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Developmental changes in resistance of mammalian embryos to elevated temperature and strategies to improve fertility in dairy cattle during heat stress

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Title:
Developmental changes in resistance of mammalian embryos to elevated temperature and strategies to improve fertility in dairy cattle during heat stress
Creator:
Ealy, Alan Dale, 1965-
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English
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xv, 220 leaves : ill. ; 29 cm.

Subjects

Subjects / Keywords:
Antioxidants ( jstor )
Cattle ( jstor )
Embryogenesis ( jstor )
Embryos ( jstor )
Heat stress disorders ( jstor )
Heat tolerance ( jstor )
Oocytes ( jstor )
Pregnancy ( jstor )
Proteins ( jstor )
Shock heating ( jstor )
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bibliography ( marcgt )
theses ( marcgt )
non-fiction ( marcgt )

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Thesis:
Thesis (Ph. D.)--University of Florida, 1994.
Bibliography:
Includes bibliographical references (leaves 172-218).
General Note:
Typescript.
General Note:
Vita.
Statement of Responsibility:
by Alan Dale Ealy.

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University of Florida
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Copyright [name of dissertation author]. Permission granted to the University of Florida to digitize, archive and distribute this item for non-profit research and educational purposes. Any reuse of this item in excess of fair use or other copyright exemptions requires permission of the copyright holder.
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DEVELOPMENTAL CHANGES IN RESISTANCE OF MAMMALIAN
EMBRYOS TO ELEVATED TEMPERATURE AND STRATEGIES
TO IMPROVE FERTILITY IN DAIRY CATTLE
DURING HEAT STRESS








By

ALAN DALE EALY


A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL
OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT
OF THE REQUIREMENTS FOR THE DEGREE OF
DOCTOR OF PHILOSOPHY

UNIVERSITY OF FLORIDA

1994



























This dissertation is dedicated to my family for their support, guidance and


strength.


I thank my wife, step-son, mother and father, grandparents, brother, sister


and brother-in-law for their encouragement throughout my academic career.


Their


selfless acts on my behalf will not be forgotten.













ACKNOWLEDGEMENTS


Few people have the opportunity to strive for and reach an important goal.


It is an honor,


therefore,


to acknowledge


individuals that have contributed to a


personal achievement such as this.


I would like


to thank Dr. Peter


Hansen,


chairman


supervisory


committee,


valued


guidance,


support


encouragement.


The time spent in Dr. Hansen'


laboratory was invaluable for my


development as a researcher and educator.


Research and individual values learned


from Dr. Hansen will no doubt be used throughout my professional career.


Deepest


gratitude for time and patience is also extended to my supervisory committee, Drs.


Maarten


Drost,


Lynn


Larkin,


Frank


Simmen


William


. Thatcher.


Special thanks are due to


Dr. Drost, for assistance with cow superovulation and


embryo recovery studies, and Dr. Thatcher, for valuable assistance on design, analysis


and interpretation of several studies.


Gratitude is also extended to Dr. Charles J.


Wilcox for assistance in data analysis and Mr. David R. Bray for development and

maintenance of housing facilities for cattle on several studies.

I also wish to acknowledge previous and present members of Dr. Hansen's


laboratory for their companionship and assistance: Dr. Carlos F


M. Barros, Dr. Gordon J.


. Ar6chiga, Dr. Ciro


Betts, Ms. Jill A. Davidson, Ms. Susan L. Gottshall, Ms.


V~~~~~~~~~* -- n. T 1 T F '-T t. 1 f ~ f


I .111T 11


ttl f 1' Ii







Skopets.


Special thanks are due


to Ciro


Barros, for his valuable assistance and


encouragement during my first few months; Carlos Ar6chiga, for assistance with all

studies, for exchange of ideas and for preparation of the monoethyl glutathione ester;


Susan


Gottshall


technical


organizational


assistance


throughout


studies; and Lannett Howell and Victor Monterroso for their successful collaboration

in development of bovine in vitro maturation/fertilization/culture techniques.

I also wish to acknowledge additional donations of facilities, knowledge and


financial support.


Mary Russell and David Herbst provided assistance with artificial


insemination for the study presented in Chapter II.


Woody Larson, Larry Wisener


and George Adams from Larson Dairy Inc. provided animals, facilities and labor for

completion of the study in Chapter V and Central Packing Co. donated ovaries for


in vitro fertilization procedures.


Dr. R. Michael Roberts and Dr. J.


J. Hernandez-


Ledezma from the University of Missouri and Dr.


Alan King from the University


Guelph


assistance


with


development


bovine


vitro


maturation/fertilization/culture techniques.


Finally, studies would not have been


possible without financial support of the Florida Dairy Check-off Program and the

United States Department of Agriculture.












TABLE OF CONTENTS

page

ACKNOWLEDGMENTS .................................................................................... iii

LIST OF TABLE S ............................................................................. ix

LIST OF FIGURES ............................................................................................... xi

ABBREVIATIONS .................................................................... xii

ABSTRACT ............................................................................................................. xiv


CHAPTERS

I. INTRODUCTION ................................................................................ 1

n. REVIEW OF LITERATURE ........................................ 3

Effects of Elevated Temperature on Reproduction
in Dairy Cattle .................. ............................................................ 3
Estrous Detection .............................................................. 4
Fertilization .................................. .................................... 5
Effects on oocytes ............................................. 6
Effects on spermatozoa ...................................... 7
Effects on spermatogenesis ................................. 8
Early Embryonic Development ...................................... 8
Uterus and Oviduct ........................................................... 11
Regulation of Luteal Function by the
Uterus and Embryo .................................................. 13
Fetal Development ........................................................ 14

Mechanisms by Which Cells are Protected from
Effects of Elevated Temperature ............................................. 15
Mechanisms of Heat-Induced Cell Damage ................ 15
nTl;rant 'ffn+e -t h, at 1







Apoptosis .............................................
Induced thermotolerance ....................................
Heat Shock Proteins ..... .............................. .......
H SP70 .................................... .. .............................
HSP70 and heat shock .......................................
H SP90 ......................................................................
H SP27 ............................. ..................................
Other HSPs ... .. ..............S.....................S.... ...
HSP gene expression ........................................
Glutathione .........................................................................
GSH synthesis, transport and recycling ............
Direct reactions of GSH ......................................
Enzyme-mediated reactions of GSH ........... .....
Importance of GSH in stressed cells .................
Taurine ............................................................................
Taurine synthesis, transport and localization ..
Free radical-scavenging properties of taurine.
Additional properties of taurine ....................
Thermoprotective property of taurine ..............
Other Antioxidant Molecules .........................................
Carotenoids (vitamin A) ...... ........................
Ascorbic acid (vitamin C) ...................................
Tocopherols (vitamin E) ....................... ...............
Presence of Protective Mechanisms in
Mammalian Embryos ....................................................
Effects of elevated temperature on
cultured embryos ....... .........................................
Ontogeny of thermotolerance in embryos .......
HSP synthesis in embryos ....................................
Other thermoprotective mechanisms ...............


