -40C
and 20mph winds (Bruemmer, 1989).
Without extensive body hair or hibernation capacities
to protect them during the coldest times, humans developed
6


complex cultural adaptations not only to environmental
stress, but also in harmony with their own physiological
responses to cold stress. The ability to maintain body
heat through both biological and cultural practices gives
humans independence and freedom to survive in a variety
of environmental niches.
In examining human adaptation to cold stress it
is vital to understand the normal physiological processes
which impact both generation and loss of body heat.
From that vantage point it then becomes possible to
investigate physical variations which developed in
populations facing a wide range of differing climates.
Heat Production
Thermoregulation requires humans to constantly
balance energy input and outflow. This balancing process
is under the control of the central nervous system, with
the hypothalamus designated thermostat for the body.
Production of body heat is generated through the oxidation
of foods consumed or stored in the body in the form
of fat. It is also produced as a by-product of body
work, such as mechanical (friction of muscle), chemical
(metabolism), or electrical (nervous system) action.
Heat is also released during hydrolysis of adenosine
triphosphate (ATP), the compound used for short term
storage of chemical energy. When ATP chemical bonds
7


are broken and the split phosphate group is transferred
to water, heat is released (Kapit, Macey, and Meisami,
1987).
Basal metabolism rate (BMR) is defined as the amount
of energy required to sustain the body at minimal
effective functioning (Halfpenny and Ozanne, 1989).
Further defined, this obligatory heat production is the
"minimum energy requirement of a resting animal at
thermoneutrality. ATP-turnover is for maintenance of
cell and organ function (e.g., ion gradients across
membranes, transport between organs.)" (Heldmaier, 1989,
p. 348).
Metabolism is divided into two phases: the anabolic
phase in which simple compounds are converted from
nutrients into organized substances used by the cell,
and the catabolic phase in which usable substances are
reconverted into simple compounds and energy needed for
functioning of the cell. The rate of metabolism may
be influenced by environmental temperature and hormonal
activity (Miller and Keane, 1978).
Metabolism and heat production are affected by diet.
Of carbohydrates, proteins, and fats, the digestion of
protein is the most energetically costly. Protein
requires one third of its ingested calories to be
metabolized. This energy cost is two to three times higher
8


than that to metabolize fat and five times that for
carbohydrate. The increased metabolism which results
produces an increase in heat production, a diet-induced
thermogenesis. Protein ingestion also increases secretion
of epinephrine and norepinephrine, neurohormones which
enhance heat production (Stini, 1971). Basal metabolism
has been shown to be sustained at higher rates in
populations ingesting mostly protein and fats than
populations consuming a western.diet (Speth and Speilmann,
1983).
Heat Loss
Understanding of heat loss begins with Newton's
law of cooling. Describing the interaction of a living
mass and its surrounding air mass with its heat deficit,
the law can be expressed as a proportion:
... the heat loss per minute is
directly proportional to the body
surface and the difference between
temperature of the body core and
that of the environment, and
inversely proportional to the thick-
ness of the body shell; i.e., heat
flows at a rate which increases with
the surface area and the temperature
drop between the core and the exterior,
and which decreases with greater thick-
ness of the barrier between core and
exterior. (Folk, 1966, p. 101)
Body heat or energy is lost by radiation, convection,
conduction, and evaporation. Radiation is the transfer
of heat from an organism to the environment by means
9


electromagnetic waves. The amount of heat lost depends
on the color of the object and its surface area. The
amount of heat transmitted in this way depends not only
on posture regulating exposed body area, but also on
insulation preventing the transfer (Frisancho, 1981).
Solar energy is acquired in this manner.
Convection transports heat by a stream of molecules
which move away from the warmer object to a colder one.
This entails the loss of heat from the body to the
surrounding air. Controlling the amount of heat lost
or gained is "the temperature gradient between the body
surface and the air. Also controlling thie volume of
transfer is the amount of circulation of air around the
body, governing the mass of cold air to which the body
is exposed (Frisancho, 1981).
Conduction involves heat loss by direct physical
transfer from one substance to another. It may mean
cell to cell, tissue to tissue, skin to skin, or skin
to clothing. This mechanism is vital to the distribution
of body heat within the body, in heat transfer from body
to clothing, and in the eventual heat loss by convection
or evaporation (Frisancho, 1981). Under cold conditions
the core of the body shrinks, while the body shell of
skin, fat and extremities actually expands (Moran, 1982),
enhancing conduction within the core and reducing it
10


to the shell.
The fourth mechanism of heat loss is evaporation
or "transfer of energy by change in phase from liquid
to vapor in the air" (Halfpenny and Ozanne, 1989,
p. 34). Evaporation results in loss of water from the
skin and respiratory tract. The corresponding loss of
heat is due to energy used in the "endothermic conversion
of water to vapor.... called the latent heat of
evaporation" (Frisancho, 1981, p. 16). To continue the
process of sweating the body must maintain skin blood
flow to move core body heat to the periphery. A high
pressure at the surface of the skin, which creates an
osmotic gradient, enhances sweat loss. In high humidity
osmotic pressure on the skin is reduced, reducing the
sweat rate (Bruck and Zeisberger, 1990).
While the first three mechanisms of heat transfer
may be two-way, evaporation is one-way, achieving heat
loss only. It must be emphasized that the amount of
heat lost through these mechanisms depends on the volume
of heat transfer from the body core to the surface, the
composition of the bodyespecially the distribution
of fat depositsand the proportion of the body surface
area to body weight (Moran, 1982).
Responses to Cold Stress
Responses to cold stress are activated through a
11


Figure 1:
THERMOREGULATION
Cerebral Cortex-

v
;j_^ Hypothal
Core
Temperature
T
Core
Thermoreceptors
amus j
Skin
Thermoreceptors
Skin
temperature
vk
TSH-RH
i
vk.
Anterior
pituitary
I
TSH
I
\k
Thyroid
xk
Thyroxin
Sympathetic.
nerves
Adrenal
medulla
V
Sweat
Glands
Epinephrine
^ \/
Skin Skeletal
arterioles muscles
(Adapted from Phipps, et al., 1983, p. 401)


system of cold and warm receptors spread throughout the
skin and body core. Homeostasis is achieved through
regulatory responses designed to create heat, conserve
heat and/or energy, or a combination of both as needed.
A complex hierarchy of receptors exists in the nervous
system designed to activate responses of assigned systems
and process further commands for increased protection
(Bruck and Zeisberger, 1990; Hissa, 1990). Careful
coordination of multiple systems is orchestrated to
maintain body heat with the lowest energy expenditure
possible ; ( see Figure 1).
Cold exposure activates skin sensors believed to
be situated in areas of the skin where temperature is
under the influence of skin blood flbw (Jessen, 1990).
Neural messages are relayed via dorsal roots, which
contain sensory fibers, along the spinal cord. The spinal
cord itself holds control over some responses to cold
and activates the shivering response, a rapid short-term
energy expensive heat production device. It also
activates vasoconstriction for heat conservation. As
the messages travel along the spinal cord to both the
sensory cortex of the cerebrum and the hypothalamus,
activation of a multi-system response begins. Coordination
of the autonomic nervous system, cardiovascular and
endocrine systems, and metabolism activates heat and
13


energy manufacturing and conserving devices based on
the intensity of the threat and the effectiveness of
the response. The neurotransmitter norepinephrine appears
to stimulate pathways involving heat gain, while serotonin
suppresses the pathways of heat loss (Hissa, 1990).
Current theory suggests that the afferents from
both cold and warm receptors are reciprocally connected
yet respond in an antagonistic manner. Cutaneous cold
receptors activate processes which protect against the
cold, such as vasoconstriction and heat production.
Inhibitory interneurons are activated to reduce loss.
Simultaneously, warm receptors are activated and serve
as the check and balance to protect against over heating.
These warm receptors serve to suppress heat production
and activate heat loss mechanisms such as vasodilation,
sweating and panting. "The actual difference between
the signals from cold and warm receptors indicates a
deviation from that point at which the two signal cancel
each other, that is, the set point" (Bruck and Zeisberger,
1990, p. 276).
Different responses are believed to be activated
at varying body temperatures, possibly explaining
vasomotor changes induced before non-shivering
thermogenesis, which is activated before shivering (Bruck
and Zeisberger, 1990). This may also explain the fact
14


that most brown adipose tissue is found at the spinal
cord between the scapula and at the cervical region.
The heat generated locally at the level of the spinal
cord may serve to inhibit shivering (Hissa, 1990).
Heat Conserving Behaviors
Heat conservation behaviors include covering the
body, seeking shelter to decrease exposure, curling up
to decrease surface area, or huddling with another being.
Voluntary physical activity such as walking or rubbing
hands together also stimulates heat production. While
these activities may have short-term results, seasonal
behaviors may include storing food supplies and increased
eating to build endogenous nutrient stores. Altering
the diet during the winter months to consume high energy
food and fats which contain twice the caloric capacity
of protein and carbohydrates is noted in both animals
and humans.
It might seem reasonable to assume that behavioral
cold adaptation options of donning protective clothing,
increasing muscle movement, building fires and building
protective lodging are simple solutions. However,
Steegmann's (1983) acknowledgment of Algonquin ritual
'tea-parties' during hunting expeditions demonstrates
the incorporation of protective actions into cultural
behaviors and illustrates the intricate understanding
15


cold-adapted populations have of their bodies. The
Indians realized that clothing, wet from well-insulated
bodies hard at work, decreased in insulatory value and
contributed to heat loss through evaporation. They also
understood the dangers of dehydration which decreased
available fluid for the circulation of energy and heat.
The ritual 'tea-parties' included frequent stops to build
fires to make tea. Steegmann initially overlooked the
value of these stops, however soon realized they served
an intentional dual purpose of replenishing fluid loss
and drying the clothing. To him what appeared as ritual
behavior had in fact been protective (Steegmann, 1983).
Physiological Cold Adaptations
The morphology traditionally associated with genetic
adaptation to cold pairs Bergmann's and Allen's rules
to suggest that it is the homeotherm with a large body
and short extremities (Steegmann, 1970). Heat generation
is attributed to a larger body with more muscle mass.
A larger body with shorter limbs has less surface area
per unit of volume and will lose less heat. Little
research actually corroborates correlation of this stature
in human beings, and much is inferential. Studies in
the 1950s concluded that an increase of body weight does
demonstrate increased insulation ability, while any
correlation of body heat to stature was weak. Longer


bodies with larger chests and shorter arms were attributed
to areas of lower annual mean temperatures. However,
delineating a specific temperature connection from
heredity, diet or other indirect causes was not done
(Steegmann, 1970).
Regulatory responses to conserve body heat includes
control of vascular function. Subcutaneous blood vessels
constrict decreasing skin temperature and reducing the
gradient between skin and environment. That process
reduces heat loss. An additional conservation mechanism
of the vascular system is countercurrent heat exchange
between arteries and veins. The warmth of the arterial
blood is shunted to venous blood through arteriovenous
anastomoses which connect arterioles to the superficial
plexuses. The heat is returned to the body core, not
lost to the environment from extremities. The body works
to prevent damage to the cooled extremities through a
periodic close of the anastomoses which allows warm blood
to heat the extremities (Frisancho, 1981; Bruemmer, 1989).
Another form of cold response is insulation by means
of layering white adipose tissue or fat. When food intake
is greater than energy expenditure the body stores the
excess. Not only is deposited fat good insulation but
it becomes an excellent source of future energy. Some
is placed in subcutaneous fat pads, while other fat is
17


deposited more deeply in the body surrounding vital organs
(Lieberman, 1987). White fat cells are shaped like signet
rings and contain large globules of fat surrounded by
a thin cytoplasm. They are tightly packed together and
have less intercellular material present than other
tissues (Grollman, 1978). Because of decreased
vascularity thermal conductivity is reduced. Fat actually
conducts heat much less than does muscle (Frisancho,
1981). Humans exposed frequently to cold water produce
a subcutaneous fat layer much in the manner of sea mammals
which layer blubber. This outer layer protects the entire
body core (Folk, 1966).
The metabolic cold response is an enhancement of
the homeothermic system already in place. The response
increases heat production through increase of basal
metabolism (BMR), stimulation of shivering, and activation
of non-shivering thermogenesis (NST).
Shivering thermogenesis increases basal metabolism
(BMR) and reduces the temperature gradient heat loss
from the body's core (Frisancho, 1981). When voluntary
muscle movement such as walking or running produces
insufficient heat, the body creates its own skeletal
muscle movement called shivering. This is described
as a synchronous tremor of flexor and extensor skeletal
muscles (Rautenberg, 1989). While running can increase
18


the BMR anywhere from 1.17 cal/min to 37.94 cal/min,
it cannot be maintained for long periods. Shivering
can increase the BMR two to three times and raises the
muscle temperature over that of the body core, alleviating
temperature gradient heat loss (Frisancho, 1981). If
work is not added to the muscle contraction load,
shivering is more energy efficient than running (Folk,
1966). However, as subcutaneous vasodilation to protect
skin tissue from frostbite accompanies shivering, some
heat loss may result (Frisancho, 1981).
Nonshivering thermogenesis (NST) manufactures heat
at a more complex level. It is a chemical response which
increases cellular metabolism without muscle movement,
able to increase the metabolism of adults 25% above basal
levels and infants 170% (Little and Hochner, 1973 as
cited by Moran, 1982). NST is also a hormonal response
through stimulation of norepinephrine from sympathetic
nerve endings and thyroxine from the thyroid (Frisancho,
1981). This type of thermogenesis is thought to be
"localized in the mitochondria and is the consequence
of loosening the coupling between ATP synthesis and
respiration" (Wang, 1978, p. 567). Heat is released
through the "uncoupling of oxidative phosphorylation"
(Hassi, 1977, p. 16). Oxidative phosphorylation is
defined as the formation of ATP in the mitochondria and
19


associated with electron flow through the respiratory
chain (Purves and Orians, 1987). NST is believed to
occur in the muscle through hormonal activation of the
mitochondria (Halfpenny and Ozanne, 1989; LeBlanc, 1986).
However, tissue specifically designed for heat production
is the main source of thermogenesis.
The specialized heat producing tissue is brown
adipose tissue (BAT) (Hassi, 1977; Heldmaier et.al.,
1989; Kuroshima, 1992). This highly vascular fat is
"comprised of cells with cytoplasm that contains several
lipid vacuoles" (Hassi, 1977, p. 15). The main substrate
is fatty acids. BAT is very active in lipogenesis and
has been shown to synthesize greater amounts of fatty
acids in cold-acclimated animals (Kuroshima, 1992).
It has a high concentration of mitochondria in the cells
along with its own fat stores. The fat is processed
easily at the site of the cells and not transferred to
the liver for processing to ATP. It is the BAT, not
the ATP, which produces the heat, as the mitochondria
of BAT contain special proteins which interrupt ATP
production and release heat directly (Halfpenny and
Ozanne, 1989). Found in human fetuses as early as 19
weeks, BAT is located at the cervical, interscapular,
and perirenal areas. Although the cell size and lipid
content appear to increase with age, the number of cells
20


themselves decrease after the first year of life. After
the age of 25, approximately 13% of humans show the
presence of brown adipose tissue (Hassi, 1977).
Researchers believe that adults with hyperplastic BAT
are those who have experienced prolonged exposure to
cold (Hassi, 1977; Leppaluoto and Hassi, 1989). While
studies document the presence of BAT in humans (Marchand,
1991), the degree to which it actively creates
thermogenesis remains questioned. LeBlanc and others
contend that muscle is the primary source for nonshivering
thermogenesis in humans (LeBlanc, 1988; Halfpenny and
Ozanne, 1989)
The major regulator of NST is sympathetic
norepinephrine, which is shown to be increased in cold
acclimated animals and humans. Cortisone and thyroid
hormones are also stimulated in response to cold and
act to enhance effects of norepinephrine. Cortisone
assists in breaking down fat and glycogen stores, while
thyroxine (T4) seems to enhance the body's response
(Halfpenny and Ozanne, 1989; LeBlanc cited in Bruck and
Zeisberger, 1990).
Hormonal Responses to Cold
Acknowledging the vast complexity of hypothalamic
functions, hormonal interaction and at least 15 different
neurotransmitting systems with no limiting borders, the
21


study of hormonal involvement in cold adaptation is no
easy task. Much of the research is based on inference
and indirect observation of disturbance relationships
(Bruck and Zeisberger, 1990). Hormone research remains
a frontier in the study of cold adaptation.
The hormones appear to be on a time release schedule
with some increasing in acute cold exposure, while others
are activated only after prolonged cold exposure. The
degree of cold also appears important to activation of
hormonal response. In attempting to diagram a consistent
picture of hormone response Fregly organized many
acclimation studies which involved exposing adult men
to varying degrees, from one to four hours, in cold
chambers. The results of these studies did not
demonstrate a clear direction with respect to thyroid
TSH, T3 and T4. Some studies documented increase and
others showed no change (Fregly, 1990).
The mechanisms of the hypothalamic-pituitary-thyroid
axis in abrupt exposure to cold are a complex issue of
the internal communication system of neurotransmitters
and hormones. It is believed that catecholamines, and
possibly serotonin, are involved in stimulating the
thyroid releasing hormone. Binding affinities of the
thyroid hormones may be altered under cold stress, but
that research is not yet complete. Varying studies
22


TABLE 1. Changes in non-shivering thermogenesis during
short and long term exposure: summary of study results.
Parameter Short-term Long-term
Thyroid hormones no change decreased
pituitary thyrotropin no change increased
Adrenal cortisol no change increased
Noradrenaline .increased increased or variable
Adrenaline no change increased or variable
Brown fat increased
Subcutaneous fat increased
(Leppaluoto and Hassi, 1991, pg. 142)
TABLE 2. Temperature-and all night cold tests. metabolic responses of during
Population Core Temp Skin Temp Metabolism
Australian Aborigine decreased decreased decreased
Nomadic Lapps decreased increased decreased
Eskimos no change increased no change
Cold-exposed no change increased increased
Norwegians
Caucasian Group 1 decreased decreased
Caucasian Group 2 decreased no change decreased
Caucasian Group 3 decreased decreased decreased
Caucasian Group 4 decreased decreased
(Leppaluoto and Hassi, 1991, p. 141)
23


exposing men for 1-3 hours in cold chambers do not give
consistent results nor any clear order for the cascade
of hormone response. Fregly did emphasize that the
one known variable is that rats with compromised hormones
could not survive in the cold. Thyroxine was needed
to. interact with norepinephrine for NST ability (Fregly,
1990, see for complete discussion of thyroid research).
;In evaluating serum concentration levels of hormones
in cold chamber^ studies it is important to account for
the hemoconcentration which increases during cold stress
(Leppaluoto et a.l,, 1988). This may be the result of
osmolal diuresis in response to the cold (Granberg,
1991b). Research by Per Granberg does indicate that at
36C (no time frame of exposure) norepinephrine,
corticoids, T3/T4, and aldosterone output does increase.
This was interpreted by the researcher to be a "typical
physiological stress response" (Granberg, 1991b). Further
studies add the observations that while thyroid hormone
activity does not.show an increase during short cold
exposure in humans, increased secretion and degradation
of thyroid hormones are noted under long-term exposures.
Increased response of cortisol, epinephrine and
norepinephrine during long term cold exposure has also
been documented (Leppaluoto and Hassi, 1991) (see Table
1 ).
24


Hormonal involvement in cold adaptation includes
not only those of the sympathicoadrenal and adrenocortical
systems but also antidiuetic (ADH) and opiods
(endorphins). While the corticosteroids are identified
as supporting changes which accompany cold adaptation,
they also appear to mediate the adaptive process (Bruck
and Zeisberger,,1990). Aldosterone decreases the sodium
and chloride concentration of sweat. Endorphins decrease
the pain from cold and are thought to have a more
expansive role during cold exposure.
Beta-endorphin sharply lowers
breathing rate and heart output,
causes decreases in thyroid hormone
activity and body temperature,
provides some relief from pain and
causes kidneys to produce a more
concentrated urine, thus conserving
water. It has also been suggested
that these endorphin-induced changes
relate to a possible effect of
hibernation in some species.
(Purves and Orians, 1987, p. 712)
Repeated stimulation by acute cold exposures results
in significantly reduced sympathetic responses. This
reduction of sympathetic response may be due to reduced
sensory stimulation supporting the idea that habituation
is part of cold adaptation (LeBlanc, 1986). Habituation
refers to the "diminution of normal neural responses
......... depending on learning and conditioning"
(Frisancho, 1981, p. 3). Finnish researchers suggest
25


that those individuals who maintain strong sympathetic
responses to cold, with its heavy load on the
cardiovascular system from increased cardiac output and
peripheral vasoconstriction, are insufficiently adapted
to cold, especially in a circulatory manner (Nayha,
1980; Leppaluoto and Hassi, 1991).
Human Variation
Research studies investigating human variation of
response to cold range from the 1950s studies of body
stature, weight, and extremity size in attempts to diagram
dines (see Steegmann, 1970, for complete discussion);
to the 1960s variation in thermoregulation through
generation of heat and insulatory regulation (see
Frisancho, 1981; Leppaluoto and Hassi, 1990, for
overviews) (see Table 2); to the late 1970s and 1980s
investigations of physiological variations of
neurotransmitters and hormonal involvement (see Schonbaum
and Lomax, 1990; Malan and Canguilhem, 1989, for complete
discussions); to the 1980's and current look at cellular
structure and adaptation (Hazel and Williams, 1990;
Hadley, 1985).
Of interest to this thesis is the current belief
that the variation in responses are not mutually exclusive
but represent different stages of adaptation. That the
various forms of cold responses ranging from hypothermic,
26


hypometabolic, metabolic and insulative remain in present
populations facing a wide range of cold temperatures
(Leppaluoto and Hassi, 1991) suggests a continuum of
adaptation. The variations developed in physiological
protection become dependent on the degree of cold, the
length of exposure, the developmental stage, diet, sex
and effectiveness of cultural technology and manifest
themselves in a mix and match selection of the
possibilities of thermal and insulatory responses.
The initial response of an unacclimated individual
is that of increased thermogenesis with shivering and
increased metabolism accompanied by profound
vasoconstriction to conserve core temperatures. Repeated
exposure may stimulate increased insulation processes
with a decrease in metabolism, accompanied by a decrease
in core temperature, such as the hypometabolic,
hypothermic adaptation seen in the Australian Aborigines
(Leppaluoto and Hassi, 1991). An extreme form of
hypothermic adaptationhibernationincludes a major
drop in body temperature accompanied by a significant
decrease in oxygen consumption, respiration and heart
beat. Adaptive hypothermia and hibernation are behavior
selections appropriate in areas and at times when food
sources are not consistently or seasonally available
(Purves and Orians, 1987). Hypothermic adaptation is
27


activated only if heat loss is not too great and
individual's physical condition allows adjustment of
the cold load (Bruck and Zeisberger, 1990). The metabolic
form of non-shivering thermogenesis may develop with
prolonged exposure to severe cold.
Accompanying responses are decreased sensitivity
to cold and subsequent decrease in autonomic stimulation
producing a cold tolerance attributed to habituation.
This 'tolerance adaptation' can be produced
experimentally in 3-7 exposures to cold within several
days. Additionally, a decrease in "subjective sensation
of cold-induced pain through negative reflex conditioning"
accompanies repeated exposure to cold (Radomski and
Boutelier, 1982, p. 615). That the sensation of pain
overrides the sensation of cold to inhibit some cold
responses has been suggested (LeBlanc, 1986), however
no research addressing that issue has been published.
Two populations are cited as having prolonged
hypermetabolic responses to cold. They are the Inuit
and the Ama pearl divers. Research suggests the Inuit*s
to be diet induced, as their metabolism reduced to a
level similar to Caucasians when the Inuit protein
consumption decreased (Itoh, 1980). The case of the
Ama presents differently, as their rise in metabolism
appeared seasonal: 35% higher in winter. Researchers
28


believe the Ama to have metabolic acclimatization, as
their nitrogen excretion did not differ from the control
group without elevated basal metabolism, indicating no
difference in protein metabolism (Folk, 1966). Whether
this is an example of non-shivering thermogenesis is
unclear. The use of wetsuits for the divers has resulted
in a decrease in this acclimatization (Leppaluoto and
Hassi, 1991) which makes further clarification by current
research techniques difficult.
Variation in peripheral circulation and warming
of extremities are also documented in the literature.
Cyclic rewarming of extremities (hunting reflex) is found
to accompany the insulative vasoconstriction which takes
place in response to cold. Inuits however show no marked
vasoconstriction, consistently maintaining warm hands
during cold exposure. This is now believed to be
attributable to blocked alpha adrenergic receptors in
the distal extremities. That this trait continues to
be exhibited among Inuit who do not face the cold
extremes of their ancestors further suggests that the
trait is genetic (Grayson, 1990). Research carried out
on Gaspe region fishermen who are frequently exposed
to cold water also documented a similar lack of
vasoconstriction. The explanation for this study
attributed the response to a functional reduction of
29


alpha adrenoreceptor activity and a result of
developmental plasticity (Grayson, 1990).
While the vasoconstrictive response to cold exposure
serves a purpose in inhibiting heat loss, it also creates
an additional load on the heart and strain on the vascular
system. The price may be seen in the increase of
cardiovascular deaths documented in the winter. Profound
vasoconstriction response and subsequent elevation of
blood pressure which remains in many populations living
in the cold are now thought to represent insufficient
adaptation (Leppaluoto and Hassi, 1991). The development
of a cold culture, with its technically devised protective
clothing and consistently heated buildings may have acted
to maintain many people at the initial level of a more
intensely reactive physiological adaptation.
Current thought about human variation in response
to cold is that the more complete cold adaptation is
exhibited by the Australian aborigines, nomadic Lapps,
and Caucasians chronically exposed to cold water
(Leppaluoto and Hassi, 1991). This response includes
the increased tolerance to cold, lower skin temperatures,
maintenance or decrease in metabolism which conserves
energy, and highly effective insulatory abilities. The
new frontier of microbiology offers knowledge of
adjustments at the cellular level which may enhance this
30


type of protection and preserve cellular function.
31


CHAPTER 3
HOMEOVISCOUS ADAPTATION
The hypothermic response to severe cold exhibited
by humans is considered to be the most prevalent human
cold adaptation (Radomski andBoutelier, 1982). It
develops with intermittent exposure to severe cold, the
type of exposure most,frequently experienced by humans.
It is accompanied by either, or both, a low metabolic
response and insulatory mechanisms which suggests that
habituation is involved. The degree and integration
of the response mechanisms may be dependent upon the
technical insulation developed by the culture, food
supply, and length of exposure to cold (Leppaluoto and
Hassi, 1990).
While the hypothermic response is considered to
be a systemic one, adaptive responses at the cellular
level also take place to protect the organism against
cold exposure. Active adaptation of the cell membrane,
termed homeoviscous adaptation, involves molecular
restructuring of the lipid content in cell membranes
to maintain their fluidity. This process preserves normal
membrane functioning (Hadley, 1985). Restructuring occurs
32


in response to a variety of changes in the environment
including temperature alterations, pressure, water
activity, and pH balance (Hazel and Williams, 1990).
It is presumed that the
strategy maintaining membrane function
independent of temperature changes
by modulating the effective viscosity
of the hydrophobic compartment of the
membranes would have survival value
during crisis periods and would also
be of considerable importance for the
fitness of species at normothermic
temperatures. (Hadley, 1986, p. 67)
Membrane Structure and Function
The cell is the fundamental unit of every living
thing. Basic human cells are eukaryotes which contain
a nucleus and various structures, each compartmentalized
by membraries. Each structure or organelle, its
subcellular membrane, and the cell with its plasma
membrane have assigned duties. Membrane activity includes
maintaining shape and internal structure of the cell
and acting as a barrier against foreign or toxic
substances (McCance and Huether, 1990), regulating the
exchange of fluid and electrolytes (Yeagle, 1989),
creating an environment for metabolic pathways,
communicating within and between cells, storing energy
(Hazel and Williams, 1990), producing prostaglandins
and influencing cell growth (Spector and Yorek, 1985).
Membranes are composed of carbohydrate, protein
and lipid substances. The main components of all
33


membranes are lipids and proteins in an almost equal
amount, while the carbohydrates are found mostly in the
form of glycoproteins. Lipids are the component of
highest molecular abundance, with a ratio of 70%
phospholipids, 5% glycolipids, and 25% cholesterol
(McCance and Huether, 1990). However some cells, such
as the erythrocyte (red blood cell which transports
oxygen) contain a ratio of 0.8-0.9 phospholipid to
cholesterol (Spector and Yorek, 1985).
Transport of substances across cell membranes is
accomplished through a variety of mechanisms. One
mechanisrii is simple diffusion which is controlled by
the concentration of substance on either side of the -
membrane. It occurs to maintain an equilibrium of the
substance on both sides and molecules pass easily through
the membrane. A second method, carrier modulated
diffusion, occurs in the face of an imbalance of substance
concentration. Solute molecules do not diffuse on their
own but combine with a carrier protein which assists
the passage of a solute in the direction of a gradient
ranging from high to low concentrations (Purves and Orian,
1987).
Active transport is required to move particles
against the concentration gradient. Primary active
transport uses energy directly acquired from ATP to move
34


particles against the gradient. The sodium-potassium
pump found in all animal cells is an example. Secondary
active transport uses energy recaptured when allowing
sodium ions to move with the gradient (Purves and Orian,
1987) (see Table 3).
Osmosis, a passive process not requiring energy,
allows passage of water across the cell membrane. This
process operates according.to the laws of diffusion,
with the direction of water movement governed by osmotic
as well as pressure potentials. Water moves to a greater
concentration of solutes to balance pressure potential
(Purves and Orian, 1987). :
TABLE 3. Transport mechanisms of vital substances.
Substance
Glucose
ATP-ADP
Sodium
Sodium/Potass ium
Calcuim
Chloride/
HC03-/other
anions
Amino acids
transporters
specific to
amino acids
Cholic acid
Mechanism
Passive
Antiport
can be active
Passive
Active
(ATP driven)
Active
(ATP driven)
Mediated
antiport
active:
symport with
sodium
active:
symport with
sodium
Tissues
Most tissues
Mitochondria
of liver
Distal Renal
plasma membrane
All cells
Erythrocytes/
many other cells
Intestines/
Kidneys/
liver
intestines
(Adapted from McCance and Huether, 1994, p. 29)
35