Strategies for Limiting Deleterious Effects of
Heat Stress on Embryonic Survival in Cattle ..........................
Long-Term Cooling ...........................................................
Short-Term Cooling .......................................................
Embryo Transfer ..........................................................
Manipulation of Embryonic HSP Synthesis .................
Thermoprotection with Antioxidants .............................


Summary


DEVELOPMENTAL CHANGES IN EMBRYONIC
RESISTANCE. TO ADVERRS. FFFrT.C nF MATFRNAT








Introduction ....................................................... ............. .
Materials and Methods .............................................................
Synchronization of Estrus and Superovulation ..........
Treatments ..........................................................................
Determination of Embryonic Survival ...........................
Statistical Analysis .............................................................
Results ..............................................................................................
Environmental Conditions and Rectal
Temperatures ........................................
Embryonic Survival ...........................................................
Embryonic Development ........................................
Discussion .......................................................................................

DEVELOPMENTAL CHANGES IN SENSITIVITY OF
CULTURED BOVINE EMBRYOS TO HEAT SHOCK.................

Introduction .....................................................................................
Materials ..........................................................................................
M methods ....................................................................................
In Vitro Maturation/Fertilization/Culture ............ ..
Effects of Heat Shock on 2-cell Embryos ...............
Effects of Heat Shock on Morula Stage Embryos ......
Statistical Analysis .............................................................
R results ...........................................................................................
D discussion ...................... ............................ ... .......................... .....

INDUCED THERMOTOLERANCE DURING EARLY
DEVELOPMENT OF MURINE AND BOVINE EMBRYOS .......


Introduction .....................................................................................
Materials and Methods .................................................................
Mouse Superovulation, Embryo Recovery
and Culture .........................................................................
Cow Superovulation, Embryo Recovery
and Culture .........................................................................
Induction of Thermotolerance ........................................
Embryonic Survival and Development ..........................
Statistical Analysis .............................................................
Results ......................................................................................
Thermotolerance to 43 C .................................................
Thermotolerance to 42 C ................................................
Thermotolerance in Bovine Blastocvsts--..........----







EFFECTIVENESS OF SHORT-TERM COOLING FOR
ALLEVIATION OF HEAT-STRESS INDUCED INFERTILITY
IN DAIRY COWS....................................

Introduction .....................................................................................


Materials and Methods .................................
Results ........................................


*4****** Stesme .mQ.....I.I..*#
* S 4( SS ...fl........ S 555c


D discussion .........................................


THERMOPROTECTION OF BOVINE AND MURINE
EMBRYOS FROM HEAT SHOCK BY GLUTATHIONE
AND TAURINE............................................................

Introduction ........................................
Materials and Methods e...................... .................
Experiment 1 ........................................
Experiment 2 .............................................................
Experiment 3 ...................................... ..................
Experiment 4 .................................................................
Experiment 5 ...............................................................
Statistical Analysis ........................................
Results ...............................................................................
D discussion .......................... ............. .. ........... .......................


VIII.


GENERAL DISCUSSION .......................................................................


APPENDICES


BOVINE IN VITRO MATURATION/FERTILIZATION/
CULTURE TECHNIQUES ........................................................


MOUSE SUPEROVULATION, EMBRYO COLLECTION
AND CU LTU RE .............................................................. .........


BIOGRAPHICAL SKETCH ................................................................................


~ST OF RE~RENC~S ........................................













LIST OF TABLES


Table 3-1.


Table 3-2.


Table 4-1.


Table 4-2.


Table 5-1.


Table 5-2.


Table 5-3.


Table 6-1.


Table 6-2.


Table 7-1.


Table 7-2.


Effects of maternal heat stress for one day during early
pregnancy on rectal temperature and embryonic viability........

Effect of maternal heat stress during early pregnancy on
stage of embryonic development on d 8 of pregnancy..............

Effect of exposure of 2-cell bovine embryos to various
temperatures on subsequent embryonic development...............

Effects of 41 C heat shock on subsequent development
of 2-cell and morula stage bovine embryos.................................

Effects of in vitro or in vivo development and
presence or absence of serum on percentage of live
embryos following heat shock........... ....... .......... ..... ....... ..........


Ontogeny of thermotolerance for embryos developed
in vitro or in vivo which proceeded in development
following heat shock. ........... ..............................................


Induction of thermotolerance in bovine blastocysts...................

Environmental temperatures for cooling and shade
treatm ents...........................................................................................


Reproductive responses of cows exposed to cooling
and shade treatments from 2 to 3 d before until 5 to 6 d
following breeding................................................ .......................................


Effect of glutathione and taurine on viability and
development of bovine morulae to 42 C heat shock for 2 h....


Dose-dependent effect of GSH on viability and
development of marine morulae exposed to a heat shock


page









Table 7-3.


Table 7-4.


Effect of GSH on viability and development of murine
morulae exposed to a heat shock of 43 C for 2 h......................

Effect of glutathione and taurine on subsequent
development of 2-cell bovine embryos exposed to
41 C heat shock for 3 h..............................................................


page












LIST OF FIGURES


Figure 2-1.

Figure 2-2.


Figure 3-1.


Figure 5-1.


Figure 7-1.


Figure 8-1.


Figure 8-2.


Synthesis, utilization and recycling of GSH within cells...........

Events associated with the ontogeny of mechanisms
conferring thermotolerance in murine embryos.........................


Effect of maternal heat stress on 4',6'-diamidino-2-
phenylindole (DAPI) score of embryos (>2-cell).......................


Temperature treatments used to determine the induction
of thermotolerance for murine and bovine embryos.................

Absence of beneficial effects of GSH ester for
alleviating heat shock induced decreases in subsequent
development of 2-cell bovine embryos..................................


Current model depicting developmental changes in
resistance of bovine embryos to elevated temperatures...........


Current model of events associated with the ontogeny
of thermal resistance in murine embryos.....................................


page












ABBREVIATIONS


ABAM
ANOVA
ATP
ATPase
BRLC
BSA
BSO
BSS
C
d
DAPI
DIM
DNA
DNAk
DPBS
ETOH
FSH-P
g
GSH
GSSG
h
hCG
H202
HOC1
HSE
HSC
HSF
HSP
htFCS
IFNr
IU
IVC
IVF
IVM
lrfla


Antibiotic-antimycotic solution
Analysis of variance
Adenosine triphosphate
Adenosine triphosphate hydroxylases
Buffalo rat liver cells
Bovine serum albumin
D,L-buthionine-[S,R]-sulfoximine
Bovine steer serum
Centigrade
Day
4',6'-Diamidino-2-phenylindole
Days in milk
Deoxyribonucleic acid
Bacterial counterpart to mammalian HSC70
Dulbecco's phosphate buffered saline
Ethanol
Follicle-stimulating hormone (pituitary-derived)
Gram
Glutathione (reduced)
Glutathione (oxidized)
Hour
Human chorionic gonadotrophin
Hydrogen peroxide
Hypochlorous acid radical
Heat shock elements
Heat shock protein cognate
Heat shock transcription factors
Heat shock protein
Heat-treated fetal calf serum
Interferon-tau
International unit
In vitro culture
In vitro fertilization
In vitro maturation
Ir;lnralltnnc







LH
m
M
mg
min
ml
mm
mo
mRNA
NADPH
*02.
* OH
PGF,
pi
PMSG
pp60s"
R202
ROH
SEM
TALP


Luteinizing hormone
Meters
Molar
Milligram
Minute
Milliliter
Millimeter
Month
Messenger ribonucleic
Nicotinamide adenine
Superoxide radical
Hydroxyl radical
Prostaglandin F,
Isoelectric point


acid
dinucleotide phosphate


Pregnant mare serum gonadotropin
Rous sarcoma virus transforming protein
Peroxide residue
Reduced peroxide; stable hydroxyl
Standard error of the mean
Modified Tyrode's solutions
Volume/volume
Week
Weight/volume
Year













Abstract of Dissertation Presented to the Graduate School
of the University of Florida in Partial Fulfillment of the
Requirements for the Degree of Doctor of Philosophy

DEVELOPMENTAL CHANGES IN RESISTANCE OF MAMMALIAN
EMBRYOS TO ELEVATED TEMPERATURE AND STRATEGIES
TO IMPROVE FERTILITY IN DAIRY CATTLE
DURING HEAT STRESS

BY

ALAN DALE EALY


AUGUST


Chairperson: Peter J.


1994


Hansen


Major Department: Animal Science


Embryos gain resistance


to adverse effects of heat stress as development


progresses.


primary goals of this dissertation research were


to identify the


ontogeny of thermal resistance in mammalian embryos and identify systems to limit


effects of heat on bovine embryo survival.


In the first study, embryonic survival was


decreased in cows heat-stressed on d


of pregnancy but not on d 3, 5


or 7 of


pregnancy,


implying


embryos


gain


increased


thermal


resistance


pregnancy.


developmental


resistance


embryos


to heat


was


verified


exposure


of bovine embryos


to elevated


culture


temperatures


heat


shock).


Subsequent in vitro development was decreased for 2-cell bovine embryos but not for


..r a~r n .1n n n i n A .~ ,~ .4 1 / r2 t.


* nc .. nail*. n nHnnarra







which confer thermal resistance was investigated by determining the ontogeny of

induced thermotolerance in murine embryos (ie., ability of embryos to resist a severe


heat shock by prior exposure to a mild heat shock).


Induction of thermotolerance


was observed between the 8-cell and blastocyst stage for murine embryos, suggesting


intracellular


thermoprotective


mechanisms


are acquired


during


embryonic


development.

Two strategies for limiting effects of heat stress on bovine embryos were


examined.


Pregnancy rates were slightly improved in cows exposed to short-term


cooling


from


to 3


d before


until


to 6 d after


breeding.


Two


molecules,


glutathione and taurine, reduced heat shock effects on viability and/or development

of cultured bovine and murine morulae but did not reduce heat shock effects on


cultured 2-cell bovine embryos.


In conclusion, embryos gain resistance to elevated


temperatures as development progresses, probably through acquisition ofintracellular

thermoprotective mechanisms. Pregnancy rates were improved in cows by short-term


cooling.


However, glutathione and taurine could not protect embryos during initial


stages of development from the adverse effects of elevated temperature.













CHAPTER I
INTRODUCTION


Failure of reproduction is costly to the American livestock industry; in 1978,


reproduction-associated


losses


farm


animals


were


estimated


at $1.4


billion


(Gerrits et at,


1979).


In lactating dairy cows, it has been estimated that $2.37 to


$4.63 of gross income is lost each day a cow remains non-pregnant after 90 days


postpartum


(Ferris


Fogwell,


1984).


One


phenomenon


contributes


economic


losses


cattle


heat-stress


induced


infertility.


Pregnancy


rates


lactating cows in Arizona, Florida and Israel have been reported to decrease from


40 to 60% during winter months to as low as


10 to 20


during summer months


(Stott and


Williams,


1962;


Badinga et


1985;


Berman and


Wolfenson,


1992).


Elevated ambient temperatures also have been reported to reduce pregnancy rates


in mice (Elliot et at,


1968; Elliot and Ulberg, 1971; Belive, 197


Baumgartner and


Chrisman, 1981a; Baumgartner and Chrisman, 1981b), rabbits (Ulberg and Sheean,


1973; Wolfenson and Blum, 1988), pigs (Warnick et al.,


1965; Tompkins et al, 1967


Edwards et a., 1968; Omtvedt et aL,


1971),


and sheep (Dutt et al.,


1959; Dutt, 1963;


Woody and Ulberg, 1964).


Thus, the problem that heat stress poses to the female


is of general importance to mammals.

The effects of heat stress in cattle can be avoided by provision of intensive









increased


to rates


observed


during


winter


months


with


exposure


to repetitive


sprinkling/forced ventilation (Wolfenson et aL,


1988) and air-conditioning (Stott et


, 1972; Thatcher et at,


1974).


However, since the economic gain from increased


fertility and milk yield may not be sufficient to make systems such as these feasible


on commercial operations, additional approaches must be investigated.


The maturing


oocyte and early developing embryo appear to be highly susceptible to heat stress


effects in


cattle


(Dunlap and Vincent,


1971;


Putney


et al.,


1988a;


Putney


et a.,


1989a).


It is quite possible that if periods of oocyte and embryonic sensitivity to heat


stress and biochemical processes which promote thermal resistance in embryos are


investigated, additional


methods may be available


to limit


heat stress effects on


pregnancy rates.

Primary goals of this dissertation research were to determine when embryos

gain increased resistance to heat stress effects and identify systems to prevent heat


stress effects.


Identification of the ontogeny of thermal resistance was accomplished


for bovine embryos in vivo and for bovine and murine embryos in vitro.


completed in vitro with murine embryos were also used


Studies


to evaluate whether the


ontogeny of thermal resistance is correlated with previous reports of the ontogeny of

heat shock proteins (HSPs) which protect intracellular macromolecules from heat.

Potential methods for reducing heat stress effects on early embryonic development


were examined.