Cold Effects on Cells
The effects of cold on the cell reduces the energy
of substrate molecules, which can effect enzyme activity.
Decreased temperature of water in cells increases its
viscosity, which results in the reduction of diffusion
rate. Both of these processes reduce the action of
membrane-bound ATPase", an enzyme which serves as an ionic
pump used to balance the sodium and potassium ratio by
pumping sodium from the cell. Should this pump fail,
sodium remains in the cell and osmotic influx of water
into the cell follows. Subsequent swelling of the cell
further disturbs cellular-metabolism. Crystallizing
of the water during freezing further increases water
influx and results in rupture and cellular death
(Zachariassen, 1991).
Cellular death during non freezing hypothermia may
be caused by inability to move calcium out of the cell.
Calcium, a regulatory ion for some enzymes, is normally
kept at a low level within the cell. Increased amounts
of intracellular calcium may result in a cellular
intoxication and eventual cellular death (Zachariassen,
1991).
Gradual cooling can trigger problems with
microcirculation and reduce cellular communication.
Peripheral vasoconstrictive responses to cold can be
36


followed by a vasomotor paralysis. Paralysis precedes
vasodilation and increased membrane permeability which
results in cellular and tissue edema. Rapid cooling
can result in vasoconstriction and increased blood
viscosity, a condition exacerbated by osmolal diuresis
occurring early in cold exposure (Granberg, 1991b).
This combination of responses reduces protection and
may result in ischemic injuries of both infarct and
necrosis. Should exposure to freezing temperatures
continue, the swelling of tissue can damage the myelin
sheath surrounding peripheral nerves and severely
compromise sensory and motor abilities (McCance and
Huether, 1990). The resulting reduction in communication
and response ability compound the effects of cold on
the cell and the system as a whole.
Homeoviscous Adaptation
The ability of the individual cells to adapt to
cold temperatures, as well as the organism's corresponding
systemic responses, enhances viability. Homeoviscous
adaptation takes place in the lipid bilayer of the cell
membrane. The mechanisms by which organisms accomplish
this form of adaptation include increasing the
unsaturation of fatty acid chains of phospholipids,
altering the branching and length of fatty acid chains
and changing to different polar head groups, and inserting
37


spacer molecules such as cholesterol (Hadley, 1985).
The state of the membrane bilayer is referred to as the
phase and the alterations as phase transitions. Phases
range from a liquid to a gel to a rigid crystalline state.
The phase state of membrane lipids affects enzyme action
and cell metabolism (Steigen and Larsen, 1991).
Singer and Nicholson's fluid mosaic model for
biological membranes illustrates the construction of
the lipid bilayer (see Figure 2). The basic component
of the bilayer is phospholipid, an ampipathic compound.
Looking much like an old-fashioned clothes pin, the
molecule contains regions which are hydrophilic with
other regions which are hydrophobic. The hydrophilic
heads of the molecule carry phosphorus with one or more
electric charges. The fatty acid tails, the lipid
component, are hydrophobic. The incompatible ends of
the molecule form the lipid bilayer of biological
membraneis by lining up with the nonpolar, hydrophobic
'tails' pack tightly together creating the interior of
the membrane. "The phosphorus-containing heads face
outward on either side of the membrane, where they
interact with the water that is excluded from the interior
of the membrane" (Purves and Orian, 1987, p. 64). The
bilayer manages to separate the two aqueous regions and
stabilize the entire structure of the cell.
38


39
Figure 2. Fluid mosaic model for biological membranes.
Transmembrane
(McCance and Heuther, 1994, p. 17)
(Reprinted by permission)


Membrane fluidity is measured by the bilayer
viscosity or resistance to flow. Normally the bilayer
viscosity is that of a lightweight oil used for machinery
(Purves and Orian, 1987). However, temperature changes
can alter the phase state of membrane lipids. Cold stress
dropping temperatures below a critical phase-transition
temperature (the temperature at which lipid restructuring
takes place) can result in transition of the lipid bilayer
to a crystalline state. Fatty acid chains or tails are
immobilized. Permeability of solutes is limited and
lateral diffusion of proteins is greatly reduced. High
temperatures create an unstable liquid-crystalline
bilayer. The fatty acid tails become very mobile,
viscosity is significantly reduced, and the phospholipids
remain together only through the noncovalent interaction
of the polar head groups. The critical phase temperatures
are not arbitrary and can themselves be altered by the
lipid structuring of the bilayer.
Research documents the predominant restructuring
of the lipid membrane under cold exposure to be that
of increasing the unsaturated lipid percentage (Yeagle,
1990; Hazel and Williams, 1990; Marachev and Lapinski,
1989). This has been shown in some species to mean the
replacing of oleic n-9 by linolenic n-3 (Hazel and
Williams, 1990; Smith R., 1989). The restructuring,
40


however, is not uniform throughout the body. The
disposition of higher concentrations of unsaturated lipids
are found in the extremities and subcutaneous fat layer
(Hadley, 1985; Draper, 1980). Unsaturated lipids are
extremely, vulnerable to lipid peroxidation (Leibovitz,
et al, 1990). To compound that threat to membranes,
remnants of peroxidation are damaging to membrane
structure (Hadley, 1985). Current research is now
investigating the possibility that it is the addition
of cholesterol into the membranes of humans which protects
their structure during cold exposure and decreases the
amount of membrane lipids vulnerable to peroxidation
(Marachev and Lapinski, 1989).
Restructuring the lipid bilayer at both low and
high temperatures may involve addition of cholesterol
molecules which interact noncovalently with fatty acid
chains to stabilize the bilayer. Cholesterol enters
spaces between the phospholipid molecules to maintain
the bilayer in an intermediate gel state despite exposure
to a wide range of temperatures (Myant, 1991).
Additionally cholesterol enhances the ordered state of
lipid molecules within the membrane. It is this ordered
but fluid state which allows the lipids to form separate
functional compartments within the cell and moderate
communication and metabolism (Gunstone, Harwood and
41


Padley, 1986). Increasing cholesterol, while protecting
structure, reduces membrane permeability (Hadley, 1985).
The placement of cholesterol in the cell membrane
is asymmetrical resulting in areas varying in viscosity
(Schroeder and Nemecz, 1990; Gordon and Mobley, 1984;
Yeagle, 1990). Exposure to low temperatures stimulates
the aggregation of membrane proteins into cholesterol-poor
domains, while cholesterol laden microvesicles cluster
to create cholesterol-rich domains. This partitioning
appears to be protective against cold induced hypertonic
lysis (Gordon and Mobley, 1984; Yeagle, 1990). Cell
membrane elasticity and strength are enhanced (Needham
and Nunn, 1990) without "dramatically altering lateral
diffusion of membrane components" (Yeagle, 1990, p. 119).
Although the time frame in which the protective
partitioning takes place is not known, research does
show that erythroctyes given some exposure to moderate
cold had time to restructure lipid domains, while sudden
exposure to severe cold interferes with the ability to
do so (Gordon and Mobley, 1984). Further research is
needed in this area.
Lipid Peroxidation
While some researchers question whether the
restructuring with cholesterol for microviscosity control
is the explanation for the cholesterol requirement in
42


mammalian cells (Yeagle, 1990),' others have investigated
the possibility that it is protective against the threat
of lipid peroxidation increased during cold exposure,
not the cold itself (Marachev and Lapinski, 1989).
Russian scientists studying this question frame
their work within the concept of adaptation. These
researchers, using V. P. Kaznacheev's theory of 'Polar
Stress Syndrome' (Soininen, personal communication,
September, 1992) document a reaction to cold which leads
to excess production of catecholamines, increased
unsaturated fatty aicids in the membrane lipids, and high
levels of lipid peroxidation indicating active catabolism
(Lapinski and Etlis, 1988). Lipid peroxidation is a
step in b-oxidation or principal oxidation route of fatty
acids for the production of ATP (Hadley, 1985). This
creates an oxidative stress, which is "the cytotoxic
consequences of oxygen radicalssuperoxide anion (02-),
hydroxy radical (OH), and hydrogen peroxide (H202)
which are generated as byproducts of normal and aberrant
metabolic process that utilize molecular oxygen (02)"
(Coyle and Puttfarcken, 1993, p. 689). Cellular structure
and function can be disrupted when the oxygen radicals
interact with cell membrane lipids, cross-linking the
fatty acids. The oxygen radicals can also attack
deoxynucleic acids and proteins to damage tissue (Coyle
43


and Puttfarcken, 1993).
Population Research
Research has compared the liver function of
indigenous peoples of Noril'sk, well above the Arctic
Circle in Russia, with that of migrant workers from
Novosibirsk who transferred to Norik'sk for varying
lengths of time (Gichev, 1990). This study documents
an increase of serum cholesterol accompanied by large
increases in esterfying function :of the liver. Serum
cholesterol continues to increase with longer stays in
the north. Lipid peroxidation also increases while the
level of antioxidants decreases. The indigenous
popluation, however., shows peculiarities in lipid
metabolism, with higher serum cholesterol levels than
early migrants, as well as higher antioxidant levels.
The researchers interpret this finding to indicate that
less peroxidation is taking place in the indigenous
population. This population also registers a lower
incidence of atherosclerosis and ischemic heart disease.
Gichev (1990) offers the following senario as an
explanation of the some of the findings:
1) exposure to cold climate
2) increase in lipid peroxidation
3) threat of destruction of membranous
structures
4) increase of cholesterol concentration
in membranes
5) increased density of membranes and
decrease of their permeability
6) inihibition of hepatocyte excretion
7) increase bilirubin in the blood
44


Another line of research in Russia examined the
erythrocytes drawn from immigrants to the north above
Magadan. This research documents increased oxidation
hemolysis of erythrocytes of new immigrants and a
correlation of decreased hemolysis as the membrane
cholesterol content increased. The researchers suggest
that cholesterol obstructs lipid peroxidation activation
atrd subsequent destruction of the cell membrane (Lapinski
and Etlis, 1988).
Further research compared the erythrocytes of
immigrants above Magadan with those of the Chukchi, an
indigenous population of the northern area and lifetime
Caucasian Russian residents of the area. Findings noted
elevated levels of cholesterol in the membranes of the
Chukchi, as well as the older Russian residents. The
early immigrants demonstrated an increasing level of
unsaturated fats in the membrane during their early
exposure to the cold region. The researchers attributed
the increase of unsaturated fats to homeoviscous
adaptation, noting that this increased the membrane
vulnerability to lipid peroxidation. This study further
reinforced the idea that the alternative role of
cholesterol as a protection against destruction, not
in the maintenance of viscosity (Marachev and Lapinski,
1989).
45


Discussion
Whether this protective concept of cholesterol
addition to cell membranes to protect against peroxidation
elevation during cold exposure falls under the cloak
of 'homeoviscous adaptation' is not clear. However, the
Russian research offers a framework for further
investigation into the matter.
That an increase of unsaturated lipids is found
in the cell membranes of such species such as fish and
sea mammal exposed to cold environment is known. That
this homeoviscous adaptation maintains membrane bilayer
viscosity is generally accepted. (Hadley, 1985). That
this cold adaptation impacts a biome's food chain and
the humans who consume a diet of those organisms is
accepted (Draper, 1980). That species who consume the
blubber of sea mammals show dramatic drops in serum
cholesterol is documented and currently under
investigation (Folk, personal communication, June, 1993).
How or why the serum cholesterol drop occurs is, however,
unexplained. Much research is now being done in the
area of nutrition as to the effects of diets high in
fish oils and omega-3, however, no research investigates
the relationship of diet and human cell membrane lipids.
Research documenting the relationship of homeoviscous
adaptation to the human hypothermic response to cold
46


or elevated serum cholesterol has not been done.
Investigation into the action of erythrocytes in
both cholesterol-rich and cholesterol-poor mediums during
cold exposure might add a new perspective to the study
of human cold adaptation. Research does show that
erythrocytes with low membrane cholesterol readily lyse
when exposed to cold (Yeagle, 1990). This information
in itself should stimulate further investigation, yet
temperature-based studies investigating the role of
cholesterol in humans under cold stress do not exist
outside Russia. The difficulty of translation, the lack
of availability in the United States of documented
references, and the danger of extrapolating from research
studies in the United States to explain Russian research
data are just a few of the difficulties in attempting
to understand this issue.
The Russian evidence is not conclusive, but the
proposal of the protective function of cholesterol is
definitely provocative However, the function of elevated
serum cholesterol remains unanswered. While the immediate
response might be that the elevation serves to increase
the needed supply for ready use, that response may dispel
the explanation of some genetic programming which results
in hypercholesterolemia. That condition centers around
defective uptake of cholesterol into the cells. To
47


further investigate the issue of elevated serum
cholesterol in cold exposure, a chapter investigating
the properties, transportation and oxidation of
cholesterol follows.
48


CHAPTER 4
CHOLESTEROL
Cholesterol, a bile acid alcohol, was first
identified in 1789 by the French chemist, A. F. Fourcroy.
However, it was not named until 1853, when M. Berthelot
found the compound to be an alcohol (Asimov, 1992).
While the basic component of most lipids, such as
triglycerides and phosphlipids, is fatty acids,
cholesterol contains none. Its steroid nucleus is
synthesized from fatty acid by-products (molecules of
acetyl-CoA) which gives it properties similar to those
of other lipids (Guyton, 1991).
The sterol cholesterol is a vital precursor to all
steroid hormones secreted by the adrenal cortex and sexual
glands. It is a large component of the myelin sheath
of the nervous system (Myant, 1991). It is a necessary
part in the corneum of the skin where it resists
absorption of water soluble substances and some chemical
agent action, as well as prevents water evaporation
through the skin. It is also a vital component of bile
salts which facilitate absorption and digestion of the
dietary fat and an integral lipid of the cell membranes
49


(Guyton, 1991). Furthermore, cholesterol plays a role
in cell growth, biosynthesis of phospholipids, DNA
synthesis, RNA synthesis and protein synthesis (Yeagle,
1990) . ..........
Cholesterol may be obtained through dietary intake,
however, it is so vital to cellular function that
virtually every cell in the body can manufacture it.
Approximately half of the body's source of cholesterol
is dietary, while half is manufactured by the body (Bishop
and Waldholz, 1990). Both the body as a whole and the
cell as a unit operate on a negative feedback system,
decreasing endogenous manufacture when exogenous sources
suffice.
The average adult human body contains approximately
1 gram of cholesterol per kilogram of body weight (Myant,
1991) , with 7% in the plasma and 93% distributed
throughout the body (Ganong, 1991). Approximately 20-30%
of serum cholesterol is free cholesterol, the remainder
is esterfied (Lenther, 1984).
Transport and Metabolism
Dietary cholesterol is emulsified by bile to
facilitate absorption by the small intestine (Miller
and Keane, 1978). From the small intestine it is
"secreted into the intestinal lymphatics and thence,
into the bloodstream, as a component of large,
50


Figure 3. Cholesterol transport system
kDu
ZSC.GFToC'
51


fat-enriched particles called chylomicrons" (Myant, 1991,
p. 411). Upon entering the bloodstream, lipoprotein
lipase degrades the chylomicrons into remnants. Left
rich with cholesterol, these remnants are virtually fat
free (Myant, 1991). The remnants then transport the
dietary cholesterol to the liver where it is further
degraded. Some is returned to the intestine as bile,
some excreted from the body, and some recycled to the
liver (see Figure 3). Cholesterol not used in bile is
transported around the body for general usage.
The endogenous pathway for cholesterol transport
originates in the liver. This transport system consists
of lipoproteins responsible for carrying cholesterol
to the cells. They include VLDL (very low density
lipoproteins) secreted from the liver as a
triglyceride-rich particle and IDL (intermediate-density
lipoproteins), the particle left after triglycerides
have been removed from VLDL through the action of
lipoprotein lipase (enzyme attached to the luminal surface
of capillaries). Additionally, LDL (low density
lipoprotein) carries about 75% of all the cholesterol
in the blood (Moore, 1989) and is created from the
remnants of degraded action and cholesterol esters
transferred from HDL. HDL (high density lipoprotein
moves cholesterol out of the cells to recirculate it
52


Table 4.
APOLIPOTROTEINS
Apolipoproteiri Synonym
Synthesis
Function
Apo-A I _____ ApoHDL III
Apo-A II......Apo IV....
Apo-B....... ApoLDL .
Apo-C I.......ApoVLDL.. .
Apo-C II......ApoVLDL...
Apo-C III .....ApoVLDL...
Apo-D.........Apo-A III.
Apo-E...................
Apo-F...................
.. Intestine...
Liver
...Intestine...
Liver
..Liver (B100).
Intestine (B48)
Liver
Liver
Liver
Liver
r>
.Cofactor
for LCAT
.Cofactor
lipoprotein
lipase
.Binding
protein
for cell
receptors
.Cofactor
lipoprotein
lipase
II
. ?
.Possible
cholesterol
exchange
ester
.Binding
protein
cell
receptors
.Possible
inhibitor
of
lipoprotein
lipase
Table 5. CHOLESTEROL PERCENTAGE
Lipoprotein Class Cholesterol Cholesterol
Ester Free
VLDL 12-14% 6-8%
LDL 35-40% 7-9%
HDL2 8-10% 5-7%
HDL3 7-9% 4-6%
Chylomicrons 1-2.5% 0.5-1%
(Table 4 and 5 adapted from Lenther, 1984, p. 117)
53


or return it to the liver (Ganong, 1991; Myant, 1991;
and Guyton, 1991). HDL is thought to be able to absorb
cholesterol which has deposited in the arterial wall,
transferring it to IDL and LDL for passage back to the
liver (Guyton, 1991).
The protein components which constitute a portion
of these transport particles are apoproteins. The include
apo-A-1 (Aalto-Setala et al., 1991) apo-E, apo-C and
apo-B which has two forms. One form is apo-B-48, of
low molecular weight associated with the exogenous
transport system, and apo-B-100, of high molecular weight
associated with the endogenous lipid transport system
(Ganong, 1991). Varying polymorphisms of apolipoprotein
E correlate to serum cholesterol levels. The presence
of e4 allele correlates to higher serum cholesterol while
e2 allele correlates to lower serum cholesterol (Boudreau,
et al., 1993).
Apo-A-1, the main protein of HDL, is a cofactor
with an enzyme responsible for converting cholesterol
to the cholesterol esters. Apo-B is vital to cholesterol
homeostasis. It is not only necessary for construction
of chylomicrons in the intestine and VLDL in the liver,
it also serves as the ligand facilitating identification
of the LDL transporter by the LDL receptor (Aalto-Setala
et al., 1991). Ligand is defined as "an ion or
54


molecule that reacts to form a complex with another
molecule (Miller and Keane, 1978). Apo-E appears to
be associated with chylomicron remnants, facilitating
their rapid removal from the bloodstream (Myant, 1991)
and acts as another ligand for the LDL receptor.
Several properties of cholesterol contribute to
the transport system. First, cholesterol is not soluble
in water and therefore is not easily mobilized. Second,
it has a strong tendency to exchange passively between
lipoproteins in the blood and cell membranes. Therefore,
multicellular organisms must first esterfy the sterol
by removing water molecules and replacing them with
long-chain fatty acids. The newly formed esters are
then sequestered within a lipoprotein core which is too
hydrophobic to pass through the cell membranes. To
achieve cell uptake of the cholesterol ester the LDL
binds at an LDL receptor site and is transported into
the cell interior through endocytosis. The LDL is then
delivered to the lysosome which hydrolyzes the esters
and creates free cholesterol for use in the cell (Brown
and Goldstein, 1986; Myant, 1991).
Many factors affect the LDL receptor and serum
cholesterol. High availability of exogenous cholesterol
decreases manufacture of the LDL receptor, while elevated
thyroid hormone's increase the number of LDL receptors
55


(Ganong, 1991). The plasma level of cholesterol decreases
prior to elevation in metabolism, and appears "independent
of stimulation of 02 consumption" (Ganong, 1991, p. 288).
Estrogens lower LDL and elevate HDL. Untreated diabetes
elevates serum cholesterol. Exercise and moderate alcohol
intake also elevate HDL, while smoking, obesity and
sedentary life styles are know to lower it (Ganong, 1991).
Genetic mutations of LDL receptors are found in some
familial hypercholesterolemias (Kontula, 1991; Ganong,
1991) and in the face of malfunctioning LDL receptors,
cells synthesize their own cholesterol (Myant, 1991).
Additionally, research is showing a decrease in size
of HDL particles in some patients with genetically caused
LDL receptor malfunction. This decrease in HDL size
is thought by some researchers to be an adaptive response
in order to increase the intracellular pool of
cholesterol.
Cholesterol Oxidation
Cholesterol is a very labile substance and in its
crystalline form can undergo spontaneous oxidation in
air. Metabolism of cholesterol is accomplished through
molecular oxidation, both by enzymic and nonenzymic
reactions. The nonenzymatic, or auto oxidation, is
believed to be uncatalyzed oxidation. However, in animal
tissue, iron or another transition metal ion is thought
56


to be necessary as a catalyst. The products of oxidation
are oxysterols believed to be regulatory agents of sterol
biosynthesis and possible moderators of plasma membrane
permeability, function and stability. Lipid peroxidation,
low level atmospheric ozone, and certain foods (such
as powdered eggs and milk) are other sources of
cholesterol oxides (R. Smith, 1989; L. Smith, 1992).
Cholesterol oxides may displace cholesterol in cell
membranes. When this occurs in erythrocytes, the cell
may be transformed into a spiny-shaped cell called an
echinocyte. Changes, in cell shape may take place within
2 minutes of exposure to the oxide. Active lipoproteins
can accept cholesterol oxides and their detrimental
effects on the cell impeded, although not totally
abolished (L. Smith, 1992; Peng and Morin, 1992).
The oxides are implicated in alteration of LDL,
either by free radical-induced peroxidation or by
oxidation with cholesterol oxidase. Both this modified
LDL and cholesterol oxides are toxic to vascular walls.
Pure cholesterol and unaltered LDL, however, do not
appear to have similar damaging effects (L. Smith, 1992;
Peng and Morin, 1992).
The presence of cholesterol oxides in the cell
membranes greatly inhibits cholesterol biosynthesis in
biomembranes. Modification of cell membranes by the
57


oxides alters fluidity, enzyme function, transport
abilities and cell proliferation (Peng and Morin, 1992).
Animal study investigation into the toxic effects of
cholesterol oxides documented adrenal gland hypertrophy
associated with adrenocortical function insufficiency,
reduced serum cholesterol levels and reduced biosynthesis
Other effects noted were loss of appetite and body weight
lethargy, growth retardation, and organ atrophy (Peng
and Morin, 1992).
Other fats and lipids
Cholesterol and its oxides are not the only lipids
which affect the body and serum cholesterol.
Triglycerides are considered simple fats, identified
by the number of double bonds in their carbon chains.
They may be used as a source of fuel and are the main
form for the storage of energy. These fatty acids come
in saturated and unsaturated forms. A saturated fat
contains no unsaturated bonds or double bonds in its
hydrocarbon tails. Monounsaturated fats such as oleic
acid contain only one carbon-carbon double bond, while
polyunsaturated fats contain fatty acid chains with two
or more. Their form is an oily liquid. Three fatty
acid molecules combine with one glycerol to make one
molecule of triglyceride (Purves and Orian, 1987; R.
Smith, 1989). By replacing one of the fatty acids with
58


certain phosphorus-containing compounds, a phospholipid
is formed (Purves and Orians, 1987). The transport system
used to deliver cholesterol around the body is used to
transport these other fats to their destinations (Bishop
and Waldholz, 1990).
Monounsaturated fats are manufactured by the body
as well as ingested. They can be found in all lipid
containing foods, both of animal and vegetable origin.
Olive oil is an excellent source. They are not a
precursor for prostaglandin production, nor are they
converted into other fatty acids. And, monounsaturated
fats are reported to be more effective at lowering serum
cholesterol than polyunsaturated fats (R. Smith, 1989).
Polyunsaturated fatty acids are divided into several
groups. They include n-3 linolenic family, the n-6
linoleic family, the n-9 oleic family, and the n-7
palmitoleic family. These acids are precursors to
polyunsaturated fats. Linoleic and linolenic acids cannot
be synthesized in the body, and are therefore considered
essential. They must be secured by diet (Hadley, 1986).
Naturally occurring polyunsaturated fats are found in
a specific configuration called a cis configuration.
Partial hydrogenation transforms this configuration into
a trans form which gives the fats a higher melting point.
(A noted example of trans fat is margarine.) The
59


incorporation of trans fat into cell membranes alters
their permeability. Erythrocytes swelled and ruptured
more easily when trans fat was present in their membranes
(R. Smith, 1989).
Polyunsaturated acids are used for structural
components and as precursors in the manufacture of
chemical mediators, prostaglandins. These prostaglandins
modify the actions of hormones, affect blood clotting,
and regulate smooth muscle tone. While the prostaglandins
produced by both n-6 and n-3 reduce platelet aggregation
and blood clotting, n-6 also produces a platelet
aggregator as well (R. Smith, 1989). N-6 is associated
with an increased inflammatory response, while the n-3
decreases the injury-response mechanism (Boudreau
et al., 1993). The phenomenon of lowering serum
cholesterol by ingestion of both n-3 and n-6 is widely
documented, however, no mechanism has been documented
(R. Smith, 1989; Folk, personal communication, June,
1993).
The Structural Antioxidant
During cold stress the cell membrane's lipid bilayer
protects itself by restructuring the lipid bilayer with
more unsaturated phospholipids in the process of
homeoviscous adaptation. Lipid peroxidation is also
increased with cold exposure. The restructuring has
60


increased membrane vulnerability to destruction by
peroxidation, as the process of peroxisomal b-oxidation
involves catabolism of long-chain fatty acids (Hadley,
1985). The peroxidation increases accessibility of lipid
and protein components of the membranes to phospholipases
and proteases, digestive enzymes which hydrolyze
pholpholipids and proteins (Stepanyan and Simonyan, 1990).
Russian researchers now suggest that lipid
peroxidation acts as a triggering mechanism of an adaptive
modification of the cell membrane. Their scenario posits
that initial exposure to cold leads to activation of
the adrenal system stimulating intensification of lipid
peroxidation, development of relative 'hypercorticism'
which facilitates the switch of energy metabolism from
carbohydrate to lipid and the restructuring of cell
membranes with more cholesterol to protect them (Marachev
and Lapinski, 1989). The apolipoproteins are thought
to provide the transport of the corticoids to cell, apo-B
competing for the same receptor used by insulin (Panin,
Biushkina, and Polyakov, 1992; Panin, personal
communication, June, 1993). The cholesterol added to
the cell membrane is believed to be a 'structural
antioxidant1 (Marachev and Lapinski, 1989).
Discussion
Both homeoviscous adaptation and the 'structural
61


antioxidant' theories offer explanations for the role
of cholesterol during times of exposure to cold stress.
As they both involve use in the cell membrane, they do
not explain elevation in serum cholesterol. It would
appear that an excess use of cholesterol would result
in decreasing circulating cholesterol. While Russian
researchers, as an aside, state that the elevation of
cell membrane cholesterol was found despite normal serum
cholesterol, no research exploring this matter has been
done. As increased membrane ratios of cholesterol
decrease membrane permeability, the uptake of serum
cholesterol might be decreased, but to what effect on
serum cholesterol is unknown. As the initial movement
of homeoviscous adaptation in cold is increasing
phospholipids, is it possible that cholesterol is moved
out into the serum, thus creating the documented seasonal
rise? No research answers this question. As cholesterol
and triglycerides are transported by the same transport
system, is cholesterol just along for the ride as the
triglycerides are mobilized for fuel? No research answers
these questions. To complicate matters, over a dozen
genes affect cholesterol and fat transport (Bishop and
Waldholz, 1990). The possibilities for mutations is
great and unless the mutations present problems, they
may not be identified.

62


Cholesterol has widely varied uses in the body.
It is the precursor to many stress and sex hormones,
a vital structural component of the body's cells, and
necessary to the synthesis of many substances. The human
body has developed an effective system of reabsorption
and retention to maintain adequate levels of this sterol.
These mechanisms to retain cholesterol in the body are
genetically determined, suggesting that the ability to
conserve cholesterol was at one time a necessary process
during human evolution screws and James, 1991). The
question remains whether the stress of living in cold
climates can be construed as an adaptive force for the
selection of individuals with greater ability to maintain
high levels of cholesterol.
63


CHAPTER 5
ADAPTATION
The investigation of a physiological trait in terms
of adaptation places the researcher in a sea of semantics,
a maze of genetics, and a never ending complexity of
biocultural possibilities when assessing variables. That
humans manage to survive in a vast range of environments
is obvious. That there is noticeable diversity among
humans is also evident. The manner in which adaptation
to the environment affects human variation becomes the
focus of the search.
To many, adaptation is defined as both a dynamic
process and an end product. The process is one of
adjustment of a species to a specific environment and
encourages the conclusion that the end product, "a given
trait, whether structural, physiological, or behavioral,
is the product of the process of natural selection and
thus favors the perpetuation of the genotype responsible
for this trait" (Mayr, 1988, p. 52).
To the anthropologist, adaptation serves as a
framework for the study of evolution as well as the
64


explanations of phenotypic and genotypic variation found
within the human species. It encourages investigation
of a phenomenon not only in terms of how or what, but
also why. It defines the search by asking, 'What is
the function?'
The study of adaptation, while assigning a
directional intention to natural selection, must also
accept that selection is an 'a posteriori' process.
Individuals survived because they had inherited a
"combination of characteristics that favored them under
the constellation of environmental conditions which they
encountered during their lifetime" (Mayr, 1988, p. 96).
Furthermore, while the study of individual traits appears
to be the focus, the fact remains that it is the manner
in which that trait supports the entire genotype that
determines its success. It is the entire package, the
genotype, which survives (Mayr, 1988).
To explore adaptation is to consider that selective
advantages may be responsible for the expressed
variations we see today. To choose the adaptation
framework is to attempt to "turn mere chronicles of past
events into historical explanations" (Lewontin, 1982,
p. 146) and to explain physiological phenomenon within
that historical evolution narrative (Mayr, 1988).
To do so is to propose that ongoing changes in an
65


environmental system maintain a causal relationship with
the human system (Lewontin, 1982).
To address the causal relationship of an environment
to a physiological trait includes both issues of proximate
and ultimate causes. The proximate causes, seen as
functional components, govern an individual's responses
to his immediate, environmental situation. The ultimate
causes are those which during the evolution of a species
are. responsible for the DNA information which becomes
part of a species programming (Mayr, 1988). While a
proximate cause of elevation of serum cholesterol might
be the cold weather, the ultimate cause may be in cell
construction and growth. The first requires the
functional explanation, the other an historical one.
The questions become what is the function of elevated
cholesterol in the face of cold weather, and why does
the mammal exhibit higher cholesterol levels than fish?
While the second issue may be touched upon only in the
description of cholesterol uses in the body, it is the
first question which remains at the forefront of this
paper.
Factors Affecting Selection
Human beings are complex biological organisms
operating to maintain homeostasis. Individuals require
a system of feedback and internal communication to respond
66


to informational input from their surroundings. As the
environment constantly challenges survival, adaptation
is a never ending process. Adjustments may be reversible
or permanent, depending not only upon the length and
intensity of exposure to the challenge, but also to the
developmental state at which the individual is exposed
(Frisancho, 1981; Lewontin, 1982).
The range of physiological responses available to
individuals for adaptation may be under environmental
and/or genetic influence. As genetic selection requires
at least several generations, selected traits may have
a lag time. The adjustment may appear well after the
exposure to the environmental force and thus be
anachronistic within the context of current environment
(Dawkins, 1982). Traits selected under certain
circumstances may become obsolete and even detrimental
under new environmental conditions. Simplistic cause
and effect or environmental determinism cannot be applied
to the appearance of individual traits. Many variables
determine the expression of genes and random forces may
direct, with serendipitous results, which genotypes
actually reproduce.
Genetic selection operates within constraints.
It is subject to an existing gene pool and its variations,
the cohesion of the genotype (in which too many sudden
67


changes may be incompatible with life), and limits of
the Bauplan (morphotype) itself (Mayr, 1988). Due to
variation of genetic material within populations, similar
environmental forces may lead to the selection of
different traits as well as differential expression of
similar traits (Lewontin, 1982; Woodward, 1992).
Forces effecting the gene pool and selection within
populations are mutation, or alteration of the genetic
information, migration and genetic drift, founder effect,
and differential survival (Dobzhansky, 1962; Lewontin,
1982; Woodward, 1992). The operation of these forces
is often influenced by the population size and history
of interaction with or isolation from other populations
and environments These forces are relevant to this paper
when tracking the migration, social history and disease
history of a population.
Investigating the relationship of human beings to
their environments presents many difficulties. Not only
has the norm of reaction for any genotype not been
established across differing environments, but humans
are also in continuous developmental transformation
through their lifetimes. Traits which are beneficial
early in life may become detrimental with age and
functional change of physiological requirements.
Additionally, a simple biological model alone is
68


insufficient due to the impact of cultural and social
environments which also influence development of a
phenotype (Lewontin, 1982).
Coevolution
The working relationship which exists between culture
and genes impacts human diversity. The theory of
'coevolution1 offers clarification of the ways in which
culture and genes affect each other. The five modes
of interaction include genetic mediation, cultural
mediation, enhancement, neutrality, and opposition
(Durham, 1991). The first two modes demonstrate an
interactive relationship between genotypes and allomemes,
the chosen term for traits of culture or 'guides to
behavior' available for selection. Allomemes include
marriage customs, differing subsistence approaches within
an ecosystem, sexual taboos, and variable work and label
definitions (Durham, 1991). Genotypes and allomemes
influence each other. They also affect a trait's quality
as a tool of survival and the selection of traits which
are passed on to future generations. Genetic mediation
is said to occur when cultural allomemes vary as a
function of genotype differences, a genetic cause of
cultural change. Neural coding of color vision and
subsequent color term definitions are an example.
Cultural mediation occurs when' cultural practices impact
69


genetic selection. An example would be the impact of
agricultural practices which enhanced the habitat of
malaria-carrying mosquitoes, in turn encouraging the
selection of the human sickle cell trait (Durham, 1991).
The other coevolutionary modes of enhancement,
neutrality and opposition attempt to explain the
directional impact which cultural allomemes can have
on genotypes. In accordance with Cavalli-Sforza's (1971)
ideas of population genetics, Durham sees the impact
of cultural practices on genetic selection as enhancing,
which increases survival and reproduction; neutral, with
no significant impact in either direction; and opposing,
in which cultural practices may impede fitness and
adaptation, thus negatively effecting survival.
Enhancement produces traits which might be similar to
those of natural selection, while opposition produces
phenotypic properties different than those evolving
through natural selection. Incest taboos are seen as
enhancing, while ritual practices such as infibulation
and foot binding, as well as traditions supporting
addictions and population control are seen as oppositional
(Durham, 1991).
Adaptation as a Multi-Modal Activity
Both human biological and cultural adaptation use
a variety of modes of responses. They include processes
70


which do not act in isolation, but work in conjunction
with each other to produce the behavior by which humans
adapt (Toulmin, 1983).
Four distinct modes of adaptation include: 'rational
adaptation1 the conscious choice-making between
alternatives based on calculation of outcome;
'homeostatic' or 'feedback adaptation,' consisting of
functional responses to maintain a steady state in
biological, psychological, or social economic realm;
'maturational adaptation' which develops during a
lifetime, and involves the abilities of effective coping
and interdependent living; and 'evolutionary' or
'selective adaptation' where "novel features, which first
appear without conscious foresight and subsequently
establish themselves selectively, as being fitter or
apter to the novel conditions than their predecessors
and rivals" (Toulmin, 1983, p. 22) become part of the
generational information.
An excellent example which illustrates the
interaction of adaptation modes to the ultimate impact
on a physiological trait is Jared Diamond's historical
tracing of the genetic heritage of African-Americans.
Diamond weaves both genetic and cultural adaptations,
from the peoples' original physiological adaptations
in Africa, to those stresses encountered during capture
71


and delivery to America as slaves, the selection forces
met during years of slavery, to the current trend of
hypertension. He builds a case for the sensitivity to
disease and migratory history, while illustrating the
interplay physiological, social, technical and economic
adaptation of several populations (Diamond, 19193).
These modes of adaptation apply to biological,
psychological, social and cultural processes. And as
they intertwine to impact each other not only currently,
but historically, it becomes no easy task to isolate
the variables which affect a physiological trait. It
is therefore necessary to examine several theoretical
concepts which will make the study more manageable.
Models for Study
An inclusive model to investigate adaptation is
proposed by Rada Dyson-Hudson (1983). Attempting to
unify biocultural adaptation studies based on Darwinian
theory, the interactive model incorporates historical
information from both the immediate and past environments
and genetic information which influences the genotype
(morphology, physiology, and behavior), all which interact
to produce the phenotypic trait (see Figure 4).
A list of parameters against which to measure
arguments for an adaptive explanation guide the
researcher. These rules require that the proposed
72


Figure 4. Dyson-Hudson's inclusive model
-j
U)
Information
from
Immediate
Environment
4-----

/
\i/
Historical
information
of past
environments
encountered

"s \
Morphological Morphological
Physiological Program Physiological trait
Behavioral Behavioral

(Adapted from Dyson-Hudson, 1983, p. 9)


adaptive trait be a unit subject to natural selection,
inheritable, that it contribute to reproductive success
or inclusive fitness, be strong enough to effect a
modification within an appropriate time span, and defined
within the context of a certain environment (Dyson-Hudson,
1983).
The rules- allow for the possibility that a
characteristic might develop new functions during the
evolutionary.history of the species. They encourage
addressing alternative adaptations used by other organisms
within the same niche and applying an adaptive trait
only to the level of organism to which it can be
attributed by evidence (Dyson-Hudson, 1983).
The arena against which development of the trait
is examined can be refined. An ecological approach
structures the environment into biomes, which can be
further reduced to areas of stressors effecting
adaptation. The components of the biome include the
'biotic1 such as available food and materials, predators,
vectors, and pathogens; the 'abiotic,' composed of
climate, inorganic materials and energy; and the cultural
or social organization, technologies and ideologies.
All of these factors influence human beings as a group,
as an individual, and at the cellular level (McElroy,
and Townsend, 1989). All elements of ,an environment
74


are potential sources for stressors which may require
adaptive responses.
Today more than ever the cultural element itself
becomes a powerful stressor. The impact of cross-
cultural exposure is great, but today's effects are now
more rapid and dramatic. Migration of groups by airlift
from one part of the world to another has led to the
engulfing of indigenous populations and exposing
populations to giant steps in technology within days.
"One of the most devastating effects of the health of
a population is rapid and irrevocable change in a people's
way of life" (McElroy and Townsend, 1989, p. 292).
The impact of cultural contact can be defined in
several ways: diffusion, acculturation, assimilation
and ethnic revitalization. Diffusion, or the selective
borrowing of ideas perceived as useful or attractive,
can impact a society. For example, use of tobacco,
imported foods, and even borrowed technology such as
snowmobiles may carry high risks by altering life style
and nutrition. Acculturation, or the continuous intense
contact between two cultures, involves not only changes
in life style and diet, but also involves major political
and economic changes which impact self-image and control.
Assimilation results in one group fully integrating itself
into another cultural structure. Adoption of the new
75


life style puts the assimilated population at risk for
the adopted culture's disease profile. The last concept
is ethnic revitalization. It involves the reclaiming
of ethnic identity and restoring of personal equilibrium.
Its impact on health is achieved by intentional selection
of cultural strengths and deselection of harmful practices
(McElroy and Townsend, 1989).
These levels of impact from cross cultural contact
may be seen on a continuum, as there is diversity within
each population which may govern the degree to which
an individual becomes involved with another culture
(McElroy and Townsend, 1989). But, whether the stressor
originates -in the physical or cultural environment, it
will carry the potential of triggering a stress response.
Stress Responses
Han Selye's general adaptation syndrome to stress
illustrates steps which an individual takes to cope with
a stressor. The first is the: identification or perception
that the stressor is a threat. Step two is mobilization
for defense, as the body attempts to resist or adjust
to the stressor. The outcome of the process may result
in one of three types of adaptation: successful
adaptation and the re-establishment of a balance or higher
level of functioning; maladaptation or strain, in which
the process to adapt is unsuccessful, resulting
76


in exhaustion, illness or death; and initial adaptation
with delayed strain, in which the outcome achieves a
balance for a period of time, but a price to the body
manifests itself at a later time (McElroy and Townsend,
1989; Ornstein and Sobel, 1987). Such a price might
be in the increase of liver failure seen in migrants
to the northern regions as their body increases
cholesterol manufacture due to the increased demand to
meet the cold stressor (Gichev, 1990).
The levels of adaptive behavior employed depend
on the success of each previous adaptive attempt. The
most rapidly deployed response to the environmental
stressor is cultural. When it is cold, humans build
shelters and control internal environments, select
clothing as needed, and find nutrition in a variety of
plants and animals sources. The specifics of these
choices have been learned within the context of a
particular tradition. The physiological responses are
initiated next (or simultaneously with cultural behaviors)
and depend again on severity and length of exposure,
as well as the success of the cultural behavior. The
repetition of exposure to a stressor also affects the
intensity of recognition as well as activated response
(habituation) (Frisancho, 1981). The slowest and least
understood of all adaptive responses is genetic selection.
77


Physiological Stress Responses
Physiology defines adaptation as "the phenotypic
plasticity that permits organisms to mold their form
to prevailing circumstances during ontogeny" (Durham,
1991, p. 14). Physiological changes are included under
the category of functional adaptation (Frisancho, 1981;
McElroy and Townsend, 1989). The level of adaptation
includes the components of morphology, body composition,
and anatomical relationships, as well as organic systems
at a functional, and structural or cellular level
(Frisancho, 1981). Regulatory adaptations occur to
maintain the stability of the organism in relation to
its environment or develop as change within an organism
occurs during response to the environment (Moran, 1982).
The internal stability of ah organism is termed
homeostasis. Homeostasis of human biological systems
must be maintained within a narrow range of values,
monitored by a feedback system. This control system
operates in a compensatory manner, constantly returning
the organism to its required internal operating range.
It detects information by way of receptors and initiates
responses through stimulating effectors. Receptors
monitor such variables as temperature, chemical balance
and arterial pressures. Effectors include cellular
membrane proteins to maintain ion pumps for maintenance
78


of fluid and electrolytes and muscles to control
vasoconstriction and shivering (Purves and Orians, 1987).
All systems operate to maintain a dynamic equilibrium
with the organism's environment.
The general physiological stress reactions which
correlate to Selye's general adaptation theory are
initiated in a hierarchy of responses. With the first
exposure to the stressor, the sympathetic nervous system
stimulates the adrenal medulla to increase the secretion
of the neurotransmitters, epinephrine and norepinephrine.
These catecholamines directly stimulate the heart to
increase its rate and the peripheral blood vessels to
constrict thus shunting blood away from the viscera and
skin to the heart and muscles. Should exposure to the
stressor continue, the general adaptation syndrome is
activated. The pituitary gland is stimulated to release
ACTH (adrenocorticotropic hormone) into the blood stream.
This hormone stimulates the release of mineralocorticoids
and glucocorticoids, other 'stress' hormones (Ornstein
and Sobel, 1987) .
Mineralocorticoids (aldosterone, desoxycorticosterone
and corticosterone) affect fluid and electrolyte balance
within the body (Miller and Keane, 1978). Aldosterone,
the principle hormone of this group, is responsible for
the maintenance of sodium and potassium
79


levels of the plasma. Sodium, the chief electrolyte
of extracellular fluid, is instrumental to the function
of cell membranes and excitability of muscle and nerve
tissue (Kapit, Macey, and Meisami, 1987).
Glucocorticoids (cortisol, cortisone, and
corticosterone) affect gluconeogenesis. They influence
metabolism, promote mobilization of fat stores, and
promote amino acids usage not only to stimulate the
liver's gluconeogenesis, but also to repair cellular
damage and increase tissue resistance in the face of
trauma (Miller and Keane, 1978). Cortisol is vital to
the promotion of long-term metabolic adaptation by
stimulating release and mobilization of nutrients for
energy and tissue repair. Cortisol must be present for
catecholamines to affect vasoconstriction and for
stimulation of other hormones to achieve lipolysis of
adipose tissue (Kapit, Macey and Meisami, 1987).
The call to action mobilizes energy and activates
protective mechanisms to support the body during the
'fight or flight' response. Cholesterol is a vital
precursor to many of the stress hormones which stimulate
and regulate the various responses within the body.
And cold is a stressor which activates the stress
response.
80


The Study of Adaptation
The study of adaptation represents a multi-level
investigation. It involves input from sociology,
psychology, biology, microbiology, chronobiology,
physiology, genetics, and anthropology. Although R.
Dyson-Hudson has accused anthropologists of treating
morphology, physiology and behavior as if "they represent
quite different phenomena" (Dyson-Hudson, 1983, p. xii),
current attempts tend to view genetic, functional, and
cultural/technical adjustments on a continuum, working
together to produce observable effects of adaptation.
The purpose of investigating human adaptation is "not
oriented to determining biological or cultural differences
among populations; the goal is to identify the sources
or causes that resulted in such adaptation and
differences" (Frisancho, 1981, pg. 8).
The operationalizing of studies across disciplinary
lines presents some problems. Research does not always
investigate adaptation with standardized concepts by
which process and outcome may be identified and measured.
Thus, comparing and contrasting studies is often
difficult. In the study of cold adaptation, several
terms appear consistently. Genetic adaptation, seen
as descent with modification, implies evolution and
natural selection of characteristics which favor survival
81


under specific conditions (Folk, 1966; Frisancho, 1981;
Halfpenny and Ozanne, 1989). Acclimatization encompasses
adaptations made under natural conditions, in natural
environments. It involves changes within the organism
during brief exposures to cold conditions, as well as
long-term adjustments made during a lifetime of exposure
to the stress. Acclimation refers to adjustments observed
specifically under laboratory conditions or very
controlled field conditions and in the face of a single
exposure to a stressor (Folk, 1966; Frisancho, 1981;
Roberts, 1979; Hochachka and Somero, 1984). Habituation
refers to the nervous system's adjustment to repeated
exposure to a specific stressor, not the adaptive
adjustments made by the system to maintain homeostasis
in the face of imbalancing forces (Folk, 1966; Frisancho,
1981). These terms incorporate not only the mechanism
of adaptation, but also the variations of the stressors
themselves.
Anthropological studies of adaptation use these
terms to evaluate studies of various cultures and the
human variation of responses to stress. A. Roberto
Frisancho's functional approach investigates adaptation
at the level of changes in "organ system function,
histology, morphology, biochemical composition, anatomical
relationships, and body composition, either independently
82


or integrated in the organism as a whole" (Frisancho,
1981, p. 2). Frisancho emphasizes that incorporation
of research on acclimatization, acclimation, and
habituation is essential to understand the complete
process of an organism's adaptation to a given
environmental condition. Additionally, he acknowledges
that while cultural adaptation may facilitate biological
adaptation by decreasing some environmental stress, it
may itself be a source of new selective forces for
biological adaptation (Frisancho, 1981). The functional
approach is flexible to apply to all levels of organisms
and suited for the study of both individuals and
populations.
Moran's ecological approach to adaptation
incorporates general systems theory and the concept of
feedback, while adding a time constraint on the
measurement of adaptive responses. Specific responses
are selected 'on the proper magnitude and occur at a
time and rate that is appropriate to the stimulus that
elicited the adjustment" (Moran, 1982, p. 7). Moran
accepts the idea that human adaptation is on a higher
plane than that of mere negative feedback. Emphasizing
that maintenance of homeostasis and dynamic equilibrium
does not imply changelessness, he notes the abilities
of complex organisms to reorder themselves to a higher
83


level of functioning to ensure survival (Moran, 1982).
Both feedback responses and movement to a higher
order are viewed within the context of conservation of
energy. The success of human adaptability is measured
by demographic, energy, and nutritional criteria.
Statistical analysis of population fluctuation and
relative energy efficiency of technology, as well as
nutritional success to support a given work capacity,
is seen as a reflection of a culture's ability to identify
and exploit the resources of a given region (Moran, 1982).
Moran sees adaptation studies once used to explore human
variation and physical response limits now used to
investigate environments and adaptation in terms of
chronic disease patterns.
McElroy also presents the concepts of health and
disease as reflections of adaptation to the environment.
She sees patterns of disease in a broad historical and
geographical framework, reflecting the ongoing adaptive
process of genetic, physiological and cultural adjustments
to dynamic environments. McElroy's model identifies
the interrelationship of all variables to emphasize that
there are no single causes of disease. "Disease is
ultimately due to a chain of factors related to ecosystem
imbalance.....health and disease are part of physical,
biological, and cultural subsystems that continually
84


affect one another" (McElroy and Townsend, 1989, p. 20).
Discussion
The study of adaptation is a complex issue which
involves input from biological, psychological, social,
and cultural realms. This chapter has only touched the
surface of issues! when exploring the many directions
by which a study of adaptation can be approached. The
search may approach the question through populations
as a whole, individual variations, or at the very reduced
level of the cell. The variations may be genetically
caused, environmentally shaped, or both. To ^investigate
such a trait as elevated serum cholesterol levels in
cold, Frisancho's (1981) functional approach reinforces
the need to study a physiological trait from all points
of view. The genetic, functional and physiological
information can then be used to paint a more compete
picture of the issue. Blending both laboratory and field
studies produces a more inclusive research.
Combining the functional approach with an ecological
perspective encourages narrowing the search to a specific
environment. The concentration on the circumpolar area
serves to focus on similar types of cold exposure, as
well as on other environmental influences such as
luminosity, radiation, and seasonal variation. It also
encourages a look at the variation in food chain and
85


nutrition among the differing populations. And, it is
the area in which most of the active research is now
being completed.
One of the most enticing study approaches is the
historical narrative illustrated by Jared Diamond.
Examining a physiological trait in perspective of the
history of a population under varying stresses including
biome, migration, economic and health presents an
inclusive longitudinal model. Additionally, it adds
the concepts of health and disease into the evaluation
of adaptation.
The following chapter investigates the most recent
population studies 'concerning elevated serum cholesterol.
It offers several ideas for future study and the problems
encountered during the beginning exploration into the
possibility of implementing one of the studies. It
represents the beginning, not the end.
86


CHAPTER 6
DISCUSSION AND PROPOSALS
Review of Studies
Reports that serum cholesterol elevates during times
of cold exposure have been documented since the 1920s
(see Robinson, et al., 1992, for historical overview).
Population comparisons completed by Keys "Seven Countries
Study' (trending cardiovascular risk factors cross
culturally) documented Finns living in the Karelian region
of Eastern Finland as having the highest serum cholesterol
levels of the seven. Countries included two cohorts
in Finland, the United States, Yugoslavia, Japan, Italy,
Greece and the Netherlands (Keys, 1980). Further
clarification found a 50% seasonal change (winter higher
than summer) in levels among the Eastern Finns, reflective
of dramatic temperature ranges (Robinson, et al., 1992).
(See Table 6 for cholesterol levels of populations to
be discussed).
Reinforcement of the theory of dose-response to
cold was found by Robinson, et al., (1992) in a study
comparing 17,200 men and women and women living in the
United Kingdom with 42,000 Japanese. The study showed
87