The first was maintaining cows in a cooled environment around the


time nf hrtedino and early Pmhrunnir dev lnnment


.enndlv nuce nf antinvidantc ac













CHAPTER II
REVIEW OF LITERATURE

Effects of Elevated Temperature on Reproduction
in Dairy Cattle


Summer infertility in dairy cattle is caused by the combination of decreased


estrous detection (Gangwar et at,


1965


Roller and Stombaugh,


1974;


Wolff and


Monty, 1974; De Silva et al.,


1981


Gwazdauskas et at


1981


Thatcher and Collier,


1986


Wolfenson et at


, 1988) and lowered pregnancy rates (Erb et at,


1940; Stott,


1960; Poston et


, 1962;


Stott


Williams,


1962


Dunlap


Vincent,


1971;


Ingraham et at,


1974; Badinga et aL,


1985


Cavestany et at,


1985


Monty and Wolff,


1974


Udomprasert and Williamson, 1987


Putney et aL,


1988a; Putney et al.,


1989a).


Environmental conditions such as elevated ambient temperature, high humidity and


intense solar radiation produce a stress on the animal, termed heat stress,


disrupts the animal'


loss.


which


ability to maintain a balance between heat production and heat


The resulting hyperthermia and the physiological changes induced to limit


hyperthermia can have detrimental effects on reproductive processes such as estrous

detection, fertilization, embryonic development, fetal development, uterine function


and changes in hormonal patterns.


This review will focus on describing effects of


heat stress on reproductive processes and physiological and biochemical mechanisms


-- l, Ir *


Ir r~ ,~ CC









mice (Elliot et at,


1968; Elliot and Ulberg,


1971; Bellv6,


1972; Baumgartner and


Chrisman, 1981a; Baumgartner and Chrisman, 1981b), rabbits (Ulberg and Sheean,


1973; Wolfenson and Blum, 1988), pigs (Warnick et at,


1965;


Tompkins et at,


1967;


Edwards et at, 1968; Omtvedt et aL, 1971), and sheep (Dutt et at,


1959; Dutt, 1963;


Woody and Ulberg,


1964).


Since processes by which heat stress alters fertility in


cattle


are probably


similar


to heat-stress


induced


infertility


other


species,


information from these species will be used when illustrative of mechanisms that are

occur in cattle.

Estrous Detection


Failure of estrous detection is a primary cause for decreased reproductive

performance in dairy cattle under many conditions and is amplified by heat stress.

In one study (Thatcher and Collier, 1986), 66% of potential heats were undetected


in a commercial herd under thermoneutral conditions while approximately 80


potential heats were not detected during heat stress (Thatcher and Collier,


1986).


The decrease in estrous detection during heat stress is a result of decreased duration


and intensity of estrous activity.


During periods of heat stress, the duration of estrus


reduced


as low


as 8 h in


lactating


cows


(Wolff


Monty,


1974;


Gwazdauskas et at


1981


Wolfenson et at,


1988) and the number of mountings


during estrus can be reduced dramatically (Roller and Stombaugh, 1974; De Silva et

at, 1981).

Although causes for diminished estrnus activity dhrinn heat stress have not







5
of behavioral estrus is reduced to decrease metabolic production associated with


physical activity.


Alternatively, physiological events that influence estrous behavior


can be altered by heat stress.


In this regard, periovulatory surges of estradiol are


diminished in heat-stressed cattle (Gwazdauskas et al.,


1981; Roman-Ponce et at,


1981) and pigs (Flowers and Day,


1990).


Attenuated estradiol secretion at estrus


may


be caused by


decreased


preovulatory


or basal


concentrations of luteinizing


hormone (LH;


Wise et at


, 1988;


Younas et aL,


1993) or decreased follicle growth


(Badinga et at


1993) during heat stress.


Fertilization


Fertilization is usually not a major contributing factor to infertility in cattle.

Fertilization rates in cattle maintained in thermoneutral environments and bred by

either natural breeding or artificial insemination have been estimated to be 80 to


100% (Kidder et aL,


1954).


Furthermore, rate of fertilization was unaffected by heat


stress in heifers (Putney et aL,


1989a), sheep (Dutt, 1963), mice (Elliot and Ulberg,


1971; Baumgartner and Chrisman,


1988) and rabbits (Alliston et al.,


1965).


Other


reports, however,


have documented that


maternal


heat stress of


ewes decreased


fertilization rates (Dutt et aL,


1959; Alliston et aL,


1961; Alliston and Ulberg, 1961).


Fertilization of cultured bovine oocytes was decreased by 24 h exposure to 41 C but


not to 40 C (Lenz et aL,


1983).


There are other deleterious consequences of heat stress during the period


accompanying fertilization.


In particular. embryonic development and survival rates









(Elliot et aL,


1968; Elliot and Ulberg, 1971; Baumgartner and Chrisman, 1988) and


rabbits (Alliston et aL,


1965) were reduced by exposure of animals to heat stress


during


either


fertilization


or the


period


final


oocyte


maturation


preceding


deposition of spermatozoa.


The above mentioned experiments suggest that heat


stress can disrupt the periovulatory oocyte or spermatozoa in a manner that results

in formation of an embryo with reduced competence.


Effects


on oocvtes.


mice,


maternal


heat


stress


during


final


oocyte


maturation caused disruption of spindle


fiber formation during metaphase


I and


increased the incidence of oocytes that did not undergo normal meiosis (Baumgartner


and Chrisman, 1981a; Baumgartner and Chrisman, 1981b).


Other investigators have


observed that maternal heat stress during this period caused oocyte degeneration,

polar body retention and increased incidence of aneuploidy (Branden and Austin,


1954).


Parthenogenic activation has also


been observed in heat-shocked mouse


oocytes (Komar, 1973; Balhkier and Tarkowski, 1976).


A possible cause for oocyte


sensitivity to elevated temperatures is a lack of intracellular protective mechanisms


such as heat-shock proteins (Manejwala et at,


1991).


This subject will be pursued


in more detail in later sections.


Maternal


heat


stress


alter


oocyte


quality


through


disruption


hormonal regulation of oocyte maturation and ovulation.


Preovulatory surges of LH


(Younas et aL,


1993) and estradiol (Gwazdauskas et at,


1981


Roman-Ponce et al,


1981) are decreased during heat stress in cattle and this could affect initiation and









by heat stress.


Serum concentrations of LH have been reported to be decreased


throughout the estrous cycle of heat-stressed cows (Wise et at,


1988) and this may


be a cause for diminished follicle growth during periods of heat stress (Badinga et al

1993).


Effects on soermatozoa.


Sensitivity of spermatozoa to elevated temperatures


in the female reproductive tract also contributes to decreased fertility.


Incubation


rabbit


spermatozoa


at 40


h had


no deleterious


effects


on in


fertilization rate but subsequent embryonic survival was decreased (Burfening and


Ulberg,


1968).


Similarly,


fertilization


female


rabbits


maintained


thermoneutral conditions were unaffected by insemination with spermatozoa that had


been recovered from a mated female that was exposed to


heat stress but, again,


subsequent


embryonic


development


was


decreased


(Howarth


1965).


Monterroso et at (1994) reported that exposure of spermatozoa to 41 or 42 C for 3

h did not effect cleavage rate of bovine oocytes in vitro but subsequent development


was impaired.


Perhaps elevated


temperatures promote chromosomal damage of


spermatozoa, similar to that of oocytes in a way that affects embryonic development.

The validity of this hypothesis may be argued, however, because spermatozoa do not


undergo


meiotic


events


during


their


residence


reproductive


tract


spermatozonal chromosomes are tightly packaged in cattle and other species (Amann


and Schanbacher,


1983).


Also, Monterroso et aL


(1994) found no effect of heat


shock on DNA damage of bovine snermatozoa using acridine orange as an indicator.







8

Effects on spermatogenesis. Adverse effects of heat stress on bulls (Erb et aL,


1942) can contribute to summer infertility in cattle bred by natural breeding.


Heat-


stressed bulls have semen with reduced motility, concentration and total amount of


spermatozoa per ejaculate (Casady et aL,


1953; Johnson and Branton, 1953


Branton


et aL.,


1956;


Fryer


et at,


1958).


These


effects


are caused


a disruption


spermatogenesis.


Rates of fertilization and implantation, and fetal survival were


decreased for 30 d following exposure of male mice to heat stress (Burfening et al.,


1970).


Similarly, sperm quality is decreased for 6 to


10 wk following exposure of


bulls to heat stress (Casady et at,


1953; Skinner and Louw, 1966; Meyerhoeffer et at,


1985).


This


period


decreased


sperm


quality


coincides


with


duration


spermatogenesis


to 60


Amann


Schanbacher,


1983).


Spermatocytes,


spermatids and B spermatogonia appear to be the most sensitive cells to elevated

temperatures (DeAlba and Riera, 1966; Amann and Schanbacher, 1983).

Early Embryonic Development

Several lines of evidence indicate that embryonic death is increased by heat


stress.


As previously mentioned, exposure to heat stress during oocyte maturation


and fertilization causes decreased embryonic development in several species (Dutt,


1963;


Woody and Ulberg,


1964; Alliston et at,


1965


Elliot et at


, 1968; Elliot and


Ulberg, 1971


Baumgartner and Chrisman, 1988; Putney et at,


1989a).


Embryonic


survival is also decreased by exposure of cattle to heat stress during the first 3 d


(frlin iol rnl aln ti~1 7 nflnnnnt ifihiX a. r A fnnrn#, 'In'.


frl,,,,l,, ~,,,~:,,


~dn~c. I


I









fertilization had a higher incidence of


death during summer months than winter


months.


Observations


in sheep


(Alliston


Ulberg,


1961;


Dutt,


1963),


swine


(Tompkins et at,


1967


Wettemann et at,


1988), mice (Bellv6,


1976) and rabbits


(Wolfenson and Blum, 1988) also indicate that maternal heat stress during the first

few days of pregnancy causes a large increase in embryonic mortality.

Embryos become more resistant to adverse effects of maternal heat stress as


development proceeds.


In swine, exposure to heat stress during the first


to 8 d of


pregnancy decreased subsequent embryonic survival, whereas heat stress after this


period did not alter embryonic survival rates (Tompkins et at,


1967


Edwards et at,


1968; Omtvedt et aL,


1971).


The ontogeny of embryonic resistance to heat stress was


further defined in sheep.


Embryonic viability was decreased with maternal heat


stress on either d 0 (breeding), 1,


or 7 of pregnancy (Dutt,


1963).


However,


when comparing heat stress effects among days, heat stress on d 0 and 1 of pregnancy


caused more severe embryonic losses than heat stress on d 3,


5 or


7 of pregnancy


(Dutt, 1963).


Similarly, exposure of rabbit embryos to 40 C for 6 h in culture was


detrimental to subsequent in vivo development at the 1-cell stage but not at the 2-cell


stage (Alliston et aL,


1965).


Cultured murine 1-cell embryos were also more sensitive


to heat shock than 2-cell embryos (Gwasdauskas et aL,


1992).


It has not been determined whether a similar phenomenon occurs in cattle.

Indirect evidence, however, suggests that bovine embryos gain resistance to heat


stress effects during early stages of development.


There is a negative correlation of









insemination or the day following insemination in dairy cattle (Ingraham et aL, 1974;


Gwasdauskas et aL


,1975; Badinga et aL, 1985).


Biggers et aL (1987) found no effect


of heat


stress


from


to 16


pregnancy


on pregnancy


embryonic


development was decreased.


In another study (Putney et aL,


1989b),


transfer of d 7


embryos retrieved from superovulated heifers to heat-stressed lactating dairy cows

increased pregnancy rates (29.2%) as compared with pregnancy rates of cows which


were inseminated artificially (13


.5%).


Similarly, there was no seasonal variation in


pregnancy


rates


resulting


from


transfer


frozen/thawed


embryos


to recipients


located in the Southwest United States (Putney et al.,


1988c).


There


are two


possible


mechanisms


which


heat


stress


could


disrupt


embryonic development.


First, elevated body temperatures could directly alter rate


of embryonic development through influences of heat on cell survival.


Alternatively,


heat stress could act indirectly, by modifying functions of the uterus and oviducts.

Alliston and Ulberg (1961) conducted a study using reciprocal embryo transfer in


sheep


to determine


pregnancy rate


relative


embryos


contribution


transferred


at d 3


these


mechanisms.


from a heat-stressed


donor to a


nonstressed recipient were 9.5


Pregnancy rate of embryos transferred from a


nonstressed donor to a heat-stressed recipient were 24.0%.


In contrast, pregnancy


rates for embryos transferred from a thermoneutral donor to a nonstressed recipient


were 56.5


Therefore, both direct and indirect effects were involved with the heat-


induced


decrease


in embryonic survival.


with 4


lirrct


-4


effects


. V V- V-ww w-,w


of heat


being


more









provided


from


studies


which


exposure


embryos


elevated


culture


temperatures, or heat shock, reduced embryonic survival.


For example,


Alliston et


(1965) found that exposure of 1-cell rabbit embryos to 40 C for 6 h in culture


decreased subsequent embryonic survival in utero.


In vitro development was also


decreased in mouse embryos exposed to 39 C for 96 h (Gwasdauskas et at,


1992) or


42 to 43 C for 2 h (Ar6chiga et at,


1992; Malayer et at, 1992; Ar6chiga et al,


1994a).


Uterus and Oviduct


uterus


oviduct


are responsible


secreting


nutrients,


growth


regulators


other


agents


which


promote


establishment


maintenance


pregnancy.