TABLE 6.
SERUM CHOLESTEROL LEVELS
Conversion 39mg/i00ml = 1mmol/l
Seasonality of serum collection unknown
Population Cholesterol Source
Icelanders 221 + 39 mg/100ml Axelsson, '90
Icelanders-Canada 205.5 + 39. 8 mg/100ml Axelsson, ' 90
Greenland Eskimo 217.6 + 9.4 mg/100ml Draper, '80
Eskimos-Denmark 284.7 + 9.8 mg/iOOml Draper, *80
Danes 264 + 7.8 mg/100ml Draper, '80
Noril'sk Natives 223.9 + 1 6 mg/100ml Gichev, '90
Noril'sk Migrants..no age factors noted in Gichev study
0-2 years 21 0.2 + 12.5 mg/100ml Gichev, '90
2-5 years 242.6 +_ 17.6 mg/1 00ml Gichev, '90
5-10 years 277.3 + 20.3 mg/100ml Gichev, '90
10 years 298.4 + 16.8 mg/100ml Gichev,. '90
Finns age 40-50
rural 284.7 mg/100ml Draper, '80
semi urban 263.3 mg/100ml Draper, '80
industrial 277 mg/100ml Draper, '80
Lapps age 40-40 269 mg/100ml Draper, '80
Karelians 40-50
rural 275 mg/1O0ml Puska, '81
urban 265 mg/100ml Puska, '81
SW Finns 40-50
rural 258 mg/100ml Puska, '81
urban 267 mg/100ml Puska, '81
Finns 255.9 mg/100ml Nayha, '94
Lapps 269.9 mg/100ml Nayha, '94
Finnish Ambassador 310 mg/100ml Mosher '91
No. Khanty male 276 mg/100ml Puzyrev '92
No. Khanty fe 328 mg/100ml Puzyrev '92
Chukchi
Tundra 186.9 mg/100ml Nikitin '91
Coastal 190.6 mg/100ml Nikitin 91
Alaskan Eskimo
Point Hope 219 _+ 49 mg/100ml Draper '80
Kasigluk/
Nunapitchuk 246 + 46 mg/100ml Draper '80
Boarding School 144.3 + 32.3 mg/100ml Draper '80
Seasonal Variations
United Kingdom
Males Jan 240.6 + 44.5 mg/100ml Robinson, '92
Males July 233.6 + 42.5 mg/100ml Robinson, '92
Fe Jan 227.8 + 41.7 mg/100ml Robinson, ' 92
Fe July 220.7 _+ 40.2 mg/100ml Robinson, '92
Japan
Males Jan 207.5 + 36.3 mg/100ml Robinson, '92
Males July 198.9 + 34.3 mg/100ml Robinson, '92
Fe Jan 213.3 + 35 mg/100ml Robinson, '92
Fe July 202.8 + 33.9 mg/100ml Robinson, '92
88


a strong correlation between elevated serum cholesterol
and winter months in both countries. Variations were
more marked in Japan, which has a greater temperature
differential between seasons (Robinson et al., 1992).
A laboratory study placing a group of Finnish men
in a cold chamber for two hours found a statistically
significant rise in serum cholesterol (Leppaluoto et
al., 1988). Leppaluoto's explanation for this rise was
a mechanical one...that cholesterol accompanied the rise
in lipoproteins. However, he offered no functional
explanation (Leppaluoto, personal communication, June,
1993).
A study comparing serum cholesterol and HDL levels
of winter swimmers in Finland to nonswimming Finns (the
swimming being outside, in natural waters, not pools)
documented both serum cholesterol and HDL to be higher
in the swimmers. This was attributed to the greater body
fat in the swimmers. In noting dimorphic variation,
the researchers stated that women swimmers had higher
hemoglobin and HDL levels than men. Unfortunately the
authors noted the control group of nonswimmers had their
blood drawn during the summer, not the winter. Blood
samples from the swimmers had been drawn in winter
(Kauppinen and Vouri, 1988).
Finnish Saami reindeer herders (Lapps) are documented
89


to have higher serum cholesterol than Finns. HDL levels
are the same (Virokannus, personal communication,
September 1992). At this writing the analysis is still
being completed in Oulu, Finland (Nayha, personal
communication, May, 1994). Finns have some of the highest
rates of cardiovascular disease (Keys, 1980), however
ischaemic heart disease is very rare in the Saami (Nayha,
1989). While it is not clear why the higher cholesterol
levels do not correlate to higher disease rate in Saami
as it does in Finns, it is worth noting that the Saami
have high levels of selenium, a noted antioxidant, in
their blood (Ringstad et al., 1991).
Research compared blood samples of Nenets (Samoyeds)
and Caucasian natives inhabiting the Archanglesk region
of Russia, including the Kola peninsula and regions around
the Arctic Circle at the White Sea. Serum cholesterol
in both groups elevated during the winter. The amplitude
of increase was more pronounced in the Caucasians (Tkachev
et al., 1991b). Jevgeny Bojko, one of the researchers
involved, stated that the diets of the two groups were
similar. He emphasized that studies of the northern
populations were done at work camps where diets were
controlled by camp personnel and were similar for all
the populations involved (Bojko, personal communication,
June, 1993).
90


Bojko's emphasis of diet control across work camps
may also apply to Gichev's study of liver function
variations. Gichev, as previously mentioned, found
elevated liver functions and serum cholesterol in 204
migrants from medium latitudes who were moved to Noril'sk
above the Arctic Circle. The migrants were compared
to a group of 229 native inhabitants of the region.
Cholesterol levels of the early migrants were lower than
the natives, but rose in correlation to the length of
stay in the North. Antioxidant levels of migrants were
also lower than the natives, but rose with the serum
cholesterol levels. After a dramatic rise in the level
of antioxidants at the ten year mark, they ultimately
decreased to levels higher than those exhibited by the
natives. Gichev stated in his study that no alteration
in diet took place for the migrants (Gichev, 1990).
A comparison of serum cholesterol levels of
inhabitants of an Alaskan village with those of a group
of Siberian Eskimos found the Alaskan subjects to have
higher serum cholesterol levels. Both researchers, Yuri
Nikitin of Russian and Sven Ebbeson from Alaska, however,
agreed that the blood samples were not drawn during the
same season. Both acknowledged seasonal variations,
but neither could offer explanations of a functional
sort. Nikitin stated a hormonal cause for this elevation,
91


Full Text

PAGE 1

THE FUNCTIONAL ROLE OF CHOLESTEROL IN COLD ADAPTATION by M. J. Mosher A.D.N., Coastal Carolina Community College, 1981 B.S.N., Metropolitan state College of Denver, 1986 A thesis submitted to the Faculty of the Graduate School of the of Colorado at Denver in partial fulfillment of the requirements for the degree of Master of Arts Anthropology 1994

PAGE 2

This thesis for the Master of Arts degree by M. J. Mosher has been approved for the Department of Anthropology by Date

PAGE 3

Mosher, M. J. (M.A., Anthropology) The Functional Role of Cholesterol in Cold Adaptation Thesis directed by Professor Linda Curran-Everett ABSTRACT The phenomeni and elevation of serum cholesterol' during exposure to cold climate have been documented in populations since the mid-1920's. The function of ""increased' serum' cholesterol is neither clearly researched. With cholesterol now implicated a's a major risk factor in cardiovascular disease, much of' it's documented benefit to the human body has Theintent of this thesis is to explore the hypothesis that elevated serum cholesterol is a functional human adaptive response to cold and to suggest that arbitrary lowering of serum cholesterol in all populations could be detrimental. This thesis is a review of international and interdisciplinary literature of cholesterol research and of human response to cold. The specific cholesterol function investigated is that of 'struc.tural antioxidant' to the cell membrane during periods of cold exposure. iii

PAGE 4

Evidence, primarily documented in Russian literature, is presented. The research in this area is new and incomplete. However, it suggests a direction for further ,investigation into the relationShip between cold climate and cholesterol. This abstract accurately represents the content of the candidate's thesis. I recommend its publication. Signed Linda Curran-Everett iv

PAGE 5

CONTENTS CHAPTER PAGE 1. INTRODUCTION 1 2. ADAPTATION TO COLD 6 Heat produc_tion .................. ..... 7 Heat loss 9 Responses to cold stress 11 Heat conserving behaviors 15 Physiological cold 16 Hormonal response to cold 21 Human Variation 26 3. HOMEOVISCOUSADAPTATION 32 Membrane structure and function 33 Cold effects on cells 36 Homeoviscous adaptation 37 Lipid Peroxidation 42 Population research 44 Discussioh 46 4 CHOLESTEROL 49 Transport and metabolism 50 Cholesterol oxidation 56 Other fats and lipids 58 The structural antioxidant 60 Discussion 61 v

PAGE 6

5. ADAPTATION 64 Factors affecting selection 66 Coevolution 69 Adaptation as a multi-modal activity 70 Models for study ; 72 Stress responses ,76 I Physiological stress responses i78 I The study of adaptation 181 Discussion 8 5 6. DISCUSSION AND PROPOSALS 87 Revi-ew of studies -. 87 Proposals for future study 94 F 106 7. APPENDIX 08 8. BIBLIOGRAPHY 11 0 vi

PAGE 7

FIGURES FIGURE PAGE 1. Thermoregulation ... .... 12 2. Fluid mosaic for biological .. 39 3. Cholesterol transport system ... 51 4. Dyson-Hudson's inclUsive model 73 vii

PAGE 8

TABLES TABLES PAGE -1. Changes in non-shivering thermogenesis during short and long term exposure 23 2. Temperature and metabolic responses during all night cold tests 2 3 3. Transport mechanisms of vital substances 35 4. Apolipoproteins ........... ................. 53 5. Cholesterol percentages 53 6. Serum cholesterol : 88 viii

PAGE 9

ACKNOWLEDGEMENTS Anssi Arpiainen Liason Officer, TUKOSPAR Helsinki, Finland Finnish Translator Harriet Mosher Oberlin, Ohio Funding Lena Peschanskaia Department of Economics Graduate Student UCD Russian Translator Diane Oliver Seattle, Washington Editor

PAGE 10

CHAPTER 1 INTRODUCTION Cholesterol is currently denounced forits potential detrimental effects on the human cardiovascular system. As early as the 1950s medical researchers documented streaky deposits 6f fat and in the vascular system of young men. noted that victims of cardiovascular disease often had high sen,lm cholesterol levels. Health officials r "esponded quickly by declaring war on cholesterol. Doctors developed arbitrary numerical parameters for serum cholesterol. levels and placed individuals into risk categories. International programs to lower serum cholesterol were implemented, despite documented evidence that is so vital to cell viability that virtually every cell in the body manufactures the Current epidemiological research associates low serum cholesterol with higher rates of cancer and risk of stroke. Polyunsaturated fats, once thought to be a beneficial exchange for high cholesterol animal fats, are now under investigation for possible detrimental effects on the cardiovascular system and cellular 1

PAGE 11

structure. And, the controversy continues. Elevated serum levels are associated with exposure to stress, particularly exposure to cold stress. Russian researchers now believe that cholesterol may in some way be piotective against the effects of cold on cellular Yet, medical science still places restrictions on acceptable levels of serum cholesterol for all humans regardless of history, circumstances, or environment. This thesis is. a review of international research on cholesterol and human response to cold. The intent r : is to reframe the research within the hypothesis that elevated serum cholesterol may be an adaptive human response and may serve a functional purpose. The goal of this thesis is to establish theframework by which to further examine the connection between cold adaptation and cholesterol. The investigation begins with a review of research addressing the effects of cold on the human body. The information presented includes general human adaptive responses and some population variations. It is followed by an examination of cellular response to cold and the adaptive response of the cell membrane's lipid bilayer. This discussion of homeoviscous adaptation is relevant in several ways, including an understanding of human food sources available in cold climate. 2

PAGE 12

Chapter four includes a general review of the accepted knowledge base concerning cholesterol utilization, transport system and oxidation. It includes a look at current research concerning oxidation stress on the cell and its'membranes. An examination into the theoretical framework for an adaptation model follows. The discussion takes into consideration biological, psychologi6al, social and cultural variables which impact adaptive processes. The review of theoretical considerations illustrates the difficulty in operationalizing research projects which address the specifics of human adaptation. However, the inclusive perspective sets the 'stage for developing several lines of research by which to study cold stress and cholesterol. These will be delineated and discussed. The final chapter is a synopsis of current research connecting cold adaptation and cholesterol, acquired through both literary review and interviews with international scientists actively investigating the issue. The studies originate from a wide variety of disciplines, each with its paradigmatic view. The research reflects the difficulties of understanding languages, scientific methods and explanatory models. Reinforcement of the idea that cholesterol is involved in adaptation to cold ... \ came from professional asides and brief comments which 3

PAGE 13

were not directly associated with the stated goals of the research projects themselves. The intent of the last chapter is to discuss the lack of consensus in explanations concerning the relationship of, cold and cholesterol. No clear explanation as to why cholesterol levels rise with cold exposure was found. Repeatedly scientist stated their belief that the elevatiQn was part of a functional or response, however, adding that on the subject had been done. No studies .. exist which correlate elevated serum-cholesterol with elevated cholesterol content in cell membranes; documenting the tnechanismbywhi-ch omega-3 reduces serum cholesterol; or examining erythrocyte behavior in high serum cholesterol under varying temperatures. Yet, the knowledge would be invaluable in further understanding of the cholesterol issue. The practical application' s of research exploring the mechanism and function of the relationship between cold and climate are many. Russians are using their studies to develop preventive health measures to protect workers now migrating above the Arctic Circle. Alaskans are searching for more information on the detrimental human effects of dietary change versus intake of dietary contaminants in order to rule on indigenous subsistence 4

PAGE 14

hunting. Finns are searching for an explanation as to why Saami (Lapp) reindeer herders have higher cholesterol levels yet lower cardiovascular disease than the Finns. And are now questioning whether trans fat may be more detrimental to women's cardiovascular system than cholesterol. Research examining cholesterol's role must be approached by a framework which incorporates theories of humarivariation,. adaptation and ecology. Knowledge gained from such studies must be applied when implementing widespread prevention programs. This thesis represents an exam'inati-onof multi-disciplinary cholesterol research and the initial stage of a research direction to blend the many approaches into a single research program. 5

PAGE 15

CHAPTER 2 ADAPTATION TO COLD Adaptation to cold is the complex interdependence which develops through interdependence of reactions interrelated within a timedependent it is a sort of integrated systemic potentiation of all the heat-producing and systems which exist in. the organism. (LeBlanc, 1975, p. 102) Humans evolved initic=!).1.Y _;in .. ::the warm climate of Africa. They were hardly to function in cold climates, but function they do. Humans are homeothermic' organisms which must maintain body temperatures within a consistent range, independent of Their core temperatures found. between 37-38C/98.6F. A drop of only 9F' in core temperature results in thermoregulatory system failure. While a naked human may maintain body temperature with its basal metabolism rate (BMR) for heat production'in an ambient temperature of 75F (Frisancho, 1981), death will occur within 15 minutes in the common conditions of the,Arctic, -40C and 20mph winds (Bruemmer, Without extensive body hair or hibernation capacities to protect them during the coldest times, humans developed 6

PAGE 16

complex cultural adaptations not only to environmental stress, but also in harmony with their own physiological responses to cold stress. The abil i ty to maintain body heat through both biological and cultural practices gives humans independence and freedom to survive in a variety of environmental niches. In examining human adaptation to cold stress it is vital to understand the normal physiological processes which. impact both and loss of body heat. From that vantage. point it then becomes possible to investigate physical variations which developed in populations facing a wide range of differihg climates. Heat Production Thermoregulat'ion requires humans to, constantly balance energy input and outflow. This balancing process is under the control of the central nervous system, with the hypothalamus designated thermostat for the body. Production of body heat is generated through the oxidation of foods consumed or stored in the body in the form of fat. It is also produced asa by,-product of body work, such as mechanical (friction of muscle), chemical (metabolism), or electrical (nervous system) action. Heat is also released during hydrolysis of adenosine triphosphate (ATP), the compound used for short term storage of chemical energy., When ATPchemical bonds 7

PAGE 17

are broken and the split phosphate. group is transf,erred to heat is released (Kapit, Macey, and Meisami, 1987). Basal metabolism rate (BMR) is defined as the amount of energy required to sustain the body at minimal effective functioning (Halfpenny and Ozanne, 1989). Further defined, this obligatory heat production is the "minimum energy requirement of a resting animal at thermoneutrality. ATP-turnover is for maintenance of cell and organ function (e.g., i6n .gradients across membranes, transport between organs.)" (I:leldmaier, 1989, p. 348) Metabolism is divided into two phases: the anabolic phase in which simple are converted from nutrients into organized sUbstances' used by the cell, and the catabolic phase in which usable substances are reconverted into simple compounds and energy needed for functioning of the cell. The rate of metabolism may be influenced by environmental temperature and hormonal activity (Miller and Keane, 1975). Metabolism and heat production are affected by diet. Of carbohydrates, proteins, and' fats, the digestion of protein is the most energetically costly. Protein requires one third of its ingested calories to be metabolized. This energy cost'is two to three times higher 8

PAGE 18

than that to fat and five times that for carbohydrate. The increased metabolism which results produces,an increase in heat production, a diet-induced ,thermogenesis. Protein ingestion also increases secretion of and norepinephrine, neurohormones which enhance, heat production 1 ,971). Basal metabolism has been shown to be, sustained at higher rates in populations mostly protein and fats than populations consuming a western ,diet (Speth and Speilmann, 1983). Heat Loss of heat loss begins with Newton's law of cooli!lg." ,the interaction of a living mass and air mass with heat deficit, the law can be as a proportion: .,. the heat loss per minute is directly proportional to the body 'surface and the difference between temperature of the body core and ,that of 'the environment, and inversely proportional 'to the thick of the body shell; i.e., heat flows'at a rate which increases with the surface area and the temperature diop between the core and the exterior, and which decreases with greater thick ness of the barrier between core 'and exterior. (Folk, 1966, p. 101) Body heat or energy is lost by radiation, convection, conduction, and Radiation is the transfer \ .. ',. of heat from an organism to ,the environment by means 9

PAGE 19

electromagnetic waves. The amount of heat lost depends on the color of the object and its surface area. The amount of heat transmitted in this way depends not only on posture regulating exposed body area, but also on insulatioti the transfer (Frisancho, 1981). Solar energy is acquired in this manner. Convection transports:heat by a stream of molecules which move away from 'the warmer object to a colder one. This ent'ails' the loss of heat from the' body 'to the' surrounding air. Controlling the amount of heat lost or gained is the temperature gradient between the body surface and the air Al'so' controlling the volume of transfer :isthe amount of circulation of the body, governing the mass of cold air to which the body is exposed (Frisancho, 1981). Conduction involves heat loss by direct physical transfer from one.substance to ,another. It may mean cell to cell, tissue to tissue, skin to skin, or skin to clothing. This mechanism is vital to the distribution of body heat within the body, in heat transfer from body to clothing, and in the eventual heat loss by convection or evaporation (Frisancho, 1981). Under cold conditions the core of the body shrinks, while the body shell of skin, fat and extremities actually expands (Moran, 1982), enhancing conduction within the core and reducing it 10

PAGE 20

to the shell. The fourth mechanism of heat loss is evaporation or "transfer of energy by change in phase from liquid to vapor in the air" (Halfpenny and Ozanne, 1989, p. 34). Evaporation results in loss of water from the skin and respiratory tract. The corresponding loss of heat' is due to energy used in the "endothermic conversion of water to vapor called the latent heat of ,evaporation" (Frisancho, 1981,' p. 16). To continue the process of'-'sweati-ng the body must maintain skin blood flow to -move core body heat to the periphery. A high pressure at the of the skin, which creates an osmotic gradient, enhances sweat loss. In high humidity osmotic pressure on--the skin is reduced, reducing the sweat rate (Bruck and Zeisberger, 1990). While the, first three mechanisms of heat transfer may be two-way, evaporation is one-way, achieving heat loss only. It must be emphasized that the amount of heat lost through these mechanisms depends on the volume of heat transfer from the body core to the surface, the composition of the body--especially the distribution of fat deposits--and the proportion of the body surface area to body weight (Moran, 1982). Responses to Cold stress Responses to cold stress are activated through a 11

PAGE 21

Figure 1: THERMOREGULATION I Cerebral Cortex ,---4? I 1 I I I I t Hypot1halamus I Skin Thermoreceptors r Skin temperature I .J/ TSH-RH I -J--, Anterior pituitary I \V TSH I \1/ Thyroid I 'V Tnyroxin --' Atrenal medulla t i 17 I' I V Sweat Glands Epinephrine Core' TemJerature Core Thermoreceptors Sympathetic .. nerves \V -j Skin Skeletal arterioles muscles (Adapted from Phipps, et al., 1983, p. 401) 12

PAGE 22

system of cold and warm receptors spread throughout the skin and body core. Homeostasis is achieved through regulatory responses designed to create heat, conserve heat and/or energy, or a combination of both as needed. A complex hierarchy of receptors exists in the nervous system designed to activate responses of assigned systems and process further commands for increased protection (Bruck and Zeisberger, 1990; Hissa, 1990). Careful coordination of multiple systems is orchestrated to maintain body heat with the lowest energy expenditure. possible ,(-see .Figure 1 ) Cold exposure,activat.s skin sensors believed to besituated.in .areas of the skin where temperature is under the: influence of skin blood flow (Jessen, 1990). Neural messages are relayed via dorsal roo'ts, which contain sensory fibers, along the spinal cord. The spinal cord itself:holds control over some responses to cold and activates the shivering response, a rapid short-term energy expensive'heat'production device. It also activates vasoconstriction for heat conservation. As the messages travel along the spinal cord to both the sensory cortex of the cerebrum and the hypothalamus, activation of a multi-system response begins. Coordination of the autonomic nervous system, cardiovascular and endocrine systems, and metabolism activates heat and 13

PAGE 23

energy manufacturing and conserving devices based on the intensity of the threat and the effectiveness of the response. The neurotransmitter norepinephrine appears to stimulate pathways involving heat gain, while serotonin suppresses the pathways of heat loss (Hissa, 1990). suggests that the afferents from both cold and warm receptors are reciprocally connected yet respond in an antagonistic.manner. Cutaneous cold receptors activate processes which protect against the cold, such as vasoconstriction and heat production. Inhibitory interneurons are activated to reduce loss. warm receptors are activated and serve as the check and balance to protect aga,tns.tover heating. 'These warm receptors serve to suppress heat production and activate heat loss mechanisms such as Vasodilation, sweating and panting. "The actual difference between the signals from cold and warm receptors indicates a deviation from that point at which the two signal cancel each other, that is, the set point" (Bruck and Zeisberger, 1990, p. 276). Different responses are believed to be activated at varying body temperatures, possibly explaining vasomotor changesiriduced before non-shivering thermogenesis, which is activated before shivering (Bruck and Zeisberger, 1990). This may also explain the fact 14

PAGE 24

that most brown adipose tissue is found at the spinal cord between the scapula and at the cervical region. The heat generated locally at the level of the spinal cord may serve to inhibit shivering (Hissa, 1990). Heat Conserving Behaviors Heat conservation behaviors include covering the body, seeking shelter to decrease exposure, curling up to decrease surface area, or huddling with. another being. Voluntary physical activity such as walking or rubbing hands together also stimulates heat production. While these activities may have:short-term results, seasonal behaviors may include storing food supplies and increased to build endogenous nutrient stores. Altering the diet during the winter months to qonsume high energy food and fats which contain twice the caloric capacity of protein and carbohydrates is noted in both animals and humans. It might seem reasonable to assume that behavioral cold adaptation options of donning protective clothing, increasing muscle movement, building fires and building protective lodging are simple solutions. However, steegmann's (1983) acknowledgment of Algonquin ritual 'tea-parties' during hunting expeditions demonstrates the incorporaiion of protective actions into cultural behaviors and illustrates the intricate understanding 15

PAGE 25

cold-adapted populations have of their bodies. The Indians realized that clothing, wet from well-insulated bodies hard at work, decreased in insulatory value and contributed to heat loss through evaporation. They also understood the dangers of dehydration which decreased available fluid for the circulation of energy and heat. The ritual included frequent stops to build fires to make tea. Steegmann initially overlooked the value of these stops, however soon realized they served an intentional dual purpose of replenishing fluid loss and drying the clothing. To him what appeared as.ritual behavior had in fact been protective (Steegmann, 1983). Physiological Cold Adaptations The morphology traditionally associated with genetic adaptation to cold pairs Bergmann's and Allen's rules to suggest that it is the homeotherm with a large body and short extremities (Steegmann, 1970). Heat generation is attributed to a larger body with more muscle mass. A larger body with shorter limbs has less surface area per unit of volume and will lose less heat. Little research actually corroborates correlation of this stature in human beings, and much is inferential. Studies in the 1950s concluded that an increase of body weight does demonstrate increased insulation ability, while any correlation of body heat to stature was weak. Longer 16

PAGE 26

bedies with larger chests and sherter arms were attributed to. areas ef lewer annual mean temperatures. Hewever, delineating a specific temperature cennectien frem heredity, diet er ether indirect causes was net dene (Steegmann, 1970). Regulatery respenses to. censerve bedy heat includes centrel ef vascular functien. Subcutaneeus bleed vessels censtrict decreasing skin temperature and reducing the gradient between. skin and envirenment. That precess reduces heat less. An additienal censervatien mechanism ef the vascular.system is seuntercurrent heat exchange between arteries and veins. The warmth ef the arterial bleed is shunted to. veneus bleed through arterieveneus anastemeses .which cennect arterieles to. the superficial plexuses. The heat is returned to.' the bedy cere, net lest to. the envirenment frem extremities. The bedy werks to. prevent damage to. the ceeled extremities threugh a periedic clese ef the anastemeses which allews warm bleed to. heat the extremities 1981; Bruemmer, 1989). Anether ferm efcold respense is insulatien by means ef layering white adipese tissue er fat. When feed intake is greater than energy expenditure the bedy steres the excess.. Net enly is depesited fat geed insulatien but it becemes an excellent seurce ef future energy. Seme is placed in subcutaneeus fat pads, while ether fat is 17

PAGE 27

deposited more deeply in the body surrounding vital organs (Lieberman, 1987). White fat cells are shaped like signet rings and contain large globules of fat surrounded by a thin cytoplasm. They are tightly packed together and have less intercellular material present than other tissues (Grollman, 1978). Because of decreased vascularity thermal conductivity is reduced. Fat actually conducts heat much less than does muscle (Frisancho, 1981). Humans exposed frequently to cold water produce a subcutaneous fat layer much in the manner of sea mammals which layer blubber. This outer layer protects the entire body core (Folk, 1966). The metabolic cold is an enhancement of the homeothermic system already in place. The response increases heat production through increase of basal metabolism (BMR), stimulation of shivering, and activation of non-shivering thermogenesis (NST). Shivering thermogenesis increases basal metabolism (BMR) and reduces the temperature gradient heat loss from the body's core (Frisancho, 1981). When voluntary muscle movement such as walking or running produces insufficient heat, the body creates its own skeletal muscle movement called shivering. This is described as a synchronous tremor of flexor and extensor skeletal muscles (Rautenberg, 1989). While running can increase 18

PAGE 28

the BMR anywhere from 1.17 cal/min.to 37.94 cal/min, it cannot be maintained for long periods. Shivering can increase the BMR two to three times and raises the muscle temperature over that of the body core, alleviating temperature gradient.heat loss 1981). If work is not added to the muscle contraction load, shivering is energy efficient than running (Folk, 1966). However, as subcutaneous vasodilation to protect skin tfssue from frostbite accompaniesshivering,sQme heat loss result (Frisancho, 1981). (NST) manufactures heat at a more complex level. It is a chemical response which increases metabolism without muscle movement, able to increase the metabolism of adults 25% above basal levels and infants 170% (Little and Hochner, 1973 as cited by Moran, 1982). NST is also a hormonal response through stimulation of norepinephrine from sympathetic nerve endings and thyroxine from the thyroid (Frisancho, 1981). This type of thermogenesis is thought to be "localized in the mitochondria and is the consequence of loosening the coupling between ATP synthesis and respiration" (Wang, 1978,p. 567). Heat is released through the "uncoupling of oxidative phosphorylation" (Hassi, 1977, p. 16). Oxidative phosphorylation is defined as the formation of ATP in the mitochondria and 19

PAGE 29

associated with electron flow through the respiratory chain (Purves and Orians, 1987). NST is believed to occur in the muscle through hormonal activation of the mitochondria. (Halfpenny and Ozanne, 1989; LeBlanc, 1986). However, tissue specifically designed for heat production is the main source of The specialized heat producing tissue is brown adipose tissue (BAT) (Hassi, 1977; Heldmaier et.al., 1989; Kuroshima, 1992). This highly vascular fat is "comprised of cells with cytoplasm that contains several lipid vacuoles" (Hassi, p. 15). The main substrate is fatty acids. BAT is very active in lipogenesis and has been shown to synthesize greater amouhts of fatty acids in cold-acclimated animals (Kuroshima, 1992). It has a high concentration of in the cells along with its own fat stores. The at is processed easily at the site of the ana not transferred to the liver for processing to ATP. It is the BAT, not the ATP, which produces the heat, as the mitochondria of BAT contain special proteins which interrupt ATP production and release heat directly (Halfpenny and Ozanne, 1989). Found inhuman fetuses as early as 19 weeks, BAT is located at the cervical, interscapular, and perirenal areas. Although the cell size and lipid content appear to increase with age, the number of cells 20

PAGE 30

themselves decrease after the first year of life. After the age of 25, approximately 13% of humans show the presence of brown adipose tissue (Hassi, 1977). Researchers believe that adults with hyperplastic BAT are those who have experienced prolonged exposure to cold (Hassi, 1977; Leppaluoto and Hassi, 1989). While studies document the presence of BAT in humans (Marchand,. 1991), the degree to which it actively creates thermogenesis remains questioned. LeBlanc and others contend that muscle is the primary source for nonshivering thermogenesis in humans (LeBlanc, 1988; Halfpenny and Ozanne, 1989): The major regulator of NST is sympathetic norepinephrine, which is shown to be increased in cold acclimated animals and humans. Cortisone and thyroid hormones are also stimulated in response to cold and act to enhance effects of norepinephrine. Cortisone assists in breaking down fat and glycogen stores, while thyroxine (T4) seems to enhance the body's response (Halfpenny and Ozanne, 1989; LeBlanc cited in Bruck and Zeisberger, 1990). Hormonal Responses to Cold Acknowledging the vast complexity of hypothalamic functions, hormonal interaction and at least 15 different neurotransmitting systems with no limiting borders, the 21

PAGE 31

study of hormonal involvement in cold adaptation is no easy task. Much of the research is based on inference and indirect observation of disturbance relationships (Bruck and Zeisberger, 1990). Hormone research remains a frontier in the study of cold adaptation. The hormories appear to be on a time release schedule with some increasing in acute cold while others are activated only after prolonged cold exposure. The degree of cold also appears important to activation of horm6nal response. In to diagram a consistent picture of Fregly organized many acclimatiori which involved exposi-ng adult men to varying degrees, from one to four hours, in cold chambers The of these studies did not demonstrate a clear direction with respect to thyroid TSH,T3.and T4. Some studies documented increase and others showed no change (Fregly, 1990). The mechanisms of the axis in abrupt exposure to cold are a complex issue of the internal communication system of neurotransmitters and hormones. It is believed that catecholamines, and possibly serotonin, are involved in stimulating the thyroid releasing hormone. Binding affinities of the thyroid hormones may be altered under cold stress, but that research is not yet complete. Varying studies 22

PAGE 32

TABLE 1. Changes in non-shivering thermogenesis during short and long term exposure: summary of study results. Parameter Thyroid hormones pituitary thyrotropin Adrenal cortisol Noradrenaline' Adrenaline Brown fat Subcutaneous fat Short-term no change no change no change ,:increased, no change Long-term decreased increased increased increased, or variable increased or variable increased increased (Leppaluoto and Hassi, 1991, pg. 142) -. TABLE 2. Temperature'and met'abolic responses of during all night cold tests. Population Core Temp Australian decreased Aborigine Nomadic decreased Lapps Eskimos no change Cold-exposed no change Norwegians Caucasian Group 1 Caucasian Group 2 Caucasian Group 3 Caucasian Group 4 decreased decreased decreased decreased Skin Temp ,Metabolism decreased decreased .increased decreased increased no change increased increased decreased no change decreased decreased decreased decreased (Leppaluoto and Hassi, 1991t p. 141) 23

PAGE 33

exposing men for 1-3 hours in cold chambers do not give consistent results nor any clear order for the cascade of hormone response. Fregly did emphasize that the one known variable is that rats with compromised hormones could not survive in the cold. Thyroxine was needed to. interact with norepinephrine for NST ability (Fregly, 19901 see for complete discussion of thyroid research). serum concentration levels of hormones in cold chamber_studies it is important to account for the hemoconcentration which increases during cold stress (Leppaluoto et.AI 1988). This may be the result of in response to the cold (Granberg, 1991b). Research by Per Granberg does indicate that at 36C (no time frame of exposure) norepinephrine, corticoids, T3/T4, and aldosterone output does increase. This was interpreted by the researcher to be a "typical physiological stress response" (Granberg, 1991b). Further studies add the observations that while thyroid hormone activity doesnot.show an increase during short cold exposure in humans, increased secretion and degradation of thyroid hormones are noted under long-term exposures. Increased response of cortisol, epinephrine and norepinephrine during long term cold exposure has also been documented (Leppaluoto and Hassi, 1991) (see Table 1 ) 24

PAGE 34

Hormonal involvement in cold adaptation includes not only those of the sympathicoadrenal and adrenocortical systems but also antidiuetic (ADH) and opiods (endorphins). While the corticosteroids are identified as supporting changes which accompany cold adaptation, they also appear to mediate the adaptive process (Bruck and Zeisberger, 1990). A19osterone decreases the sodium and chloride concentration of sweat. Endorphins decrease the pain from cold and are thought to have a more expansive role during cold exposure. lowers breathing rate and heart output, causes decreases in thyroid hormone activity and body temperature, provides some relief from-pain and causes kidneys to produce a more concentrated urine, thus water. It has also been that these endorphin-induced changes relate to a possible effect of hibernation in sonie species. (Purves and Orians, 1987; 712) Repeated stimulation by acute cold exposures results in significantly reduced This reduction of sympathetic response may be due to reduced sensory stimulation supporting the idea that habituation is part of cold adaptation (LeBlanc, 1986). Habituation refers to the "diminution of normal neural responses . . depending on learning and conditioning" (Frisancho,1981, 3). Finnish researchers suggest 25

PAGE 35

that those individuals who maintain strong sympathetic responses to cold, with its heavy load on the cardiovascular system from increased cardiac output and peripheral vasoconstriction, are insufficiently adapted to cold, especially in a circulatory manner (Nayha, 1980; Leppaluoto and Hassi, 1991). Human Variation Research studies investigating human variation of response to cold range from the 1950s studies of body stature, weight, and extremity size in attempts to diagram clines (see'Steegmann,1970, for discussion); to the 1960s variation in thermoregulation through generation of heat and insulatory regulation (see Frisancho, 1981;.Leppaluoto and Hassi, 1990, for overviews) (see Table 2); to the late 1970s and 1980s investigations of physiological variations of neurotransmitters and hormonal involvement (see Schonbaum and Lomax, 1990; Malan and Canguilhem, for complete discussions); to the 1980's and current look at cellular structure and adaptation (Hazel and Williams, 1990; Hadley, 1985). Of interest to this thesis is the current belief that the variation in responses are not mutually exclusive but represent different stages of adaptation. Tnat the various forms of cold responses ranging from hypothermic, 26

PAGE 36

hypometabolic, metabolic and insulative remain in present populations faCing a wide range of cold temperatures (Leppaluoto and Hassi, 1991) suggests a continuum of adaptation. The variations developed in physiological protection become dependent on the degree of cold, the length of exposure, the developmental stage, diet, sex and effectiveness of cultural technology and manifest themselves in a mix and match selection of the possibilities of thermal and insulatory responses. The initial response of an unacclimated individual is that of increased thermogenesis with shivering and increased metabolism accompanied by profound vasoconstriction to conserve core temperatures. Repeated exposure may stimulate increased insulation processes with a decrease in metabolism, accompanied by a decrease in core temperature, such as the hypometabolic, hypothermic adaptation seen in the Australian Aborigines (Leppaluoto and Hassi, 1991). An extreme form of hypothermic adaptation--hibernation--includes a major drop in body temperature accompanied by a significant decrease in oxygen consumption, respiration and heart beat. Adaptive hypothermia and hibernation are behavior selections appropriate in areas and at times when food sources are not consistently or .seasonally available (Purves and Orians, 1987). Hypothermic adaptation is 27

PAGE 37

activated only if heat loss is not too great and individual's physical condition allows adjustment of the cold load (Bruck and Zeisberger, 1990). The metabolic form of non-shivering thermogenesis may develop with prolonged exposure to severe cold. Accompanying responses are decreased sensitivity to cold and subsequent decrease in autonomic stimulation producing a cold tolerance attributed to habituation. This 'tolerance adaptation I can be produced experimentally in 3-7 exposures to cold within several days. Additionally, a decrease in "subjective sensation of cold-induced pain through negative reflex conditioning" accompanies iepeated exposure to cold (Radomski and Boutelier, 1982, p. 615). That the sensation of pain overrides the sensation of cold to inhibit some cold responses has been suggested (LeBlanc, 1986), however no research addressing that issue has been published. Two popu1ations are cited as having prolonged hypermetabolic responses to cold. They are the Inuit and the Ama pearl divers. Research suggests the Inuit's to be diet induced, as their metabolism reduced to a level similar to Caucasians when the Inuit protein consumption decreased (Itoh, 1980). The case of the Ama presents differently, as their rise in metabolism appeared seasonal: 35% higher in winter. Researchers 28

PAGE 38

believe the Ama to have metabolic acclimatization, as their nitrogen did not differ from the control group without elevated basal metabolism, indicating no difference in protein metabolism (Folk, 1966). Whether this is an example of non-shivering thermogenesis is unclear. The use of wetsuits for the divers has resulted in a decrease in this acclimatization (Leppaluoto and Hassi, 1991) which makes further clarification by current research techniques difficult. Variation in peripheral circulation and warming of extremities are also documented in the literature. Cyclic rewarming of extremities (hunting reflex) is found to accompany the insulative vasoconstriction which takes place in "resporise to cold. Inuits however show no marked vasoconstriction, consistently maintaining warm hands during cold exposure. This is now believed to be attributable to blocked alpha adrenergic receptors in the distal extremities. That this trait continues to be exhibited among Inuit who do not face the cold extremes of their ancestors further suggests that the trait is genetic (Grayson, 1990). Research carried out on Gaspe region fishermen who are frequently exposed to cold water also documented a similar lack of vasoconstriction. The explanation for this study attributed the response to a functional reduction of 29

PAGE 39

alpha adrenoreceptor activity and a result of developmental plasticity (Grayson, 1990). While the vasoconstrictive response to cold exposure serves a purpose in inhibiting heat loss, it also creates an additional load on the heart and strain on the vascular system. The price may be seen in the increase of cardiovascular deaths documented in the winter. Profound vasoconstriction response and elevation of blood pressure which remains in many populations living --in the cold are now thought to represent insufficient adaptation (Leppaluoto and Hassi, 1991). The development of a cold culture, with its technically devised protective clothing and consistently heated buildings may have acted to maintain many people at the initial level of a more intensely reactive physiological adaptation. Current thought about human variation in response to cold is that the more complete cold adaptation is exhibited by the Australian aborigines, nomadic Lapps, and Caucasians chronically exposed to cold water (Leppaluoto and Hassi, 1991). This response includes the increased tolerance to cold, lower skin temperatures, maintenance or decrease in metabolism which conserves energy, and highly effective insulatory abilities. The new frontier of microbiology offers knowledge of adjustments at the celiular-level which may enhance this 30

PAGE 40

type of protection and preserve cellular function. i 31

PAGE 41

CHAPTER 3 HOMEOVISCOUS ADAPTATION The hypothermic response to severe cold exhibited by,humans is considered-to be the most prevalent human cold adaptation (Radomski and_Boutelier, 1982). It develops with intermittent exposure to.severe cold, the type of exposure most,requently experienced by humans. It is aecompanied by ei ther, or both, a low metabolic. response and insulatory mechanisms which suggests that habituation is involved. The degree and integration of the response mechanisms may be dependent upon the technical insulation developed by the culture, food supply, and length of exposure to cold (Leppaluoto and Hassi, 1990). While the hypothermic response is considered to be a systemic one, adaptive responses at the cellular level also take place to protect the organism against cold exposure. Active adaptation of the cell membrane, termed homeoviscous adaptation, involves molecular restructuring of the lipid content in cell membranes to maintain their fluidity. This process preserves normal membrane functioning (Hadley, 1985). Restructuring occurs 32

PAGE 42

in response to a variety of changes in the environment including temperature alterations, pressure, water activity, and pH balance (Hazel and Williams, 1990). It is presumed that the strategy maintaining membrane function independent of temperature changes by modulating the effective viscosity of the hydrophobic compartment of the membranes would have survival value during crisis periods and would also be of considerable importance for the of species at normothermic temperatures. (Hadley, 1986, p. 67) Membrane structure and Function The cell is the fundamental unit of every living thing. Basic human cells are eukaryotes which contain a nucleus and various structures, each compartmentalized by membranes. Each structure or organelle, its subcellular membrane, and the cell with its plasma membrane have duties. Membrane activity includes maintaining and internal structure of the cell and acting as a barrier against foreign or toxic substances (McCance and Huether, 1990), regulating the exchange of fluid and electrolytes (Yeagle, 1989), creating an environment for metabolic pathways, communicating within and between cells, storing energy (Hazel and Williams, 1990), producing prostaglandins and influencing cell growth (Spector and Yorek, 1985). Membranes are composed of carbohydrate, protein and lipid substances. The main components of all 33

PAGE 43

membranes are lipids and proteins in an equal amount, while the carbohydrates are found mostly in the form of glycoproteins. Lipids are the component of highest abundance, with a ratio of 70% phospholipids, 5% glycolipids, and 25% cholesterol (McCance and'Huether, 1990). However some cells, such as the erythrocyte (red blood cell which transports oxygen) a of' phospholipid to dlolesterol':(Spector and Yorek, 1985)" stibstances across cell membranes is accornplisned'through a 'variety of i:nechanisms. One mechanism is' simple-diffusion which is controlled by the concentration of substance ort either side tif the membrane. It occurs to maintain an equilibrium of the substance on both sides and molecules pass easily through the membrane. A second method, carrier modulated diffusion, occurs in the face of an imbalance of substance concentration. Solute molecules do not diffuse on their own but combinewith a carrier protein which assists the passage of a solute in the.direction of a gradient ranging from high to low concentrations (Purves and Orian, 1987) Active transport is required to move particles against the concentration gradient. Primary active transport uses energy directly acquired from ATP to move 34

PAGE 44

particles against the gradient. The sodium-potassium pump found in all animal celli is an example. Secondary active transport uses energy recaptured when allowing sodium ions to move with the gradient (Purves and Orian, 1987) (see Table 3). Osmosis, a passive process not requiring energy, allows passage of water across the cell membrane. This process operates according.to the laws of diffusion, with the direction of .water'movement governed by osmotic as well as pressure Water moves to a greater concentration of solutes to balance 'pressure potential (Purves and Orian, 1987) TABLE 3. Transport mechanisms of vital substances. Substance Glucose ATP-ADP Sodium Sodium/Potassium Calcuim Chloride/ HC03-/other anions Amino acids transporters specific to amino acids Cholic acid Mechanism Passive Antiport can be active Passive Active (ATP driven) Active. (ATP driven) Mediated antiport active: symport with sodium active: symport with sodium Tissues Most tissues Mitochondria of liver Distal Renal plasma membrane All cells Erythrocytes/ many other cells Intestines/ Kidneys/ liver intestines (Adapted from McCance and Huether, 1994, p. 29) 35

PAGE 45

Cold Effects on Cells The effects of cold on the cell reduces the energy of substrate molecules, which can effect enzyme activity. Decreased temperature of water in cells increases its viscosity, which results in the reduction of diffusion rate. Both of these processes reduce the action of membrane-bound ATPase, an enzyme which serves as an ionic pump used toba"lance 'the" sodium and potassium ratio by pumping sodium from the, cell. Should this pump fail, sodium remains in the cell and osmotic influx of water into the cell_follows. 'Subsequent swelling of the cell further Crystallizing of the water during'freezing further increases water influx and resuiti in rupture and cellular death (Zachariassen, 1991). Cellular death during non freezing hypothermia may be caused by inability to move calcium out of the cell. Calcium, a regulatory ion for some enzymes, is normally kept at a low level within the cell. Increased amounts of intracellular calcium may re.ult in a cellular intoxication and eventual cellular death (Zachariassen, 1 991 ) Gradual cooling can trigger problems with microcirculation and reduce cellular communication. Peripheral vasoconstrictive responses to cold can be 36

PAGE 46

followed by a vasomotor paralysis. Paralysis precedes vasodilation and increased membrane permeability which results in cellular and tissue edema. Rapid cooling can result in vasoconstriction and increased blood viscosity, a condition exacerbated by osmolal diuresis occurring .early in cold exposure (Granberg, 1991b). This combination 'of responses reduces protection and may result in ischemic injuries of both infarct and necrosis. Should exposure to freezing temperatures continue, the swelling of tissue can' damage the myelin sheath surrounding peripheral ne'rves and severely compromise-sensory and motor abilities (McCance and Huether, 1990). The resulting reduction in communication and response ability compound the effects of cold on the cell and the system as a whole Homeoviscous Adaptation The ability of the individual cells to adapt to cold temperatures, as well as the organism's corresponding systemic responses, viability. Homeoviscous adaptation takes place in the lipid bilayer of the cell membrane. The mechanisms by which organisms accomplish this form of adaptation include increasing the unsaturation of fatty acid chains of phospholipids, altering the branching and length of fatty acid chains and changing to different polar head groups, and inserting 37

PAGE 47

spacer molecules such as cholesterol (Hadley, 1985). The state of the membrane bilayer is referred to as the phase and the alterations as phase transitions. Phases range from a liquid to a gel to a rigid crystalline state. The phase state of' membrane affects enzyme action and cell metabolism (Steigen and Larsen, 1991). Singer and Nicholson's fluid mosaic model for biological illustrates the construction of the lipid (see Figure 2). The basic component of the bilayer is phospholipid, an ampipathic compound. Looking much'iike'ariold-fashioned clothes pin, the molecule coniains regibris which are hydrophilic with other regions'which are hydrophobic. The hydrophilic heads ofthe molecule carry phosphorus with one or more electric charges. The fatty acid tails, the lipid component, are hydrophobic. The incompatible ends of the molecule form the lipid bilayer of biological membranes by lining up with the nonpolar, hydrophobic 'tails' pack tightly together crea.ting the interior of the membrane. "The phosphorus-containing heads face outward on either side of the membrane, where they interact with the water that is excluded from the interior of the membrane" (Purves and Orian, 1987, p. 64). The bilayer manages to separate the two aqueous regions and stabilize the entire structure of the cell. 38

PAGE 48

Figure 2. Fluid mosaic model for biological membranes. Polysaccharides Transmembrane protein Transmembrane protein HydrophilicJ layer layer "" Hydrophilic layer/" (McCance Heuther, 1994, p.17) (Reprinted by permission)

PAGE 49

Membrane fluidity is measured by the bilayer viscosity or resistance to flow. Normally the bilayer viscosity is that of a lightweight oil used for machinery (Purves and Orian, 1987). However, temperature changes can alter the phase state of membrane lipids. Cold dropping temperatures below a cri.tical phase7""transition temperature (the at which lipid restructuring takes place) can result in transition of the lipid bilayer to a crystalline state. Fatty acid chains or tails are immobilized Permeability of solutes is limited and lateral qiffusion of proteins is ,greatly reduced. High '. temperatures' liquid-crystalline bilayer. The fatty acid tails become very mobile, viscosity is significantly reduced, and the phospholipids remain together only through the noncovalent interaction of the polar groups. critical phase temperatures are not arbitrary and can themselves be altered by the lipid structuring of the bilayer. Research documents the predominant'restructuring of the lipid membrane under cold exposure to be that of increasing the unsaturated lipid (Yeagle, 1990; Hazel and Williams, 1990; Marachev and Lapinski, 1989)., This has been shown in some species to mean the replacing of oleic n-9 by linolenic n-3 (Hazel and Williams, 1990; Smith 1989). The restructuring, 40

PAGE 50

however, is not uniform throughout the body. The disposition of higher concentrations of unsaturated lipids are found in the extremities and subcutaneous fat layer (Hadley, 1985; Draper, Unsaturated lipids are extremely_vulnerable to lipid peroxidation (Leibovitz, et aI, 1990). To. compound that threat to membranes, remnants of peroxidation are damaging to membrane structure 1985). Current research is now '. investigating the possibility that it is the addition of cholesterol into the membranes of humans which protects their structure. during cold exposure and.decreaseS the amount ot vulnerable to perbxidation (Marachev 1989). the lipid bilayer at both low and high may involve addition of cholesterol molecules which interact noncovalently with fatty acid chains to stabilize the bilayer. Cholesterol enters spaces between the phospholipid molecules to maintain the bilayer in an intermediate gel state despite exposure to a wide range of temperatures (Myant,1991). Additionally cholesterol enhances the ordered state of lipid molecules within the membrane. It is this ordered but fluid state which allows the lipids to form separate functional compartments within the cell and moderate communication and metabolism (Gunstone; Harwood and 41

PAGE 51

Padley, 1986). Increasing cholester61, while protecting structure, reduces membrane, permeability (Hadley, 1985). The placement of cholesterol in the cell membrane is asymmetrical resulting in areas varying in viscosity (Schroeder and Nemecz, 1990; Gordon and Mobley, 1984; 1990). Exposure to'low stimulates the aggregation of membrane proteins into cholesterol-poor domains, while cholesterol laden microvesicies cluster to create cholesterol-rich domains. This partitioning appears t6 be against 'cold induced hypertonic (Gciidcinand 1990). Cell membrane elastlcity:and strength are enhanced (Needham and Nunn, 1990)' without '="dramatically altering lateral diffusion of membrane components" (Yeagle, 1990, p.' 119). Although the time frame in, which the protective partitioning takes place is not known, research does show that erythroctyes given some exposure to moderate cold had time to restructure lipid domains, while sudden exposure to severe with the ability to do so (Gordon and Mobley, 1984). Further research is needed in this area. Lipid Peroxidation While some researchers question whether the restructuring with cholesterol for microviscosity control is the explanation for the cholesterol requirement in 42

PAGE 52

mammalian cells (Yeagle, 1990) others have investigated the possibility that it is protective against the threat of lipid peroxidation increased during cold exposure, not the cold itself (Marachev and Lapinski, 1989). Russian scientists studying this question frame their work within the concept of adaptation. These researchers, using V. P. Kaznacheev's theory of 'Polar stress Syndrome' (Soinine'n,personal communication, September, 1992) reaction to cold which leads toexcessprodtiction of cat echola mines, increased unsaturatedatty acids in the membrane lipids, and high levels of lipid peroxidation active catabolism (Lapinski and Etlis, 1988). Lipid peroxidation is a step in b-oxidation or principaloxdation route of fatty acids for theprodu.ction of ATP (Hadley, 1985). This creates an oxidative stress, whichis "the cytotoxic of oxygen radicals--superoxide anion (02-), hydroxy radical (OH), and peroxide (H202)--which are generated as normal and aberrant metabolic process that utilize molecular oxygen (02)" (Coyle and Puttfarcken, 1993, p. 689). Cellular structure and function can be disrupted when theoxygentadicals interact with cell membrane lipids, cross-linking the fatty acids. The oxygen radicals can also attack deoxynucleic acids and proteins to damage tissue (Coyle 43

PAGE 53

and Puttfarcken, 1993). Population Research Research has compared the liver function of indigenous peoples of Noril'sk, well above the Arctic Circle in Russia, with that of migrant workers from Novosibirsk who trarisferred to Norik'sk for varying lengths of time (Gichev, 1990). This study documents an increase of serum cholesterol accompanied by large increases in esterfying the liver. Serum cholesterol continues to increase with stays in the north. Lipid peroxidati'on also increases while the level of antioxidants decreases. The indigenous popluation, however," shows pebuliarities in lipid metabolism, with higher serum cholesterol levels than early migrants, as well as higher antioxidant levels. The researchers interpret this finding to indicate that less peroxidation is taking place in the indigenous population. This population also registers a lower incidence of atherosclerosis and ischemic heart disease. Gichev (1990) offers the following senario as an explanation of the some of the findings: 1) exposure to cold climate 2) increase in lipid perbxidation 3) threat of of membranous structures 4) increase of cholesterol concentration in membranes 5) increased de"nsi ty Qfmembranes and decrease of their permeability 6) inihibition of hepatocyte excretion 7) increase bilirubin in the blood 44

PAGE 54

Another line of research in Russia examined the erythrocytes drawn from immigrants to the north above Magadan. This research documents increased oxidation hemolysis of erythrocytes of new immigrants and a correlation of decreased hemolysis as the membrane cholesterol content increased. The researchers suggest that cholesterol obstructs lipid peroxidation activation and. subsequent destruction of the cell membrane (Lapinski and Etlis, 1988). Further.research compared the erythrocytes of immigrants above. Magadan with those of the.Chukchi, an indigenous population of the northern area and lifetime Caucasian Russian residents of the area. Findings noted elevated levels of cholesterol .in the membranes of the Chukchi, as well as the older Russian residents. The early immigrants demonstrated an increasing level of unsaturated fats in the membrane during their early exposure to the cold region. The researchers attributed the increase of unsaturated fats to homeoviscous adaptation, noting that this increased the membrane vulnerability to lipid peroxidation. This study further reinforced the idea that the alternative role of cholesterol as a protection against destruction, not in the maintenance of viscosity (Marachev and Lapinski, 1989) 45