Hence, alterations in the function of the uterus and oviduct by heat stress


could be detrimental for fertilization, embryonic development and maintenance of


pregnancy.


As mentioned previously, a reciprocal embryo transfer study indicates


that substantial decreases in pregnancy rate result from effects of heat stress on the

uterus (Alliston and Ulberg, 1961).

Detrimental effects of heat stress on the uterus and oviduct may be caused,

in part, by altered synthesis and secretion of uterine and oviductal proteins in direct


response to elevated temperatures.


Culture of endometrial explants from cows at 43


C increased protein synthesis and secretion by the endometrium (Malayer et aL, 1988;


Malayer and Hansen, 1990).


In one study (Malayer et aL,


1988), secretion of seven


individual proteins from the ipsilateral uterine horn of cows (obtained from d 0 to


d 8 nostestrus)


were c


decreased bv


exposure


to heat


shock.


a second


study









proteins from oviductal explants ipsilateral to the site of ovulation for Holstein cows.

Malayer and Hansen (1990) also determined that in contrast to protein secretion

from oviducts of Holsteins, heat shock increased protein secretion from oviductal


explants


ipsilateral


to the


ovulation


Brahman


cows.


Perhaps


these


differences are related to enhanced thermal tolerance of Brahmans to adverse effects


of heat stress on reproduction.


At d 17 of pregnancy, in vitro exposure to elevated


temperatures did not affect endometrial explant synthesis or secretion of proteins

(Putney et aL, 1988b), whereas in vivo, uterine content of proteins collected from the


ipsilateral uterine


horn at


d 16 were


decreased with


heat stress from


d 8 to


(Geisert et aL,


1988).


Alterations in protein synthesis and secretion by the uterus and oviduct may


also be caused by altered secretion of progesterone and estradiol.


Several studies


have reported decreased serum progesterone concentrations during summer months


(Rosenberg et aL,


1977; Wise et at,


1988; Wolfenson et al.,


1988; Imtiaz-Hussain et


1992;


Younas et aL


, 1993; Howell et aL,


1994).


In contrast, increased plasma


concentrations of progesterone have also been reported during heat stress (Abilay


et aL


, 1975;


Vaught et at,


1977


Roman-Ponce et al.


, 1981).


This latter effect is


probably short-lived and caused by a possible acute heat stress effect on adrenal


secretion


progesterone


(Thatcher,


1974).


Roman-Ponce


et al.


(1981)


Gwasdauskas et aL (1981) also concluded that acute heat stress decreased the peri-


vnll]ltnrvA riA in Cenim PcfrrJnl -rkn ratratn nc f


Tk;e PffLIFf ;r nmkrlklrr FrlllcLIA krr










in uterine blood flow may also influence uterine and oviductal function.


Estradiol-


stimulated uterine blood flow was reduced in cows exposed to heat stress (Roman-


Ponce et at,


1978).


Regulation of Luteal Function by the Uterus and Embryo

Conceptus tissue protein content and protein secretion at d 17 of pregnancy


is affected by heat stress.


Exposure of


conceptuses


to 43 C for


h decreased


overall protein synthesis and secretion and decreased secretion of interferon-r (IFN r


Putney et al, 1988b).


In contrast, secretion of IFN r from conceptuses was unaffected


by maternal heat stress from d 8 to 16 of pregnancy (Geisert et al.,


1988).


Secretion


of PGF, from the endometrium is altered during periods of thermal stress.


Basal


secretion of PGF, from endometrial explants at d 17 of pregnancy or d 17 of the


cycle was increased by heat shock (Putney et aL,


1988b; Putney et at,


1988c; Putney


et a.,


1989c;


Malayer


et al.


, 1990).


v~iVO,


heat stress


cyclic cows on d


postestrus increased oxytocin-stimulated release of PGFu in one study (Putney et al.,


1989c) but not another (Wolfenson et at,


1993).


Basal secretion of PGF, was also


increased in pregnant cows exposed to heat stress (Putney et aL,


1989c).


Under


thermoneutral conditions, oxytocin-stimulated release of PGF, from endometrium


on d 17 of pregnancy is minimal (Putney et at,


1989c;


Wolfenson et aL


, 1993).


one study (Wolfenson et at,


1993), heat stress caused increased levels of oxytocin-


stimulated


PGFz,


pregnant


cows.


another


study


(Putney


et at


, 1989c),


d t t I -I~F F


1


t 'I







14

release also was increased from endometrial explants of pregnant cows exposed to


heat shock (Putney et aL,


1988b).


Taken together, these results suggest that both


basal and oxytocin-stimulated secretion of PGF, is increased for both cyclic and

pregnant cows exposed to heat stress.

Fetal Develooment


Exposure of animals to heat stress during mid and late gestation can promote


fetal malformations in several species (Mirkes, 1987


Webster et al., 1985; Tikkanen


and Heinonen,


increase


1991).


Imposition


incidence


cranial


of heat stress at


malformations


d 9 to


such


10 of pregnancy


microphthalmia,


encephalocele and maxillary hypoplasia in rats (Webster et alt,


1985).


This effect is


caused by a direct action of elevated temperature on the fetus since developmental

defects have also been observed after exposure of cultured d 9 rat fetuses to heat


shock (Mirkes, 1987).


Fever in pregnant women has been reported to increase the


incidence of


cardiovascular malformations in


offspring (Tikkanen and Heinonen,


1991).


Since


approximately


60%


fetal


growth


occurs


during


90 d


gestation in cattle (Eley et at,


1978),


hyperthermia could be detrimental to fetal


development during this period.


Heat stress during the last few months of pregnancy


causes decreased birth weights of dairy calves (Bonsma, 1949; Collier et aL,


1982;


Thatcher and Collier,


1982) and decreased placental


tissue weights (Head et at,


1981).


Heat stress also affects other species in a similar manner including mice









Brown et at


, 1977; Brown and Harrison, 1981; McCrabb et at,


1993).


The decrease


in birth weight is probably a consequence of decreased uterine and placental blood


flow, as evidenced in sheep (Alexander and


Williams,


1971;


Brown et at,


1977


Brown and Harrison, 1981; McCrabb et al., 1993).


In heat-stressed cattle, decreased


birth weights are associated with decreased prepartum concentrations of estrone


sulfate in maternal serum (Collier et at,


impaired by heat stress.


1982), confirming that placental function is


Collier et al. (1982) also found that exposure of cows to heat


stress during the last 90 d of gestation reduced subsequent milk yield.


This effect is


probably


to decreased


lactogenesis


caused


decreased


placental


function


(Thatcher et at,


1980; Collier et al.,


1982).


In contrast, traits such as days to first


estrus, days open and services per conception were not affected by exposure to heat


stress during late gestation (Lewis et at,


1984).