PAGE 55

Discussion Whether this protective concept of cholesterol addition to cell membranes to protect against peroxidation elevation during cold exposure falls under the cloak of 'homeoviscous is not clear. However, the Russian research offers a framework for further investigation into the That an increase of unsaturated lipids is found in the cell membranes of such spe.cies such as fish and sea mammal exposed to cold environment is known. That this homeoviscous adaptation maintains membrane bilayer viscosity is generally That this cold adaptation impacts a biome'sfood chain and the humans who consume a diet of those organisms is accepted (Draper, 1980). That species who consume the blubber of sea mammals show dramatic drops in serum cholesterol is documented and currently under investigation (Folk, personal. communication, June, 1993). How or why the serum cholesterol drop occurs is, however, unexplained. Much research is now being done in the area of nutrition as to the effects of diets high in fish oils and omega-3, however, no research investigates the relationship of diet and human cell membrane lipids. Research documenting the relationship of homeoviscous adaptation to the human hypothermic response to cold 46

PAGE 56

or elevated serum cholesterol has not been done. Investigatiqn into the action of erythrocytes in both cholesterol-rich and cholesterol-poor mediums during cold exposure might add a new perspective to the study of human cold adaptation. Research does show that erythrocytes with low membrane cholesterol readily lyse when exposed to cold (Yeagle, 1990). This information in itself should stimulate further investigation, yet temperature-based studies investigating the role of cholesterol in humans under cold stress do not exist outside Russia. The difficulty of translation, the lack of availability in the United states of documented references, and the danger of extrapolating from research studies in the United states t6 Russian research data are justa few of the difficulties in attempting to understand this issue. The Russian evidence is,not conclusive, but the proposal of the protective function of cholesterol is definitely provocative However, the function of elevated serum cholesterol remains unanswered. While the immediate response might be that the elevation serves to increase the needed supply for ready use, that response may dispel the explanation of some genetic programming which results in hypercholesterolemia. That condition centers around defective uptake of cholesterol into the cells. To 47

PAGE 57

further investigate the issue of elevated serum cholesterol in cold exposure, a chapter investigating the properties, transportation and oxidation of cholesterol follows. 48

PAGE 58

CHAPTER 4 CHOLESTEROL Cholesterol, a bile acid alcohol, was first identified in 1789 by the chemist, A. F. Fourcroy. However, it was not named u-ntil'1853, when M. Berthelot found the compound to be an alcohol (Asimov, 1992). While the basic component of most lipids, such as triglycerides and phosphlipids" is fatty acids, cholesterol contains none. Its steroid nucleus is synthesize' d from. fatty acid by-products (molecules of acetyl-CoA) which gives it properties similar to those of other lipids (Guyton, 1991). The sterol cholesterol is a vital precursor to all steroid hormones secreted by the adrenal cortex and sexual glands. It is a large component of the myelin sheath of the nervous system (Myant, 1991). It is a necessary part in the corneum of the skin where it resists absorption'of water soluble substances and some chemical agent action, as well as prevents water evaporation through the skin. It is also a vital component of bile salts which facilitate absorption and digestion of the dietary fat and an integral lipid of the cell membranes 49

PAGE 59

(Guyton, 1991). Furthermore, cholesterol plays a role in cell growth, biosynthesis of phospholipids, DNA synthesis, RNA synthesis and protein synthesis (Yeagle, 1990) Cholesterol may be obtained through dietary intake, however, it is so vital to cellular function that virtually every cell in the body can manufacture it. Approximately half of the body's source of cholesterol is dietary, while half is manufactured by the body (Bishop and Waldholz, 1990). Both the body as a whole and the cell as a unit operate on a negative feedback system, decreasing endogenous manufacture when exogenous sources suffice. The average adult human body contains approximately 1 gram of cholesterol per kilogram of body weight (Myant, 1991), with 71 in the plasma and 93% distributed throughout the body (Ganong, 1991). Approximately 20-30% of serum cholesterol is free cholesterol, the remainder is esterfied (Lenther, 1984). Transport and Metabolism Dietary cholesterol is emulsified by bile to facilitate absorption by the small intestine (Miller and Keane, 1978). From the small intestine it is "secreted into the intestinal lymphatics and thence, into the bloodstream, as a component of large, 50

PAGE 60

Figure 3. Cholesterol transport system J Hh \-51

PAGE 61

fat-enriched called chylomicrons" (Myant, 1991, p. 411). Upon entering the bloodstream, lipoprotein lipase degrades the chylomicrons into remnants. Left rich with cholesterol, these are virtually fat free' (Myant,' 1991). The remnants then transport the dietary cholesterol ,to the liver where it is further degraded. 'Some is returned to' the intestine as bile, some from the body, and some recycled, to the liver (see Figure 3). 'Cholesterol not used in bile is transported around the body for general usage. The eridogenous pathway for cholesterol transport originates in -the liver. 'This transport system consists of lipoproteins responsible for carrying cholesterol to the cells. They include VLDL (very low density lipoproteins) secreted from the liver as a triglyceride-rich particle and IDL (intermediate-density lipoproteins), the particle left after triglycerides have 'been removed from VLDLthroughthe action of lipoprotein lipase (enzyme attached to the luminal surface of capillaries). Additionally, LDL (low density lipoprotein) carries about 75% of all the cholesterol in the blood (Moore, 1989) and is created from the remnants of degraded'action and cholesterol esters transferred from HDL. HDL (high density lipoprotein moves cholesterol out of the cells to recirculate it 52

PAGE 62

Table 4. APOLIPOTROTEINS Apolipoprote:iI'i" Synonym. Synthesis Function Apo-A I ApoHDL III Cofactor Liver for LCAT Apo-A II Apo IV lntestine Cofactor Liver lipoprotein lipase Apo-B .ApoLDL Liver (B1 00) Binding Intestine (B48) protein for cell receptors Apo-C I .......... ApoVLDL Liver Cofactor lipoprotein .. .." lipase "II .... ApoVLDL e" Li ver .......... .. Apo-C III ApoVLDL Li ver ? Apo-D Apo-A III ? Possible cholesterol exchange ester Apo-E ......... .............. Liver ........ Binding protein cell receptors Apo-F -._ .... .; .............. ....... ? e possible Table 5. CHOLESTEROL PERCENTAGE Lipoprotein Class Cholesterol Ester VLDL LDL HDL2 HDL3 12-14% 35-40% 8-10% 7-9% 1-2.5% inhibitor of lipoprotein lipase Cholesterol Free 6-8% 7-9% 5-7% 4-6% 0.5-1% (Table 4 and 5 adapted from Lenther, 1984, p. 117) 53

PAGE 63

or return it to the liver (Ganong, 1991; Myant, 1991; and Guyton, 1991). HDL is thought to be able to absorb cholesterol which has deposited in the arterial wall, transferring it to IDL and LDL for passage back to the liver (Guyton, 1991). The protein components which constitute a portion of these transport particles are apoproteins. The include apo-A-1 (Aalto-Setala et al., 1991) apo-E, apo-C and apo-B which has. two forms. One form is apo-B-4B, of low molecular weight associated with the exogenous transport system, and apo-B-100, of high molecular weight associated with the endogenous lipid transport system (Ganong,1991). Varying polymorphisms of apolipoprotein E correlate to serum cholesterol levels. The presence of e4 allele correlates to higher serum cholesterol while e 2 allele correlates to lower serum cholesterol (Boudreau, et al., 1993). ApO-A-1, the main protein of HDL, is a cofactor with an enzyme responsible for converting cholesterol to the cholesterol esters. Apo-B is vital to cholesterol homeostasis. It is not only necessary for construction of chylomicrons in the intestine and VLDL in the liver, it also serves as the ligand facilitating identification of the LDL transporter by the LDL receptor (Aalto-Setala et al., 1991). Ligand is defined as "an ion or 54

PAGE 64

molecule that reacts to form a compl,ex with another molecule (Miller and Keane, 1978). Apo-E appears to be associated with chylomicron remnants, facilitating their rapid removal from the bloodstream (Myant, 1991) and acts as another ligand for the LDLreceptor. Several of cholesterol contribute to the transport system. First, cholesterol is not soluble in water' and '-therefore is not easily mobilized. Second, it a strong teridency toeichange passively between in the and cell membranes. Therefore, first esterfy the sterol by-removing water molecules and replacing them with long-chain fatty acids. The newly formed esters are then sequestered within a lipoprotein core which is too hydrophobic to pass through the cell membranes. To achieve cell uptake of the cholesterol ester the LDL binds at an LDL receptor site and is transported into the cell frtterior through endocytosis. The LDL is then delivered-to the lysosome which hydrolyzes the esters and free cholesterol for use in the cell (Brown and Goldstein, Myant, 1991). Many factors affect the LDL receptor and serum cholesterol. High availability of exogenous cholesterol decreases manufacture of the LDL receptor, while elevated thyroid hormone's increase the number of LDL receptors 55

PAGE 65

(Ganong, 1991). The plasma level of cholesterol decreases prior to elevation in metabolism, and appears "independent of stimulation of 02 consumption" (Ganong, 1991, p. 288). Estrogens lower LDL and elevate HDL. untreated diabetes elevates serum cholesterol. Exercise and moderate alcohol intake also elevate HDL, while smoking, obesity and sedentary life styles are know to lower it (Ganong, 1991). Genetic mutations of LDL receptors are found in some familial (Kontula, 1991; Ganong; 1991) and in the face of malfunctioning LDL receptors, cells synthesize their'own cholesterol (Myant, 1991). Additionally, research is showing a 'decrease in size of HDL particles in some patients with genetically caused LDL receptor malfunction. This decrease in HDL size is thought by some researchers to be an adaptive response in order to increase the intracellular pool of cholesterol. Cholesterol Oxidation Cholesterol is a very labile substance and in its crystalline form can undergo spontaneous oxidation in air. Metabolism of cholesterol is accomplished through molecular oxidation, both by enzymic and nonenzymic reactions. The nonenzymatic, or auto oxidation, is believed to be uncatalyzed oxidation. However, in animal tissue, iron or another transition metal ion'is thought 56

PAGE 66

to be necessary as a catalyst. The products of oxidation are oxysterols believed to be regulatory agents of sterol biosynthesis and possible moderators of plasma membrane permeability, function and stability. Lipid peroxidation, low level atmospheric ozone, and certain foods (such as powdered eggs and milk) are other sources of cholesterol oxides (R. Smith, 1989; L. Smith, 1992). Cholesterol oxides may displace cholesterol in cell membranes. When tpisoccurs in erythrocytes, the cell may be transformed into a spiny-shaped cell called an echinocyte. Changes, in. cell shape may take place within 2 minutes. of exposu,re to the oxide. Active lipoproteins can accept cholesterol oxides and their detrimental effects on the cell impeded, although not totally abolished (L. Smith, 1992; Peng and Morin, 1992). The oxides are implicated in alteration ofLDL, either by free radical-induced peroxidation or by oxidation with cholesterol oxidase. Both this modified LDL and cholesterol oxides are toxic to vascular walls. '. Pure cholesterol and unalteredLDL, however, do not appear to have similar damaging effects (L. Smith, 1992; Peng and Morin, 1992). The presence of cholesterol oxides in the cell membranes greatly inhibits cholesterol biosynthesis in biomembranes. Modification of cell membranes by the 57

PAGE 67

oxides alters fluidity, enzyme function, transport abilities and cell proliferation (Peng and Morin, 1992). Animal study investigation into the toxic effects of cholesterol oxides documented adrenal gland hypertrophy associated adrenocortical function insufficiency, reduced serum cholesterol levels and reduced biosynthesis. Other effects noted were loss of appetite and body weight, lethargy, growth retardation, and organ atrophy (Peng and .Morin, 1992). Other fats and lipids .Cholesterol and its oxides are not the only lipids which affect the. body and serum cholesterol. Triglyceridesare considered simple fats, identified by the number of double bonds in their carbon chains. They may be used as a source of fuel and are the main form for the storage of energy. These fatty acids come in saturated and unsaturated forms. A saturated fat contains no unsaturated bonds or doublebonds in its hydrocarbon tails. MOnounsaturated fats such as oleic acid contain only one carbon-carbon double bond, while polyunsaturated fats contain fatty acid chains with two or more. Their form is an oily liquid. Three fatty acid molecules combine with one glycerol to make one molecule of triglyceride (Purves and Orian, 1987; R. smith, 1989). By replacing one of the fatty acids with 58

PAGE 68

certain ,phosphorus-containing compounds, a phospholipid is formed (Purves and Orians, 1987). The transport system used to deliver cholesterol around the body is used to transport these other fats to their (Bishop and Waldholz, 1990). Monounsaturated fats are manufactured by the body as well as ingested. They can be found in all lipid containing foods, both of animal and vegetable origin. Olive oil is an excellent source. They are not a :.: :. for prostaglandin production, nor are they converted into other fatty acids. And, monounsaturated fats are reporte be. more, effective at lowering serum cholesterol than polyunsaturated fats JR. smith, 1989). Polyunsaturated fatty acids are divided into several groups. They include n-3 linolenic family, the n-6 linoleic family, the n-9 oleic family, and the n-7 palmitoleic family. These acids are precursors to polyunsaturated fats. Linoleic and linolenic acids cannot be synthesized in the body, and are therefore considered essential. They must be secured by diet (Hadley, 1986). Naturally occurring polyunsaturated fats are found in a specific configuration called a cis configuration. Partial hydrogenation transforms this configuration into a trans form which gives the fats a higher melting point. (A noted example of trans fat is margarine.) The 59

PAGE 69

incorporation of trans into cell membranes alters their permeability. swelled and ruptured more easily when trans fat was present in their membranes (R. Smith, 1989). Polyunsaturated acids are used for structural components and as precursors in the manufacture of chemical mediators, prostaglandins. These prostaglandins modify the actions of hormones, blood clotting, and regulate smooth muscle tone. While the prostaglandins produced by both n-6 and n-3 reduce platelet aggregation and blood clotting, n-6 also produces a platelet aggregator as well (R; Smith, 1989). N-6 is associated with an increased inflammatory response, while the n-3 the injury-response mechanism (Boudreau et al., 1993). The phenomenon of lowering serum cholesterol by ingestion of both n-3 and is widely documented, however, no mechanism has been documented (R. Smith, 1989; Folk, personal communication, June, 1 993) The Structural Antioxidant During cold stress the cell membrane's lipid bilayer protects itself by restructuring the lipid bilayer with more unsaturated phospholipids in the process of homeoviscous adaptation. Lipid peroxidation is also increased with cold exposure. restructuring has 60

PAGE 70

increased membrane vulnerability to destruction by peroxidation, as the process of peroxisomal b-oxidation involves catabolism of long-chain fatty acids (Hadley, 1985). The peroxiaation increases accessibility of lipid and protein components of the membranes to phospholipases and proteases, digestive enzymes which hydrolyze pholpholipids and proteins -(Stepanyan and Simonyan, 1990). Russian researchers now suggest that lipid peroxidation acts as a triggering mechanism of an adaptive modification of the cell membrane. Their scenario posits that initial-exposure to cold leads to activation of the adrenal system stimulating-intensification of lipid peroxidation, development of relative 'hypercorticism' which facilitates the switch of energy metabolism from carbohydrate to lipid and the restructuring of cell membranes with more cholesterol to protect them (Marachev and Lapinski, 1989). The apolipoproteins are thought to provide-the transport of the corticoids to cell, apo-B competing same receptor used by insulin (Panin, Biushkina, and Polyakov, Panin, personal communication, June, 1993). The cholesterol added to the cell membrane is believed to be a 'structural antioxidant' (Marachev and Lapinski, 1989). Discussion Both homeoviscous adaptation and the 'structural 61

PAGE 71

antioxidant' theories offer explanations for the_role of cholesterol during times of exposure to cold stress. As they both involve use in the cell membrane, they do not explain elevation in serum cholesterol. It would appear that excess Use of cholesterol would result in decreasing circulating cholesterol. Russian researchers, as an aside, state that the elevation of cell membrane cholesterol was found despite normal serum cholesterol, no research exploring this matter has been done. As increased membrane ratios-of cholesterol decrease membrane permeability, the uptake of serum cholesterol might be decreased, but to what effect on serum cholesterol is unknown. As the initial movement of homeoviscous adaptation in cold is increasing phospholipids, is it possible that cholesterol is moved out into the serum, thus creating the documented seasonal rise? No research answers this question. As cholesterol and triglycerides are by the same transport system, is cholesterol just along for the ride the triglycerides are mobilized for fuel? No research answers these questions. To complicate matters, over a dozen genes affect cholesterol and fat transport (Bishop and Waldholz, 1990). The possibilities for mutations is great and unless the mutations present problems, they may not be identified. 62

PAGE 72

Cholesterol has widely varied uses in the body. It is the precursor to many stress and sex hormones, a vital structural component of the body's cells, and necessary to the synthesis of many substances. The human body has developed an effective of reabsorption and retention to maintain adequate levels of this sterol. These mechanisms to retain cholesterol in the body are genetically determined, that .the ability to conserve at time necessary process during human' 'evolution -( Crews and James, 1991). The question remairis 'whether of living in cold clima'tes can be con'strued :as an adaptive force for the selection of individuals with greater ability to maintain high levels of cholesterol. 63

PAGE 73

CHAPTER 5 ADAPTATION The investigation of a physiological trait in terms of adaptation places the researcher in a sea of semantics, a maze of genetics, and a never ending complexity of biocultural possibilities when assessing variables That humans manage to survive in a vast range of environments is obvious. That there is noticeable diversity among humans is also evident. The manner in which adaptation to the environment affects human variation becomes the focus of the search. To many, adaptation is defined as both a dynamic process and an end product. The process is one of adjustment of a species to a specific environment and encourages the conclusion.that the end product, "a given trait, whether structural, physiological, or behavioral, is the product of the process of natural selection and thus favors the of the genotype responsible for this trait" (Mayr, 1988, p. 52). To the anthropologist, adaptation serves as a framework for the study of evolution as well as the 64

PAGE 74

explanations of phenotypic and genotypic variation found within the human species.-It encourqges investigation of a -phenomenon not only in terms of how'or what; but also why. It defines the search by asking, 'What is the function? I The study of, while assigning a directional intention to natural selection, must also accept that is Indi vidua-ls survived because they had' :1.nheri ted a "combination of characteristics tha:t favored them under the constellation c;;f environmental conditioris which they encountered during their lifetime" jMayr,' {988, p. 96}. Furthermore, while the study of in_(lividual traits appears to be the focus, the fact remains that it is the manner in' which that trait supports the entire genotype that determines its success. It is the entire ,package, the genotype, which ,survives (Mayr, 1988'). To explore,adaptation is to consider that selective advantages may be responslbie'for-the variations we see 'today. To choose the adaptation framework is to attempt to "turn mere chronicles of past events into historical explanations II (Lewontin, 1982, p. 146) and to explain physiological phenomenon within that historical evolution narrative (Mayr, 1988). To do so is to propose that ongoing changes in an 65

PAGE 75

environmental system maintain a causal relationship with the hpman system (Lewontin, 1982). To address the causal relationship of an environment to a physiological both issues of proximate and ultimate causes. The proximate causes, seen as functional components, govern an individual's responses to his immediate. environmental situation. The ultimate causes are those which during .the evolution of a species are responsible for the DNA information which becomes part of a species programming (Mayr, 1988). While a proximate cause of elevation of serum cholesterol might be the cold weather, the ultimate cause may be in cell construction and growth .. The first requires the functional explanation, the other an historical one. The questions become what is the function of elevated cholesterol in the face of cold weather, and why does the mammal exhibit higher cholesterol levels .than fish? While the second issue may be touched upon only in the description of cholesterol uses in the body, it is the first question which remains at the forefront of this paper. Factors Affecting Selection Human beings are complex biological organisms operating to maintain homeostasis. Individuals require a system of feedback and internal communication to respond 66

PAGE 76

to informational input from their surroundings. As the environment constantly challenges survival, adaptation is a never ending process. Adjustments may be reversible or permanent, depending not only upon the length and intensity of exposure to the challenge, but also to the developmental state at which .the individual is exposed (Frisancho, 1981; Lewontin, 1982). The range of physiological responses available to individuals for adaptation may be .under environmental and/or genetic influence. As selection requires at least several generations, selected traits may have a lag time. The adjustment may appear well after the exposure to the environmental forceand thus be anachronistic within the context of current environment (Dawkins, 1982). Traits selected under certain circumstances may become obsolete and even detrimental under new environmental conditions. Simplistic cause and effect or environmental determinism cannot be applied to the appearance of individual traits. Many variables determine the expression of genes and random forces may direct, with serendipitous results, which genotypes actually reproduce. Genetic selection operates within constraints. It is supject to an existing gene pool and its variations, the cohesion of the genotype (in which too many sudden 67

PAGE 77

changes may be incompatible with life), and limits of the Bauplan (morphotype) itself (Mayr, Due to variation of material within populations, similar environmental forces may lead to the selection of different traits as well as differential expression of similar traits (Lewontin, 1982; Woodward, 1992). Forces effecting the gene pool and selection within populations are mutation, or alteration of the genetic information, migration and genetic drift, founder effect, and differential survival (Dobzhansky, 1962; Lewontin, 1982; Woodward, 1992). The operation of these forces is bften by the population size and history of interac'tion with or isolation from other populations and environments These forces are relevant to this paper when tracking the migration,'social history and disease history of' a population. Investigating the relationship of human beings to their environments presents many difficulties. Not only has the norm of reaction for any genotype not been established across differing environments, but .humans are also in continuous developmental transformation through' their lifetimes. Traits which are beneficial early in life may become detrimental with age and functional change of physiological requirements. Additionally, a simple biological model alone is 68

PAGE 78

insufficient due to the impact of cultural and social environments which also influence development of a phenotype (Lewontin, 1982). Coevolution The working relationship which exists between culture and genes impacts human diversity. The theory of 'coevolution' offers clarification of the ways in which culture and genes affect each other. The five modes of interaction genetid mediation, cultural mediation, enhancement, neutrality, and opposition (Durham, 1991). The first two 'demonstrate an interactive relationship between genotypes and allomemes, the chosen term for traits of culture or 'guides to behavior' available for selection. Allomemes include marriage customs, differing sUbsistence approaches within an ecosystem, sexual taboos, and variable work and label definitions (Durham, 1991). Genotypes.and allomemes influence each other. They also affect a trait's quality as a tool of survival and the selection of traits which are passed on to future generations. Genetic mediation is said to occur when cultural allomemes vary as a function of genotype differences, a genetic cause of cultural change. Neural coding of color vision and subsequent color term definitions are an example. Cultural mediation occurs when-'cultural practices impact 69

PAGE 79

genetic selection. An example would be the impact of agricultural practices which enhanced habitat of malaria-carrying mosquitoes, in turn encouraging the selection of the human sickle cell trait (Durham, 1991). The other coevolutionary modes of enhancement, neutrality and opposition attempt to explain the directional impact which cultural allomemes can have on genotypes. In accordance with Cavalli-Sforza's (1971) ideas of population genetics, 'Durham sees the impact of ctiltural on genetic selection as enhancing, which increases survival and' reproduction; neutral, with no significant impact in either direction; and opposing, in which cultural practices may impede fitness and adaptation, thus survival. Enhancement produces traits. which rriight be similar to those of natural selection, while opposition produces phenotypic properties different than those evolving through natural selection. Incest taboos are seen as enhancing, while ritual practices such as infibulation and foot binding, as well as traditions supporting addictions and population control are seen as oppositional (Durham, 1991). as a Multi-Modal Activity Both human biological and cultural adaptation use a variety of modes of responses. They include processes 70

PAGE 80

which do not act in isolation, but work in conjunction with each other to produce the behavior by which humans adapt (Toulmin, 1983). Four distinct modes of adaptation include: 'rational adaptation' the conscious choice-making between alternatives based on calculation of outcome; 'homeostatic' or 'feedback adapt_ation,' consisting of functional responses to maintain a steady state in biological, psychological, or social economic realm; 'maturational adaptation' which -develops during a lifetime, and involves the abilities of effective coping and interdependent living; and _'evolutionary' or 'selective adaptati-on' where _"novel features, which first appear without conscious foresight and subsequently establish themselves selectively, as being fitter or apter to ,the novel conditions than their predecessors and rivals" (Toulmin, 1983, p. 22) become part of the generational information. An excellent example which illustrates the interaction of adaptation modes to the ultimate impact on a physiological trait is Jared Diamond's historical tracing of the genetic heritage of African-Americans. Diamond weaves both genetic and cultural adaptations, from the peoples' original physiological adaptations in Africa, to those stresses encountered during capture 71

PAGE 81

and delivery to America as slaves, the selection forces met during years of slavery, to the current trend of hypertension. He builds a case forthe sensitivity to disease and migratory history, while illustrating the interplay physiological, social, technical and economic adaptation of several populations (Diamond, These modes of adaptation apply to biological, psychological, social and cultural processes. And as they to impact each other not only currently, ,but becomes no easy task to isolate the variables which affect a physiological trait. It t is therefore necessary to examine several theoretical concepts which will make the study more manageable. Models for study An inclusive model to investigate adaptation is proposed by Rada Dyson-Hudson (1983). Attempting to unify biocultura' l adaptation studies based on Darwinian theory, the interactive model incorporates historical information from both the immediate and past environments and genetic information which influences the genotype (morphology, physiology, and behavior), all which interact to produce the phenotypic trait (see Figure 4). A list of parameters against which to measure arguments for an adaptive explanation guide the researcher. These rules require that the proposed 72

PAGE 82

Figure 4. Dyson-Hud$on's model Information from Immediate Environment I \j/ Historical information of past environments encountered Genetic Information Morphological ) Physiological Behavioral ------Program ---Morphological Physiological trait Behavioral ,.."." (Adapted from Dyson-Hudson, 1983, p. 9)

PAGE 83

adaptive trait be a unit subject to natural selection, inheritable, that it contribute to reproductive success or inclusive "fitness, be strong enough to effect a modification-within an appropriate time span, and defined within the context of a certain environment (Dyson-Hudson, 1983). The allow for the possibility that a characteristic develop new functions during the evolutionarY"history of the species. They encourage addressing .lternative adaptations used by other organisms within the -same niche and-applying an adaptive trait only totne level of organism to which it can be attributed by evidence (Dyson-Hudson, 1983). The arena against which development of the trait is examined can be refined. An ecological approach structures the environment into biomes, which can be further reduced to areas of stressors effecting adaptation. The components of the biome include the 'biotic' such as_available food and materials, predators, vectors, and pathogens; the 'abiotic,' composed of climate, inorganic materials and energy; and the cultural or social organization, technologies and ideologies. All of these factors influence human beings as a group, as an individual, and at the cellular level (McElroy, and Townsend, 1989). All elements of ,an environment 74

PAGE 84

are potential sources for stressors which may require adaptive responses. Today more than ever the cultural.element itself becomes a powerful stressor. The impact of cross exposure is great, but today's effects are now more rapid and dramatic. Migration of groups.by airlift from one part of the worldtoanother.has led to the engulfing of indigenous populations and exposing populations to giant steps in technology within days. "One of themost devastating effects of thehealthof a population is rapid and irrevocable change in a people's way of life" (McElroy and Townsend, 1989, p. 292). The impact of cultural contact can be defined in several ways: diffusion, acculturation, assimilation and ethnic revitalization. Diffusion, or the selective borrowing of ideas perceived as useful or attractive, can impact a society. For example, use of tobacco, imported foods, and even borrowed technology such as snowmobiles may carry high risks by altering life style and nutrition. or the continuous intense contact between two cultures, involves not only changes in life style and diet, but also involves major political and economic changes which impact self-image and control. Assimilation results in one group fully integrating itself into another cultural structure. Adoption of the new 75