Mechanisms byv Which Cells are Protected from


Effects of Elevated Temoerature


Mechanisms of Heat Induced Cell Damage


Elevated


body


temperatures


exposure


cells


to elevated


culture


temperatures (i.e.,


heat shock) adversely affect structure and functional capabilities


of lipids, proteins and nucleic acids.


Alterations of cellular


components by heat


shock occurs as a result of three potential mechanisms.


First, elevated temperature


can directly affect structure and function of macromolecules and cellular organelles.









shock and these molecules can in turn oxidize most cellular molecules.


Lastly, heat


shock may induce the onset of programmed cell death, or apoptosis.


Direct effects of heat shock.


Lipids in cellular membranes are highly sensitive


to changes in temperature.


Increased temperatures of 40 to 45 C causes bilayer


expansion and formation of inverted micelles (Overath et at,


1970; McElhaney, 1974;


Yatvin,


1977;


Bowler,


1981).


These conformational


changes,


termed membrane


blebbing, are caused primarily by decreased stability of saturated fatty acids (Konings,


1988).


One consequence of increased fluidity of membranes following heat shock is


alterations in ion permeability.


For example,


calcium influx increases during heat


shock (Stevenson et aL, 1986; Stevenson et at,


1987), and this can promote cell death


in several cell types (Fawthrop et at,


1991).


Protein denaturation also occurs upon exposure to temperatures of 40 to 45

C, primarily through disruption of weak amino acid bonds that confer tertiary and


quartenary structure (ie.,


hydrogen bonds and hydrophobic interactions; Privalov,


1979; Lepock et


, 1983).


Heat-induced alterations


protein structure


cause


disassembly of microtubules (Coss et at,


1982;


Wiegant et at,


1987), intermediate


filaments (Wiegant et at,


1987; Welch and Mizzen, 1988) and microfilaments (Welch


and Suhan, 1985


Iida et at


,1986).


As a result, cell division, cell-cell communication,


and cell adherence to substrates can be


impaired.


It has also been shown that


conformational changes in membrane-associated proteins caused by heat shock can


nltP.r gincnl trnncdilrtinn uevtemc ( {rnn\rr oat nl


102It r"aAltxn-, nt nI


1O2C* T hn









to 45 C, however (Ashburner and Bonner, 1979; Walton et al., 1989).


For example,


activity


ornithine


decarboxylase was


maximal


at 40 C


in rat tissues,


whereas


activity decreased dramatically with exposure to higher temperatures (Penafiel et at,


1988).


This biphasic effect is probably caused by an increase in specific activity of


enzymes at slight elevations in temperature but denaturation of enzymes as a result

of more severe heat shock.

Purine and pyrimidine ring structures on nucleic acids are also sensitive to


heat shock.


Modifications in ring structures have been observed to cause unwinding


of supercoiled DNA, double stranded DNA breaks, chromosomal exchanges and


increased incidence of aneuploidy (Vig, 1979; Sherwood et at,


1987


Mackey et aL,


1988; Borrelli et at,


1991).


Temperatures required to produce such effects are high


>45 C), however, suggesting that this effect is not observed during exposure of most


cells to elevated temperatures.


Additionally, repair of damaged DNA is retarded


following


exposure


heat


shock,


since


activities


topoisomerase


enzymes


(particularly topoisomerase II) are reduced by heat shock (Dewey and Esch, 1982;


Chu and Dewey, 1987).


Translational capabilities of cells also are affected adversely


heat


shock


because


alterations


ribosomal


RNA


structure


denaturation


ribosomal-associated


proteins


(Warocquier


Scherrer,


1969;


Bouche et at,


1979; Sadis et at,


1988).


Free


radicals.


addition


to direct


actions


heat


shock


on cellular


components, lipids, proteins and nucleic acids also may be modified by reaction with









unpaired electron, as well as other reactive oxygen species (i.


H202).


Production


of free radicals (Skibba et at,


1986;


Freeman et at,


1990;


Lin et al.,


1991) and


intracellular antioxidant systems (Omar and Lanks, 1984; Loven et al.,


et at,


1985; Harris


1991) have been shown to increase during heat shock.


Free radicals are formed by normal metabolism of oxygen by mitochondrial


electron


transport


chain


reactions


metabolic


reactions


endoplasmic


reticulum and peroxisome.


Normally, four electrons are transferred to oxygen to


yield water (Oz


+ 4e"


-->


2 H,0; Chance et at,


1979) and generate ion gradients


for phosphorylation of


desired substrates.


However, oxygen also readily accepts


single electron transfers to yield formation of superoxide (* O2_) by univalent electron

acceptance, hydrogen peroxide (H202) by bivalent electron acceptance, and hydroxyl


radical (.OH) by trivalent electron acceptance (Fidovich, 1975; Chance et al.,


1979;


Allen,


1991).


The most prevalent free radical formed by mitochondrial electron


transfer is *02, (Ramasarma, 1982; DiGuiseppi and Fridovich, 1984), which can be


readily dismutated to H202 by superoxide dismutase (Chance et aL,


1979).


The *OH


radical is formed primarily by reaction of


*


each other (Halliwell and Gutteridge, 1984).


and H202 with heavy metals or with


Additionally, free radicals are formed


by metabolism of specific cellular molecules such as xanthine and hypoxanthine


(Halliwell,


1987).


possible


during


heat


shock,


disruption


electron


transport systems causes increased production of free radicals.

Trmmpdintplv fnllnurwino fnnmntirn frso rOAiralc rsQ rt inrth valiilCor mnlrnliac









(Halliwell


Gutteridge,


1984).


However,


*OH


*02,


radicals


are more


reactive than H2O,.


The most devastating effect of free radical reactivity on cells is


peroxidation of membranes caused by extraction of hydrogen molecules from lipids.

The reactive carbon molecule formed by reaction with free radicals forms a peroxide


which


extracts


hydrogen


from


other


fatty


acids,


thus


catalyzing


continuous


peroxidation of lipids (Sevanian and Hochstein, 1985; Halliwell, 1987).


The resulting


peroxidation decreases membrane stability, alters ion and macromolecule transport,

and increases production of water soluble aldehydes which can cause membranes to


completely


their integrity


(Comporti,


1985;


Sevanian and


Hochstein,


1985).


Additionally, free radicals react with thiol groups or hydrophobic residues of proteins


(Wolff and Dean, 1986; Davies et at,


1987


Hunt et at,


1988; Pacifici et aL,


1989;


Salo et at, 1990) and purine and pyrimidine structures of nucleic acids (Johnson and


Demple, 1988;


Teebor et aL


, 1988; Povirk and Steighner, 1989; Simic et at,


1989).


Apoptosis.

(apoptosis) in cells.