PAGE 85

life style puts the assimilated population at risk for the adopted cUlture's disease profile. The last concept is ethnic revitalization. It involves the reclaiming of ethnic identity and restoring of personal equilibrium. Its impact ,on health is achieved by .intentional selection of criltural strengths and deselect ion of harmful practices (McElroy and Townsend,. 1989). These levels of from cross cultural contact may be seen ona continuum, as there is diversity within each population which may govern.the degree to which an individual becomes involved with another culture (McEl;:oy and Townsend, 1989). BU.t, whether the stressor originates .in the physical or cultural environment, it will carry the potential of triggering a stress response. stress Responses Han Selye's general ada:ptation syndrome to stress illustrates steps which an individual takes to cope with a stressor. first. is thaidentification or perception that the stressor is a threat. step two is mobilization for defense, as the body attempts to resist or adjust to the stressor. The outcome of the process may result in one of three types of adaptation: successful adaptation and the re-establishment of a balance or higher level of functioning; maladaptation or strain, in which the process to adapt is unsuccessful, resulting 76

PAGE 86

in exhaustion, illness or death; and initial adaptation with delayed strain, in which the outcome achieves a balance for a period of time, but a -price to the body manifests itself at a later time (McElroy and Townsend, 1989; Ornstein and Sobel, 1987). Such a price might be in the increase of liver failure seen in migrants to the northern regions as Uleir body increases cholesterol manufacture due to the increased demand to meet the cold stressor (Gichev, 199.0). The levels of adaptive behavior employed depepd on the success of each previous attempt. The most rapidly deployed response to the environmental stressor is cultural. When it is cold, humans build shelters and control internal environments, select clothing as needed, and find nutrition in a variety of plants and animais sources. The specifics of these choices have been learned within the context of a particular tradition. The physiological responses are initiated next (or simultaneously with cultural behaviors) and depend again on severity and length of exposure, as well as the success of the cultural behavior. The repetition of exposure to a stressor also affects the intensity of recognition as well as activated response (habituatiori) (Frisancho, 1981). The slowest and least understood of all adaptive responses is genetic selection. 77

PAGE 87

stress Responses Physiology defines adaptation as lithe phenotypic plasticity that permits o -rganisms to mold their form to prevailing circumstances during ontogeny II (Durham, 1991, p. 14). ,Physiological changes are included under .the categoryoffunctional adaptation (Frisancho, 1981; McElroy and Townsend, 1989). The level includes the components of morphology, body composition, '. and anatomical .relationships,> well as organic systems at a and structural or ,cellular level (Frisancho, 198,1). Regulatory adaptations occur to maintain the bf in ralation to its environment or develop as change within an organism occurs dl.lr:i.ng J::esponse to the environment (Moran, 1982). The internal. stability of artorganisIn is termed homeostasis. Homeostasis of ,human biological systems must be within a narrow range of values, monitored by a feedback system. This control system operates in a manner, constantly returning the organism to its required internal operating range. It detects informa'tion by way of. receptors and ini tia tes responses through stimulating effectors. Receptors monitor such variables as temperature, chemical balance and arterial pressures. Effectors include cellular membrane proteins to maintain ion pumps for maintenance 78

PAGE 88

of fluid and electrolytes and muscles to control vasoconstriction and shivering (Purves and Orians, 1987). All systems operate to maintain a equilibrium with the organism's environment. The general physiological stress reactions which correlate to Selye's general adaptation theory are initiated in a hierarchy of responses. With the first exposure to the stressor, the sympathetic nervous system stimulates the adrenal medulla to increase the secretion of the neurotransmitters, epinephrine and norepinephrine. These catecholamines directly stimulate the heart to increase its rate and the peripheral blood vessels to constrict thus shunting blood away from the and skin to the heart and muscles. Should exposure to the stressor continue, the general adaptation syndrome is activated. The pituitary gland is stimulated to release ACTH (adrenocorticotropic hormone) into the blood stream. This hormone stimulates the release. of mineralocorticoids and glucocorticoids, other 'stress'hormones (Ornstein and Sobel, 1987). Mineralocorticoids desoxycorticosterone and corticosterone) affect fluid and electrolyte balance within the body (Miller and Keane, 1978). Aldosterone, the principle hormone of this group, is responsible for the maintenance of sodium and potassium 79

PAGE 89

levels of the Sodium, the chief electrolyte of extracellular fluid, is instrumental to the function of cell membranes and excitability of muscle and nerve tissue (Kapit, Macey, and Meisami, 1987). Glucocorticoids (cortisol, cortisone, and corticosterone) affect gluconeogenesis. They influence metabolism, promote mobilization of fat stores, and promote amino acids usage not only to stimulate the liver's gluconeogenesis, but also to cellular damage and increase tissue resistance in the face of trauma (Miller and Keane, 1978 ) Cortisol is vital to the promotion of metaboli9 adaptation by ", 1 : ( ; :.' . .' stimulating release and mobilization of nutrients for energy and repair. Cortisol must be present for catecholamines to affect vasoconstriction and for stimulation of other hormones to achieve lipolysis of adipose Macey and Meisami, 1987). .1'... The call to action mobilizes energy arid activates protective mechanisms to support the body during the 'fight or flight' response. Cholesterol is a vital precursor to many of the stress hormones which stimulate and regulate the various responses within the body. And cold is a stressor which activates the stress response. 80

PAGE 90

The study of Adaptation The study of adaptation represents a multi-level investigation. It involves input from sociology, psychology, biology, microbiology, chronobiology, physiology, genetics, and anthropology. Although R. Dyson-Hudson has accused of treating morphology, physiology and behavior as if "they represent different phenomena" (Dysori-Hudsori, 1983, p. xii), current attempts tend to view genetic, functional, and cultural/technical adjustments on a continuum, working together to produce observable effects of adaptation. The purpose of inve'stigating human adaptation is "not oriented to determining biological cultural differences among populations; the goal is to identify the sources or causes that resulted in such adaptation and differences" (Frisancho, 1981, pg. 8). The operationalizing of studies across disciplinary lines presents some Research does not always investigate adaptation with standardized concepts by which process and outcome.may be identified and measured. Thus, comparing and contrasting studies is often In the study of cold adaptation, several terms appear consistently. Genetic adaptation, seen as descent with modification, implies evolution and natural selection of characteristics which favor survival 81

PAGE 91

under specific conditions (Folk, 1966; Frisancho, 1981; Halfpenny and Ozanne, 1989). Acclimatization encompasses adaptations made under natural conditions, in natural environments. It involves changes wi thin the o 'rganism during brief exposures to cold conditions, as well as long-term adjustments made during a lifetime of exposure, to the stress. Acclimation refers to adjustments observed specifically under laboratory conditions or very controlled field conditions and in the face of a single exposure to a stressor (Folk, 1966; Frisancho, 1981; Roberts, 1979i Hochachka and Somero, 1984). Habituation refers to the nervOus adjustment to repeated exposure to a specific stressor, not the adaptive adjustments made by 'the system to maintain homeostasis in the face of imbalancing forces (Folk, 1966; Frisancho, 1981). These terms incorporate not only the mechanism of adaptation, but also the variations of the stressors themselves. Anthropological' studies of adaptation use these terms to evaluate studies of various cultures and the human variation of responses to stress. A. Roberto Frisancho's functional approach investigates adaptation at the level of changes in "organ system function, histology, morphology, biochemical composition, anatomical relationships, and body composition, either independently 82

PAGE 92

o.r integrated in the o.rganism as a who.le" (Frisancho., 1981, p. 2). Frisancho. emphasizes that inco.rpo.ratio.n o.f research o.n acclimatizatio.n, acclimatio.n, and habituatio.n is essential to. understand the co.mplete process o.f an adaptatioh to. a given enviro.nmental co.nditio.n. Additio.nally, he ackno.wledges that while cultural adaptatio.n may facilitate bio.lo.gical adaptatio.n by decreasing some enviro.nmental stress, it may itself bea so.urce o.f new selective forces fo.r bio.lo.gical adaptation : ( Frisancho.,1 981) The functio.nal appro.ach is flexible to apply to. all'levels o.f o.rganisms and suited fo.r th'e study o.f bo.th individuals and po.pulatio.ns. i ... Mo.ran's eco.lo.gical appro.ach to. adaptatio.n inco.rpo.rates general systems theory and the co.ncept o.f feedback, while adding a time co.nstraint o.n the measurement o.fadaptive respo.nses. Specific respo.nses are selected 'o.n the pro.per magnitude ando.ccur at a time and rate that is appro.priate to. the stimulus that elicited the adjustment" (Mo.ran, ;982, p. 7). Mo.ran accepts the idea that human adaptatio.n is o.n a higher plane than that o.f mere negative feedback. Emphasizing that maintenance o.f ho.meo.stasis and dynamic equilibrium do.es no.t imply changelessness, he no.tes the abilities o.f co.mplex o.rganisms to. reo.rder themselves to. a higher 83

PAGE 93

level of functioning to erisuresurvival (Moran, 1982). Both feedback responses and movement to a higher order are viewed within the context of conservation of energy. The success of human adaptability is measured by demographic, energy, and nutritioriai criteria. Statistical analysis of population and relative energy efficiency of technology, as well -as nutritional success to support a given work capacity, is seen as a -reflection ofa culture's ability to identify and exploit' ,the-resources of a gi'ven (Moran, 1982). Moran sees adaptation'studies once used to explore human variation and-physical response limits now used to investigate environments and adaptation in terms of chronic patterns. McElroy also presents the of health and disease as reflections of adaptation to the, environment. She sees patterns of disease in a ,broad historical and geographical framework, reflec,ting the ongoing adaptive process of genetic, physiological and cultural adjustments to dynamic environments.. MCElroy's model identifies the, interrelationship of all variables to emphasize that there are no single causes of disease. "Disease is ultimately due to a chain of factors related to ecosystem imbalance health and disease are part of physical, biological, and that continually 84

PAGE 94

affect one another" (McElroy and Townsend, p. 20). Discussion The study of adaptation is a bomplex issue which involves input from biological, psychological,social, and cultural realms. This chapter has only touched the surface of issues when exploring the many directions by which a study of adaptation can be approached. The search may approach the question through populations as a whole; individual variations, or at the very reduced level of the cell. The variations may be genetically caused, environmentally shaped, or both. To such a trait as elevated serum cholesterol levels in cold, Frisancho's (1981) functional approach reinforces the need to study a physiological trait from all points of view. The genetic, functional and physiological information can then be used to paint a more compete picture of the issue. Blending both laboratory and field studies produces a more inclu.ive research. Combining the functional approach with an ecological perspective encourages narrowing the search to a specific environment. The concentration on the circumpolar area serves to focus on similar types of cold exposure, as well as on other environmental influences such as luminosity, radiation, and seasonal variation. It also encourages a look at the variation in food chain and 85

PAGE 95

nutrition among the differing populations. And, it is the area in which most of the active research is now being completed. One of the most enticing study approaches is the historical narrative illustrated by Jared Diamond. Examining a physiological trait in perspective of the history of a population uhder varying streises including biome, migration, economic and health presents an inclusive longitudinal model. Additionally, it adds the concepts of 'health and disease into the evaluation of adaptation. The following chapter investigates the most recent population studies'concerriirig elevated serum cholesterol. It offers several ideas for future study and the problems encountered during the beginning exploration into the possibility of implementing one of the studies. It represents the beginning, not the end. 86

PAGE 96

CHAPTER 6 DISCUSSION AND PROPOSALS Review of Studies Reports that serum cholesterol elevates duri-ng times 6fbold exposure have been-documented since the 1920sRobinson, et al., 1992,for historical overview). Population compar;i.sons completed by Keys "Seven Countries Study' cardiovascular risk factors cross culturally) documented Finns living in the Karelian region of Eastern "Finland as having the highest serum cholesterol levels of the seven. Countries included two cohorts in Fin1and, the United States, Yugoslavia, Japan, Italy, Greece and the Netherlands (Keys, 1980). Further clarification found a 50% seasonal change (winter higher thari summer) in levels among the Eastern Finns, reflective of dramatic temperature ranges (Robinson, et al., 1992). (See Table 6 for cholesterol levels of populations to be discussed). Reinforcement of the theory of dose-response to cold was found by Robinson, et al., (1992) in a study comparing 17,200 men and women and women living in the United Kingdom with 42,000 Japanese. The study showed 87

PAGE 97

TABLE 6. SERUM CHOLESTEROL LEVELS' Conversion 39mg/iOOml = 1mmol/l seasonality of serum collection uriknown Population Cholesterol Source Icelanders 221 + 39 mg/100ml Axelsson,'90 IcelanderS-Canada 205.5 + 39.8 mg/100ml Axelsson, '90 Greenland Eskimo 217.6 + 9.4 mg/100ml Draper, '80 Eskimos-Denmark i84.7 + 9.8 mg/100ml Draper, '80 Danes 264 + 7.8 mg/100ml Draper, '80 Noril'sk Natives 223.9 + 16 mg/100ml Gichev, '90 Noril'sk.Migrants no age-factors noted in Gichev study '0-2 years 210.2 + 12.5 mg/100ml Gichev, '90 2-5 ,years 242.6 + 17.6 Gichev, '90 5-10 years 277.3 + 20.3 mg/100ml Gichev, '90 10 years 298.4 + 1S.8mg/100ml Gichev"'90 Finns age 40-50 rural semi urban' industrial Lapps age 40-40 Karelians 40':"'50 284.7 263.3 277 269 rural '275 urban 265 SW Firins 40-50 rural 258 mg/100ml mg/100ml mg/100ml mg/100ml mg/100ml mg'/100ml mg/.100ml mg/100ml urban Finns Lapps Finnish Ambassador No. Khanty male No. Khanty fe Chukchi Tundra Coastal Alaskan Eskimo Point Hope Kasigluk/ 267' -255.9 269.9 310 276 328 186.9 190.6 219 Nunapitchuk 246 Boarding School, 144.3 Seasonal Variations Unl.ted Kingdom Males ,Jan Males -July Fe -Jan Fe -July Japan Males Males Fe Fe -Jan -July Jan -July 240.6 233.6 227.8 220.7 207.5 198.9 213.3 202.8 mg/100ml mg/100ml mg/100ml mg/100ml mg/100ml mg/100ml mg/100ml + 49 mg/100ml + 46 mg/1 .00ml + 32.3 mg/100ml + 44.5 mg/100ml -42.5 mg/100ml + + 41.7 mg/100ml + 40.2 mg/100ml + 36.3 mg/100ml mg/100ml + 34.3 + 35 mg/100ml -+ 33.9 mg/100ml 88 Draper, Draper, Draper, Draper, Puska, puska, puska, puska, Nayha, Nayha, Mosher puzyrev puzyrev Nikitin Nikitin Draper Draper Draper '80 '80 '80 '80 81 81 81 '81 '94 '94 91 '92 '92 91 91 '80 '80 '80 Robinson, '92 Robinson, 92 Robinson, 92 Robinson, '92 Robinson, 92 Robinson, 92 Robinson, '92 Robinson, '92

PAGE 98

a strong correlation between elevated serum cholesterol and winter months in both countries. Variations were more marked in Japan, which has a greater temperature differential between seasons (Robinsonet al., 1992). A laboratory study placing a group of Finnish men in a cold chamber for two hours found a statistically significant rise in serum cholesterol (Leppaluoto et al., 1988). Leppaluoto's explanation for this rise was a mechanical one that cholesterol accompanied the rise in lipoproteins. However, he offered no functional explanation ( ,Leppaluoto, personal communication, June, 1993) A stuqy,comparing serum cholesterol and HDL levels of winter swimmers in Finland to nonswimming Finns (the swimming being outside, in natural waters, not pools) documented both serum cholesterol and HDL to be higher in the swimmers. This was attributed to the greater body fat in the swimmers. In noting dimorphic variation, the researchers stated that women swimmers had higher hemoglobin and HDL levels than men. Unfortunately the authors noted the control group of non swimmers had their blood drawn during the summer, not the winter. Blood samples from the swimmers had been drawn in winter (Kauppinen and Vouri, 1988). Finnish Saami reindeer herders (Lapps) are documented 89

PAGE 99

to have higher serum cholesterol than Finns. HDL levels are the same (Virokannus, personal communication, September 1992). At this writing the analysis is still being completed in Qulu, Finland (Nayha, personal communication, May, 1994). Finns have someof the highest rates of cardiovascular disease (Keys, 1980), however ischaemic disease is very rare in the Saami (Nayha, 1989). While it is not clear why the higher cholesterol levels do not correlate to higher disease rate in Saami as it does in Finns, it is worth noting that the Saami have high levels of selenium, a noted antioxidant, in their blood (Ringstad et al., 1991). Research compared blood samples of Nenets (Samoyeds) and Caucasian natives inhabiting the Archanglesk region of Russia, including the Kola peninsula and regions around the Arctic Circle at the White Sea Serum cholesterol in both groups elevated during the winter. The amplitude of increase was more pronounced in the Caucasians (Tkachev et al., 1991b). Jevgeny Bojko, one of the researchers involved, stated that the diets of the two groups were similar. He emphasized that studies of the northern populations were done at work camps where diets were controlled by camp personnel and were similar for all the populations involved (Bojko, personal communication, June, 1 99 3 ) 90

PAGE 100

Bojko's emphasis of diet control across work camps may also apply to Gichev's study of liver function variations. Gichev, as previously mentioned, found elevated liver functions and seru. m cholesterol in 204 migrants from medium latitudes who were moved to Noril'sk above the Arctic tircle. The migrants were compared to a group of 229 native inhabitants of the region. ofthe early were lower than the in correlation to the length of stay in the North. Antioxidant levels of migrants were also lower than the natives, but rose with the serum cholesterol levels. After a dramatic rise in the level of antioxidants at the ten year mark, they ultimately decreased to lev.els higher than thos e exhibited by the natives. stated in his study that no alteration in diet took place for the migrants (Gichev, 1990). A comparison of serum cholesterol levels of inhabitants of an Alaskan village those of a group of Siberian Eskimos found the Alaskan subjects to have higher serum cholesterol levels. Both researchers, Yuri NikitinofRussian and Sven Ebbeson from Alaska, however, agreed that the blood samples were not drawn during the same season. Both acknowledged seasonal variations, but neither could offer explanations of a functional sort. Nikitin stated a hormonal cause for this elevation, 91

PAGE 101

however ,it was not clear whether the rise is a result of hormonal influence or need for their manufacturing (Nikitin, personal communication, June 1993; Ebbesson, personal communication, June, 1993). Comparison of populations noted that the Finns have the highest serum cholesterol levels of any Arctic people. The study also noted that adult northern Eskimos showed a high absorption efficiency of dietary Although no numerical parameter documented the level of the human being is noted to absorb only 10-50% of ingested (Lieberman, study also documented the variation in levels of serum cholesterol between Eskimo populations living in different Eskimos living in Greenland showed lower cholesterol levels than those living in Denmark. Yet,Eskimos'living,in Denmark had higher levels than the Danes (Draper,1980). No study investigated whether the Eskimo exhibited any variation in body feedback' system. More research into the lipid of Eskimo (Inuit) is needed with updated technology to fully clarify the findings. Specific differences in plasma composition were also documented in the circumpolar studies. Higher rate of polyunsaturated acids were in blood samples of the Greenland population alon.g with a lower proportion 92

PAGE 102

of linoleic to eicosapentanoic acids. The study correlated low incidence of cardiovascular disease with the Greenland diet of long-chained polyunsaturated fats (Bang and Dyerberg, 1972 cited by Draper, 1980). Alaskan Eskimos showed those eating a more Western diet of processed foods exhibited 40% cholesterolemia (defined as greater than 260mg/100ml.) (Draper, 1980). No discussion of lipid peroxidation or cholesterol oxides is included in Draper's article. In light of Peng and Morin's work which showed increased levels of cholesterol oxide products in.processed foods and fried foods, a re-examination of the dietary habits as -well -serum _cholesterol and cardiovascular rates of Eskimos -needs to be completed. While repeated studies correlate higher cholesterol levels with cold stress and dietary mono and polyunsaturated fats to lower serum cholesterol levels, 'no mechanism or functional explanation is documented. Most of the current research presented at the Conference of the International Society for Health held in Iceland in June of 1993 followed that trend of documenting these phenomena, while offering no physiological explanations. One anecdotal presentation does stimulate questions. Several polar bears kept in captivity at Point Barrow, 93

PAGE 103

and fasted .for four months, had serum cholesterol rates well over 400mg/100ml. After the bears ingested the blubber from a seal (not the meat), their serum cholesterol fell to the mid 200s. The researcher presenting this discussion, an.environmental physiologist, could not offer any mechanical.or functional explanation (Folk, personal communication, June, 1993). Could this be seen in the light of during times of decreased food availability Or, is it an illustration of catabolism, the breakdown Of cells for fuel. Is cholesterol, not a fuel, ,r.eleased into the serum during the, cell breakdown? What is the cell membrane does it vary with the serum levels? No research addresses .these issues. Proposals ,for Futtire study That research continually document. serum cholesterol correlating with exposure to cold, without any investigation as to why, stimulates this writer to find the answer. Several directions by which to address the issue are readily apparent. Two involve population research, and one involves laboratory work on rats. The first proposal of population research patterns after'Oiamond's scenario of African-Americans' genetic selection of sodium retention and sribsequent problem with hypertension. That scenario-traced the historical 94

PAGE 104

migration and environmental stressors which led to the genetic selection. To examine the possible genetic selection for .cholesterol retention, the Finnish population, with its unique genetic markers present a beginning. Documented not only as having one of the highest cholesterol levels in the world (K.eys, .1980), they also have documented two genetic mutations which cause hypercholesterolemia (Kontula, 1 99 1 ). Finns also live in an extremely cold climate. The two mtitations documented in Finnish population are the FH-Helsinki and the FH-Karelian allele. The first one, the FH-Helsinkiallele, appears unique to the Finnish population. This particular allele leads to "an internalization-defective phenotype in which the receptor-bound LDL cannot be moved into the cell interior. This allele is in up to 58% of hypercholesterolemia patients, except in Karelia, where it is found in only 4%. Among the general Finnish population it is thought to.be 1 in 1000. The FH-Karelian allele is believed to affect the protein coding region of the LDL receptor gene which results in defective synthesis of the LDL receptor. Two other mutations are now being investigated in the populations around Oulu in Northern Finland, the research is not complete. Dr. Kontula believes the prevalence of these alleles 95

PAGE 105

is a of founder due to the continued isolation of the Finnish population (Kontula, 1991). Kontula noted that despite the prevalence of the FH-Helsinki allele in the population, the relatively high serrim cholesterol Finland are more attributable to a diet high in saturated fat and the common occurrence of the apoprotein E4 genotype. This particular genotype-occurs 1.4 in the normal Finnish population as opposed to those with and twice as high in Finns as in any other 1990: Kontula, 1991). The E4 allele, -positively correlated with higher serum cholesterol levels, is in high rates in the Alaskarrnatives (Botidreati al., 1993). However, it is not necessarily to higher,coronary heart disease. A study of Finns found no regional difference in E4 prevalence (Kontula, 1990)., although higher rates of cardiovascular exists ,in the' eastern Finnish area of Karelia, (Keys, 1980). The research in Finland does not address HDL function or endogenous manufacture of cholesterol as it relates to elevated serum levels. Dr. Kontula treated the issue totally within the framework of pathology, not adaptation. He could add no information concerning the relationship of living in the cold and experiencing elevated serum 96

PAGE 106

cholesterol (Kontula, personal communication, October, 1 991 ) In tracing the early migraiiori of Finns, Russian research documented a Russian populat-ion of North Khanty as a genetic intermediate between North Asian Mongoloids, such as Chukchi, and other Finno-Ugric peoples such as Finns and Komi. The North Khanty, belonging to the Finno-Ugric grduPi occupy _the basin of the Lower Ob rivero, in West Siber.ia. The Russian study of 262 men and 289 females documen,ts serum cholesterol levels averaging 276 ,for males, 328 for 'femal-es. (These numbers are slightly higher than the 270mg/100ml. average of Karelians noted by Keys, 1980; Draper, 1980). The researchers attributed these levels to genetic factors and added that they considered the genetic structure to be a result of evolution under extreme arctic ,conditions (Puzyrev et aI, 1992; Saljukov et aI, 1992). No discussion as to the specific alleles involved was offered. -And, no comparison of diet was discussed. Whether the genetic alleles referred to in this study are the same found in the Finnish population is not known, but if they are, it would be a beginning of a genetic tracing using those alleles as markers. The known population history of the Finns dates to the-fourth millennium B.C., -when ancestors of the 97

PAGE 107

present day Finns were thought to live with ancestors of the Samoyed and Nenets in the Ural Mountain Range of Russia. The groups gradually split, and both moved west into what is now Finland and the Kola Peninsula (Vuorela, 1.964). The Nenets havebe,en documented by Tkachev to show seasonal increases of cholesterol during the winter months, rising from 4.60mmol/1 to 5.33/mmol/l. (Tkachev et aI, More statistical ,data on the serum cholesterol levels of Kola peninsula populations given to me by one of the researchers, is not yet translated. In tracing the Finnish family tree, it appears that some of the branches show serum cholesterol levels higher than other populations. No specific genetic information documents whether the Finnish FH alleles are found in these populations. ,And, as these populations currently live in Russia, the difficulty of securing any becomes subject to the political forces of that country. Investigations onto genetic causes for hypercholesterolemia are currently being done. The belief that they are mutations which have existed for many generations, but are only now lethal due to the modern diet high in fats and cholesterol, remains readily accepted (Bishop and Waldholz, 1990). However,the genetic explanation for decreased LDL receptors does 98

PAGE 108

not explain why serum cholesterol exhibits seasonal variation and elevation during cold exposure. While the first population approach would investigate groups of similar history, exposed to similar environmental.stressors, a second possibility exists. This proposal focuses on a population traditionally not adapted or acclimatized to cold. Over the past 11 years the Scandinavian countries and Finland have accepted Vietnamese Iboat people. I 1000 Vietnamese, approximately 100 per year, have migrated to Finland. This population is not accustomed to the severe cold weather conditions which exist in Finland. Following Bakerls lead that the "greater the environmental contrast to which human populations are exposed, the greater the biological and social problems will bell (Baker, 1977, p. 145), this population presents a potential by which to study adaptation under current conditions. Because this population is Asian; with a traditional diet lower in animal fats and higher in complex carbohydrate, it has not traditionally been subject to cardiovascular problems. Investigation into several issues would be of interest. First, because some of these Vietnamese may have been exposed to cooler nights in the mountain regions of Vietnam-where it can be as cool as 30F on winter 99

PAGE 109

nights, it would of interest to ascertain the populations previous exposure to cold. There is a possibility that they demonstrate adaptation similar to Australian Aborigine (that of hypothermic and insulative), and in the light of technical protection of the Finnish population, no further adaptation change would be noted. There is a possibility that the Vietnamese would demonstrate increased liver function, elevated cholesterol in the serum and elevated choles.terol ratios of the lipid bilayer, as was noted in Gichev's study. To mimic Gichev's study, I attempted to acquire baseline medical data for the Vietnamese immigrant population, however the Finnish doctors state that no blood samples of immigrants were tested for Overall the medical approach been to investigate these migrants for diseases which might infect the Finns; and Dr. Tuomilehto, chief epidemiologist of Finland, stated that there are no pla,ns to study this group for effects of migration (Tuomilehto,personal communication, 1991). Additionally, no plans appear to exist for preventive medicine designed for this population. Dr. Kamela Liebkind, a social psychologist at the University of Helsinki, is the only researcher who has studied the Vietnamese population in Finland. She documented the degree of depression which Vietnamese 100

PAGE 110

people suffered as a result of the migration itself, the long periods of darkness in the north, and other forces. Her study documented discrimination to be one of the major factors in the high levels of depression. The response to these findings by the Finnish government was so that she has been pressured to stop this research and not publish her results (Liebkind, personal communication, 1992; Arpiainen, personal communication, March, The political ramifications have resulted in decreased access of information to others. I have been unable to : g -et_ -any demographic information from the Finnish government andihave been unable to establish contact with the social -group of the Vietnamese located in Espoo, Finland. Dr. Liebkind referred me to Dr. E. Hauff in Oslo, .. Norway, who is studying the Vietnamese immigrants in Norway. When questioned about the problems of diet adjustment, he assured me that the Vietnamese were able to acquire their native diets in Norway. He also raised the possibility that liver functions baseline might be available in conjunction with hepatitis screening (Hauff, personal communication, July, 1993). I question both issues and cannot accept that the foods, although of similar type, offer the same minerals and trace elements if grown i o n areas different than Vietnam. Analysis of 101

PAGE 111

foods would be necessary to validate Dr. Hauff's assumption. As to blood samples, hepatitis screening does include lipid profiles. Simple blood studies of both Finns and Vietnamese to investigate cholesterol levels and erythrocyte membrane lipids would be a start. Statistical analysis by means of regression line analysis might document a trending of cholesterol levels in the Vietnamese, and a population comparison with the Finns, over a period of time, might show variations in lipid profiles as did Gichev's study. Mere cannot account for the serum elevation however. 'Cholesterol levels are documented to be higher in migrant urban populations (Baker, 1977). One might easily attribute this to stress. Research documented that under the stress of 'tax time,' accountants show elevated cholesterol and decreased clotting times (Pelletier, 1977). To examine Vietnamese in Finland, measurement of personally identified stress, the degree of acculturation, and the effectiveness of support systems and personal coping styles must be included. Also a full accounting of diet' changes would be imperative. One further issue, not previously addressed in this paper, is that of altered sunlight. Finland experiences long periods of darkness throughout the winter 102

PAGE 112

months and three summer months with prolonged daylight. The effect on the circadian rhythm is another stressor. Disruption of the circadian rhythm can result in hypercortisolism and other disruptions in hormonal releases Whether this plays into the problem serum cholesterol in Arctic is not known. The possibility exists that endogenous manufacture cholesterol occtirs during higher levels of melatonin which elevates during darkness and the winter months. It may be connected to the 'predictive and 'pre-adaptation of early morning elevation in the prior sunrise (Minors and waterhouse, 1990). The issue of circadian rhythm al terations d\i:ring long darkness and exposure to synthetic light sources needs to be investigated A third for research into the relationship of serum cholesterol and cold stress lies in the laboratory. Rats, acclimatized to both cold and warm (normal room temperatures) can be exposed to cold stress, while being fed a varying fat diet. Several studies, beginning in 1945, have attempted to show a correlation between dietary fat and cold acclimation. Research demonstrated that rats with higher fat intake lived longer than those fed higher carbohydrate diets. Further research demonstrated that the type of fat intake 103

PAGE 113

was also important. Rats fed a diet with corn oil gained weight in cold, while those fed rapeseed oil lost weight and died (Heroux, 1981). The fact that rapeseed oil is toxic to the heart muscle was not addressed. A further study noted that rats fed -diets containing 2% cholesterol higher incidence of atherosclerosis when chronically exposed to cold (Heroux, 1981). As those studies took place in the 1940s and 1950s (Heroux, 1981), prior to 1974 concept of homeoviscous adaptation and the current understanding of cholesterol oxides and their damage, repeating similar rat studies-seems worthy. New techniques in microbiology by which to closely -investigate cellular membrane structure during 'varying diets and under varying might offer new light on this issue. Only one study in recent literature addresses the movement of cholesterol and lipid restructuring under cold stress. That study, completed by Russians, cites varying percentages of cholesterol in cell membranes at varying low temperatures. Rats exposed to 10C showed a decrease in cholesterol in liver tissue, but no changes in brain, lung, or thigh tissue. Rats then exposed to 3C showed increases in cholesterol content in the brain, lungs and liver (Ternevoi et al., 1989). No mention of any functional explanation for the findings appeared 104

PAGE 114

in the research. As myelin sheath and surfactant in the lungs both contain cholesterol, the possibilities to continue investigation into functional explanations is warranted. By marking of exogenous cholesterol with radioactive and Waldholz, 1990) and exposing the ,rats to the cold, some explanation might be found. The practical application of the rat studies could be in proposing a model" by which to address the questions concerning dietary changes of the Inuit. Much documentation already ,exists into the new cardiovascular ,-and diabetes by the indigenous Alaskans as they embrace our Western diets. To further complicate the issue, animal activists have tried to prohibit sUbsistence hunting by arguing that sea mammals are high in toxins such as cadmium and mercury. Dr. Middaugh, Alaska's epidemiblogist, states that no studies document the parameters of toxic levels in humans. And he suggests that the changes in Inuit diet may be itself more detrimental than eating foods containing the questionable substances. Middaugh called for studies which could clarify the issues That the dietary alterations of the Inuit might alter the traditional hypermetabolism of Inuit adaptation to cold, and therefore create other stressors, is worthy of investigation 105

PAGE 115

(Folk, personal communication, June, 1993; Middaugh, personal communication, June, 1993). Population studies offer valuable information by which to design preventive medicine programs aimed at reducing effects of migrating or working in cold climates. Functional explanations for variation in lipid metaboliSm would offer approaches to the study in cardiovascular disease and its prevention. And the traditional approach to variation as pathology might be replaced with an appreciation of adaptation. Conclusion The phenomenon of elevated serum cholesterol during cold exposure has been documented in two hour cold chamber exposures (Leppaluoto et al., 1988), during cold seasons (Robinson et al., 1992), and during long term migration to cold regions (Gichev, 1990). Genetic. selection resulting in elevated serum cholesterol has been documented in the Finns (Kontula, 1991). The amount of data which supports the phenomenon calls for further clarification. This thesis has. attempted to investigate the function role elevated serum cholesterol might play in cold climate. Many explanations are possible, from transporting remnants of cell catabolism, to storage, to providirig precursors for stress hormones, to protection 106

PAGE 116

of cells against _the elevated oxidation stress. No one answer can be considered complete, however, in the face of the varied_uses of cholesterol in the body. Research into the relationship of cholesterol in the cell membrane under conditions of sickle cell (Kucuk et al.,1992); oxidative stress on nervous tissuein relationship to Parkinson's, _Huntington' s, and ALS .. and Puttfa-rcken, 1'99 3 to issues of preeclampsia (Anceschi et al., 1992), illustrate the --importance _of investigation in-this area. The search for-answers _has just begun.; Microbiology, epidemiology, genetics, and preventive:medicine are just a few of the areas which will provide answers. It seems logical that the inclusive "approach oft"he med.1.cai anthropologist offers the platform to blend interdisciplinary information into a biocultural package. The global approach to promote, eradicate disease demands the ability of researchers to understand the human diversity in all its complexity .. 107

PAGE 117

APPENDIX Personal interviews and communications Anssi Arpiainen, Liason Officer, Ongoing corrununication TUKOSPAR, Helsinki, Finland Dr Bojko, ICCH, June 1993 Insti tute of Physiology, :UraI Dfvis.ion Archanglesk,-Russia Dr. Sven Ebbesson, ICCH,June-1993 Institute University of Alaska, Anchorage Dr. G Edgar folk, J .une 1 993 Professor of Environmentcil Physiology College of Medicine, University of Iowa Dr. Edvaard Hauff, July 1993 Psychosocial Centre University of oslo Dr. Kirruno Kontula, October 1991 Assistant of Medicine University of Helsinki Dr. Juh-ani Leppaluoto,Iccif, Jurie 1993 University of Oulu, Finland Dr. Kamela Leibkind, 1992 Department of Sociology University of Helsinki Dr John Middaugh, ICCH, June 1993 state Epidemiologist, Alaska Dr. Simo Nayha, ICCH, June 1993 and ongoing corrununication Regional Institute of Occupational Health Oulu, Finland Dr. Yuri Nikitin, MD, ICCH, June 1993 Institute of Internal Medicine:,-Academy of .Sciences Siberian Branch, Novosibirsk," Russia -1 08

PAGE 118

Dr. L. E. Panin, ICCH, June Institute Df Biochemistry, Academy of Medical Sciences Siberian Branch, NovoSibirsk, Russia Dr. Leena Soininen, ICCEF, September 1992 Director, Lapland Regional Medicine Rovaniemi, Finland Dr. Jaako Tuomilehto, 1991 Researcher Karelian Epidemiologist, National Public Health Institute Helsinki, Finland Dr. Hannu Virokannus ,.' MD, ICCEF, September 1992 and ongoing communcation Regional Institute of "Occupational Health OuTu, Finl.and ICCH: ICCEEF: .-. .... International" Conference" on Circumpoiarliealth International Conference on Combined Effects of Environmental 109

PAGE 119

BIBLIOGRAPHY Aalto-Setala, K., Viikari, J., Akerblom, H. Kuusela, V., & Kontula, K. (1991). DNA polymophisms of the apolipoprotein Band A-I/c-III genes are associated with variations of 6f serum. low density lipoprotein cholesterol level in childhood. Journal of Lipid Research, 32, 1477-1485. Anceschi, M., Coata, G., Cosmi, E., Gaiti, A.; TrovaIli, & Di-Renzo (1992). Eryrocyte membrane composition in Evidence for lipid profile. British Journal.of Obstetrics and Gynaecology, 99(6), 503-507. Asimov, I. (1992). The human body: Its structure and operation. New York: Ment;or .... --c .. -. : Axelsson; Karlsson, M., Petursdottir, G., Asegeirdottir, A., Olafsson, 0., Sigfusson,N., Way, A., Sigvaldason, H., & Sigurdsson, B.(1990). Prevalence of cardiovascular risk factors in two separate but genetically-comparable populations. Circumpolai Health 90, 509-514. Baker, P. (Ed.). (1977). Human population problems in the Some research strategies and designs. Paris. : United Nations Educational, Scientific and Cultural Organization, Untion Typographique. Bishop, J. & Waldholz, M. Genome. New York: Simon and Schuster. Boudreau, D., Middaugh, J., Misfeldt, J., Pedersen, H., Newman, W., & Malcom, G. (1993). Meeting Report: Arctic Native Atherosclei6sis& w3 fatty acids. Arctic Medical Research, 52(2), 73-73. Brown, M. & Goldstein, J.(1986). A receptor-mediated pathway for cholesterol homeostasis. S .cience, 232(34), 34-47. -Bruck, K. & Zeisberger, E. (1990). Adaptive changes in thermoregulation and their neuropharmacological basis. In Schonbaum, E. & Lomax, P. (Eds.),. Thermoregulation: Physiology and biochemistry, (pp. 255-307). New York: Pergamon. 110

PAGE 120

Bruemmer, & Taylor, W. The arctic world. New York: Portland House. Cavalli-Sforza, L. & Bodmer, w. (1971). Thegenetics of human populations. San Francisco: Freeman. Coyle, J. & Puttfarcken, P. (1993). Oxidative stress, glutamate, and neurodegenerative disorders. Science, 262, 689-695. Crews, D. & James, G. (1991) Human ev_ol ution and the genetic epidemiology of chronic degenerative diseases. In Mascie-Taylor, C. & Lasker,' G. (Eds.), Applications of biological anthropology to human affairs, (pp 185-206). Cambridge: .Cambridge University Press. .. .... Dawkins, R. (19.82) _The: Extended Genotype. Oxford: Oxford 'University -Press. ,_ DeGroot, (Ed.) <-1989.). Endocrine In Endocrinology, (PP Philadelphia: Saunders. -..----Diamond, J. (1993). The saltshaker's curse. In (Ed.). '93/94, (pp 221-225). Guilford: Dushkin. Dobzha.nsky, T. (1962). Mankind evolving. New Haven: University Press. Draper, H. (1980). Nutrition. In Milan,-F. (Ed), Human biology of circumpolar populations, (pp 257-284). Cambridge: Cambridge University Press. Durham, w. (1991). Coevolution. Stanford: Stanford University Press. Dyson-Hudson, R. (1983). Rethinking human adaptation. Boulder: Westview. Fregly, (1990). Activity of the hypothalamic -pi tui tary -thyroid axis du'ring exposure to cold. In Schonbaum, E. & Lomax, P. (Eds.), Thermoregulation: physiology and biochemistry, (pp 437-494). New York: Pergamon. Folk, G. (1966). Introduction to environmental physiology: Environmental ,extremes and mammalian survival. Philadelphia: Lea & Febiger. 111

PAGE 121

Frisancho, A. Human adaptation: A functional Interpretation. Ann Arbor: University of Michigan Press. Ganong, W. (1991). Review of medical physiology. Norwalk: Appleton & Lange. Gichev, J., (1990). Change liver function during adaptation of man to northern conditions. Artic Medical Research, 68-73. Gordon, L. & Mobley, P. (1984). Thermotropic lipid phase separations in human erythrocyte ghosts and cholesterol-enriched rat liver plasma membranes. Membrane BiologX" 79, :75-86.'-Granberg, P.(1991a). Freezing cold 1nJuries :Arctic M .edi,cal Research, .50, fsuppl-. -6), -76-79. Granberg, P. (1991b). Human physiology under cold '. 'exposure. Arctic 'Medical Research, 50, (suppl. 6), 23-27. Grayson, J. (199Q). Microcirculation responses to hot and cold environments. InSchonbaum, E & ,Lomax, P. (Eds.)" Thermoregulation: Physiology and biochemistry, (pp 229-230). New York: Pergamon. Grollman, S. The human body: Its structure and physiology. New York: MacMillan. Gunstone, F., Harwood, j., & Padley, F. (1986). The, lipid handbook. London: Cliapmanand Hall. Guyton, A. (1991). Text'book of medical,physiology. Philadelphia: Saund'ers. Hadley, N. (1985). The adaptive role of lipds in biological systems. New York: Wiley. Halfpenny, J. & Ozanne, R. (1989). Winter: An ecological handbook. Boulder: Johnson Books. Hassi, J. (1977). The brown adipose tissue in man; structural and functional aspects in relation to age. Oulu: University of Oulu. Hazel, J., & Williams, E. (1990). The role of alterations in membrane lipid composition in. enabling physiological adaptation of organisms to their physical environment. Prog. Lipid Research, 29, 167-227. 112

PAGE 122

Heldmaier, G., Klaus, S., Wiesinger, H., Friedrichs, V., & Wenzel, M. (1989). Cold acclimation and Thermogenesis. In Malan, A. & Canguilhem, B., (Eds.), Living in the cold, (pp 347-358). Montrouge: Libbey. Press. Heroux, D. (1981). Nutrition in cold environments. In Rechcigl, M. (Ed), eRC Handbook of nutritional requirements in a functional context: Vol. II. Hematopoiesis, metabolic function, and resitance to physical stress, (pp. 523-537). Boca Raton: CRC Press. Hissa, R. (1990). Central.control of body temperature. Arctic Medical Research, 49, 3-15. Hochachka, P. & Somero, G. (1984). Biochemical adaptation. Princeton: Princton University Press. Itoh, S. (1980). Physiology of people. In Milan, F.(Ed.), Human biology 'of circumpolar populations, (pp. 285-303). Cambridge: Cambridge University Press. Jessen, C. (1990). The control of body temperature. In Schonbaum E., & Lomax, P. (Eds ), Thermoregulation: Physiology and biochemistry,. (p._ ,163-173). New York: Pergamon. Kauppinen, K., & Vouri, I. (1988). Health' status of active swimmers. Arctic Medical Research, 47(2), 71-82. Kapit, W.,Macey, R., & Meisami, E. (1987). The physiology coloring book. Cambridge: Harper. Keys, A. iEd.) (1980). Seven countries. Cambridge: Harvard University Press. Kontula, K. (1990). basis of hyperlipidemia: Lessons from the Finnish gene inheritage. Ann Med 22, (5), 303-305. Kontula, K. (1991). Prevalance and geographical distribution of major' LDL receptor gene rearrangements in Finland. Author's manuscript. Kucuk, D., Lis, L., Dey, T., Mata, R., Westerman, M., Yachnin, S., Szostek, R.,.Tracy, D., Kauffman, J., Gage. D." & Sweeley; C. (1992). The effects of cholesterol oxidation products in sickle and normal red blood cell membranes. Biochimica et Biophysica Acta, 1103(1992}, 296-302. 113

PAGE 123

Kuroshima, A. (1992). Brown adipose tissue thermogenesis as physiological strategy for adaptation. Japanese Journal of Physiology, il,(2), 117-139. Lapinski, A. & Etlis, M. (1988). Various indicators of lipid composition of erythrocyte membranes in .healthy persons and in chronic alcoholic inhabitants of the north-east part of USSR. ZhNevropatol Psikhiatr, 88(9), 121-125 LeBlanc, J. (1975). Man in the cold. Springfield: Thomas. LeBlan.c" J. (1986). Adaptation to low. ambient temperature In. Dejours, P. (Ed.), physiology of' 'envIronmental adaptation. 2-Adaptations to extreme environments. Basel: Karger. LeBlanc, J (1988). Factors affecting c6ld acclimation and., thermogenesis in Medicine and Science in Sports and Exercise, 20(5), s193-196. Leibovitz, B., Hu, M., & Tappel, A., (1990). Lipid peroxidation in rat tissue Effect of dietary vitamin E, corn oil-lard and menhaden oil. Lipids, 25(3) 125-129. Lenther, C. (Ed.). (1984). Geigy scientific tables. Vol.3 Physical chemistry composition of .blood, Hematology. Basle: Ciba Geigy. Leppaluoto, J., Korhonen, I., Huttenen, P., & Hassi, J. (1988). Serum thyroid and adrenal hormones, testosterone, TSH, LH, GH, and prolactin in men after a 2-hour stay in a cold room. Acta Physiology Scandanavia, 132, 543-548. Leppaluoto, J. & Hassi, J. (1989). Physiological adaptation of humans to the Finnish climate. In Heionen, J. (Ed.t, Cold climate research in Finland, (pp. 18-26). Helsinki: Finnish Government Printing center. Leppaluoto, J., & Hassi, J. (1991). Human physiological adaptations to the arctic climate. Arctic, 44(2), 139-145. Lewontin, R. (1982). Human Diversity. New York: Scientific American. 114

PAGE 124

Lieberman, L. (1987). Biocultural consequences of animal versus plants as sources of fats, proteins, and other nutrients. In Harris, M. & Ross, E. (Eds.), Food and evolution, (pp. 225-258). Temple University Press. Malan, A. & Canguilhem, B. (Eds.). (1989). Living in the cold. Montrouge: Libbey Eurotext. Marachev, A. & Lapinski, A. (1989). Physiological aspects of adaptive, modifications of human biomembrane lipids under arctic conditions. Human Physiology, .2.2.(6),427-436. Marchand, P. (1991). 'Life Hanover: University Press of New England. Mayr, E. (1988). Toward anew philosophy of biology. Cambridge! Harvard University Press. McCance, K., & Huether, S. (1990). Pathophysiology: The biologic basis for disease in adults and children. st. Louis: Mosby. McCance, K., & Huether, S. (1994). The biologic basis for disease in adults and children. st. Louis: Mosby. McElroy, A., & Townsend, P. (1989). Medical anthropology in ecological perspective. Boulder: Westview Press. Miller, B., & Keane, C. (1978). Encyclopedia and dictionary of medicine, nursing and allied health. Philadelphia: Saunders. Minors, D., & Waterhouse, J. (1990). Circadian rhythms in general. Occupational Medicine, 165-183. Moore, T.(1989). The Cholesterol Myth. Atlantic Monthly, 37-70. Moran, E. (1982). Human adaptability: An introduction to ecological anthropology. Boulder: Westview Press. Myant, N. (1991). Cholesterol. In Dulbecco, R. (Ed.), Encyclopedia of human biology, Vol. 2 Br-De, (pp. 400-410). San Diego: Academic Press, Harcourt. Nayha,S. (1980). Short arid medium-term variations in mortality in Finland. Oulu: Kirjapaino Osakeyhtio Kaleva. 115

PAGE 125

Nayha, S. "(1989). in cardiovascular mortality in Finland, 1961-1985. Oulu: Kirjapaino Osakeyhtio Kaleva. Nayha, $.,& Hassi, J. (1993). Poronhoitajien elintavat, tyo ja terveys. [Life style; work and health of Finnish reindeer herders]. Helsinki: Jakelu. Needham, D., & Nunn, R. (1990). Elastic deformation failure of lipid bilayer membranes containing cholesterOl. Biophysical Journal, 58, 997-1009. Nikitin, Kloshkova, E., & Mamleeva, F. (1991). Comparison of diets in two native Chukotka populations and prevalence of" ischemic heart disease risk factors. Arctic Medical" Research, 50(2), 67-72. Ornstein, R., & Sobel, D. (1987). The healing brain. New York: Simon and Schuster. Panin, L., Biushkina, N.,& Polyakov, L. (1992). of interaction between serum lipoproteins and.steroid hormones. Bulletin of Experimental Biology and Medicine, 1l!(7), 950953. Pelletier, K. (1977). Mind as healer, mind as slayer. New York: Peng,S., & Morin, R. "(1992). Biological effects of cholesterol oxides. Boca Raton: CRC Press. Phipps, W. Lorig B., & Woods, W. (1983) .. "Medical-surgical nursing: Concepts and clinical practice, p. 401. st. Louis: Mosby. Purves, W., & Orians, G. (1987). Life: The science of biology, (pp .. 41..,.232). Sunderland: Sin"auer. Puska, P. (f). Community control of cardiovascular diseases. Copenhagen: WHO. Puzyrev, v., Lemza, S., Nazarenko, L., & Panphilov, v. (1992). Influence of genetic and demographic factors on etiology and pathogenesis of chronic disease in north Siberian aborigines. Arctic Medical Research, 51 (3), 136-142. Radomski, M. & Boutelier, c. (1982). Hormone response of normal and intermittentcold-preadapted humans to continuous cold. Journal of Applied Physiology, 53, 610-615. 11 6

PAGE 126

Rautenberg, w. (1989). Shivering thermogenesis and its interaction with autonomic controlled systems. In Malan, A. & Cang'uilhem, B. (Eds.), Living in' the cold, (pp. 409-417). Montrouge: Libbey Eurotext. Ringstad, J., Aaseth, J., Johansen, K., Utsi, E., & Thomansen, Y. (1991). High serum selenium concentrations in reindeer breeding Lappish men. Arctic Medical Research, 50(3), 103-106. Roberts, J. (1979). Special enzymatic mechanisms of cold adaptations. In Underwood, L., Tieszen, L., Callahan, A., & Folk,G., (Eds.), Comparitive mechanisms of cold adaptation, (pp.129-142). New York: Academic Press. Robinson, Bevan, E., Hinohara, S., & Takahashi, T. (1992). Seasonal variation in serum cholesterol levels. Evidence from the UK and Japan. Atherosclerosis, 95, 15-24.. .. -Saljukov, V., Limza, S., Kucher,A., & Puzyrev, V. (1992) The role of hereditary factors in phenotypic variability or hormone levels in the population genetically adapted to circumpolar environment. Arctic Medical Research, 143:...149. Schonbaum, E. ,& Lomax ,P. (Eds.) (1 990). Thermoregulation: Physiology and bi6chemistry. New York: Pergamon. Schroeder, F., & Nemecz, G., (1990). Transmembrane cholesterol distribution. In Esfahani,M., & Swaney, J., (Eds.), Advances in cholesterol research, (pp. 47-83). Philadelphia: Telford Press. Smith, L. (1981). Cholesterol Oxidation. New York: Plenum. Smith, L. (1992). The oxidation of cholesterol. In Peng, S., & Morin, R., (Eds.), Biological effects bf cholesterol oxides, (pp 7-32). Baton Rouge: CRC Press. Smith, R. (1989). Nutritio"n, hypertension, & cardiovascular disease. Portland:. Hyncean. Spector, A., & Yorek, M. (1985). Membrane lipid composition and cellular function. Journal of Lipid Research, 26, 1015-1035. Speth, J., & Speilmann, K ( 1 983) Energy source. protein and hunter-gatherer subsistence strategies. Journal of Anthropological Archaelogy, 1, 1-31. 117

PAGE 127

, steegmann, A., (1970). Human adaptation to cold. In Damon, (Ed.), Physiological anthropology, (pp. 131-166). New York: Oxford Press. steegmann, A., (1983). Boreal forest adaptation: The northern Algonkians. New York: Plenum. Steigen, T., & Larsen, (1991). Membrane phospholipid metabolism of rat myocardial cells during hypothermia and rewarming. Arctic Medical Research, 50 (Supp. 6), 53-57. stepanyan, R., & Simonyan, A. (1990). Lipid peroxidation and oxidative phosphorylation in chicken heart and skeletal muscles during development under conditions of'brief chilling. Zhurnal Evolyutsionnoi Biokimii i Fiziologii, 25(1), 73-77. Stini, W. (1971). Evolutionary implications of changing nutritional patterns in human populations. American Anthropologist, 73, 1019-1030. Toulmin, s. (1983). The natural post and the human future: An introductory Essay. In Ortner, D., How humans adapt: A biocultural6dyssey, (pp. 11-28). Washington; Smithsonian Institutional Press. Ternevoi, V., Shipitsyna, V., & V., (1989). Changes in cholesterol and different types of phospholipid contents of rat tiss.ues in acclimation to cold. Zhurnal Evolyutsionnoi Biokhimii i Fiziologii, 25(1), 15-19. Tkachev, A., Bojko, J., (1991a). Dynamics hormone and metabolic state in depend on daylight duration. Arctic Medical Research, 50 (supp. 6), 152-155. Tkachev, A., Bojko, J., & Ramenskaya, E. (1991b). Endocrine status and,plasma lipids inhabitants of the northern european part of the USSR. Arctic Medical Research, 50(supp 6), 148-151. Vietnam. New Age Encyclopedia, Lexicon Publication. Wang, L., & Hudson, J., (Eds.). (1976). strategies in cold, natural torpidity and thermogenesis. New York: Academic Press. Woodward, V. (1992). Human heredity & society. st. Paul: West. 11 8

PAGE 128

Vourela, T., (1964). The Finno-Ugric Peoples. Bloomington: Indiana University. Yeagle, P. (1989). Lipid regulation of cell membrane structure and function. FASEBJournal, l(7), 1833-1842. Yeagle, P. (1990). Roles of cholesterol in cellular functions. In Esfahani, M., & Swaney, J., (Eds.) Advances in cholesterol research, Philadelphia: Telford Press. Zachariassen; K. (1991). Hypothermia and cellular physiology. Arctic Medical Research, SO(supp 6), 13-17. 11 9