It is possible that heat shock promotes programmed cell death

Apoptosis represents cell death occurring from intrinsic cellular


stimuli, which usually requires novel protein synthesis (Kerr et aL,


1972; Fawthrop


et aL,


1991


Eastman, 1993).


Such a phenomenon is observed during development


(Gramzinski et aL,


1990) as well as in differentiated cells (Duvall and Wyllie, 1986).


However, it remains unknown whether apoptosis is a mechanism by which heat shock

causes cell death.


A l -i,,bnnhi ka0 carht, tLr nrnrntac A-l m ao nf rnonui


Incittnrrrl t~pn~n~nlnrnnna









mechanisms which confer thermal resistance.


Such systems include


HSPs,


which


serve to protect cellular components from potential damage caused by heat shock,

and antioxidants, which scavenge free radicals and restore cellular components that


have reacted with free radicals. Resistan

enhanced by induction of thermotolerance.


ce of cells to heat shock can be further

This is a transient cellular event defined


as the ability of cells to withstand a severe heat shock after prior exposure to a less


severe heat shock (Gerner and Schneider, 1975; Henle and Leeper, 1976).


Induction


of thermotolerance has been observed to reduce effects of heat shock on survival of

d 10 rat embryos (Mirkes, 1987), viability of several cell lines (Gerner and Schneider,

1975; Henle and Leeper, 1976; Li and Werb, 1982; Li and Mak, 1989; Maytin et al.,

1990; Hatayama et aL, 1991), translational activity of cells (Mizzen and Welch, 1988)


and cytoskeletal disassembly (Welch and Mizzen, 1988).


It is possible that embryonic


survival could be improved by manipulation of these mechanisms if the regulation

of thermal resistance or regulation of induced thermotolerance for embryos can be


further defined during early embryonic development.


The following sections will


review mechanisms involved with conferring thermal resistance of cells.

Heat Shock Proteins


Heat shock induced gene expression is a ubiquitous phenomenon of eukaryotic


prokaryotic


cells


(Nover


Scharf,


1991).


major


series


such


heat-


inducible proteins include heat shock proteins (HSPs).


Since many HSPs serve as


chaperone


molecules


ellss


during


non-stress


conditions.


HSPs


have


been


... .









cellular components.


The protective actions of HSPs involve preventing structural


damage


proteins


nucleic


acids


or targeting


damaged


components


degradation or rejuvenation.


The protective role of HSPs are not limited to heat


shock; synthesis of HSPs also occurs with exposure to other stresses including anoxia


(Sciandra et


, 1984),


oxidizing


agents


(Kim et


1983a;


Spitz et


, 1987),


chelating agents (Levinson et al.,


1980), sulfhydryl agents


(Levinson et aL,


1979;


Carlson and Rechsteiner, 1987), amino acid analogs (Kelley and Schesinger,


Li and Laszlo, 1985; Hatayama et at,


1978;


1986), gene expression inhibitors (Hatayama


et at


, 1986;


Dewey,


1987),


organic solvents


(Hahn et


, 1985),


viral


infection (Rose and Khandjian, 1985), mutagenic agents (Carr et at,


1986; Forance


, 1989a),


high


(Whelan


Hightower,


1985),


serum


or mitogen


supplementation (Wu and Morimoto,


1985;


Wu et at


, 1986), glucose deprivation


(Sciandra and Subjeck, 1983


Whelan and Hightower, 1985), ischemia (Cairo et aL,


1985)


ultraviolet radiation


(Brunet and


Giacomoni,


1989).


chaperone


characteristics of HSPs are likely to also aid in protecting cells from damage caused

by a number of these stress conditions as well as to play an essential role in normal

cellular function.

Proteins within the HSP family are identified according to their molecular

weight; for example, HSP70 represents heat-induced proteins whose molecular weight


is approximately 70 kDa.


HSPs have also been classified into distinct protein classes


based on similarities in molecular weight, sequence


homology and function.









HSP27 and ubiquitin (Nover and Scharf, 1991; Welch, 1992).


Genes encoding HSPs


are highly conserved; at least 40% sequence homology has been observed between


bacterial


human


HSP


genes


(Craig,


1985;


Lindquist,


1986).


This


high


conservation suggests that these proteins are essential for cell function and survival


during heat shock or other cellular stresses.


Additionally, roles for many HSPs have


been identified in cells under normal conditions and evolutionary conservation may


have


been


achieved because


essential


constitutive


roles


HSPs.


following section will review structure, function and gene regulation of HSPs and

propose specific functions accomplished by HSPs during heat shock which confer

cellular resistance to heat.

HSP70. Heat shock proteins within this class represent a major group of heat-


induced proteins within most cells.


Multiple genes encode a number of proteins in


this class, which can be classified according to differential gene expression patterns


(Nover


Scharf,


1991;


Welch,


1992;


McKay,


1993).


One


group


of proteins


includes heat shock cognate proteins, which are constitutively expressed proteins of


70 to


76 kDa with a pI of 5.3 to 5.6 (Dworniczak and Mirault,


1987; Sorger and


Pelham,


1987


Giebel


et aL,


1988


Masumi


et al.


, 1990).


Cognate


proteins,


abbreviated as HSC70 in this dissertation, are enhanced


2 to 3 fold by heat shock


(Milarski et at,


1989).


A second group of proteins, abbreviated as HSP68 in this


dissertation, are highly heat-inducible proteins.


Expression of HSP68 proteins is low


during nonstressed conditions but increases 20 to 30 fold in response to heat shock









in molecular weight (68 to


74 kDa) and of more basic pi


(5.6 to 6.3; Lowe and


Moran, 1984; Hunt and Calderwood, 1990; Masumi et aL,


1990; Meerson et aL, 1992).


A third class of proteins in the HSP70 family is the glucose-regulated protein


abbreviated as GRP78 (Shiu et at,


1977; Lee, 1987


Lui and Lee, 1991).


GRP78 is


not heat-inducible, however.

There is 75 to 100% amino acid sequence identity between HSC70 and HSP68


proteins within mammalian species and


> 50% homology between mammalian HSP70


molecules


those


Drosophila


(Hunt


Morimoto,


1985;


Dworniczak and Mirault, 1987).


A distinct characteristic of HSC70 and HSP68, as


well as most other HSPs, is their function as chaperone molecules within cells.


Such


activity


is conferred


from


ability


of HSPs


to bind


hydrophobic


domains


proteins.


Hydrophobic domains are not normally accessible on proteins with normal


tertiary and quartenary structure but are readily accessible in proteins which have


been


denatured.


HSC70


bacterial


counterpart,


DNAk,


associate


with


denatured proteins at a higher affinity than for non-denatured proteins (Liberik et


, 1991; Palleros et aLt, 1991; Palleros et at,


1992).


With use of random oligomers,


HSC70 has been reported to preferentially bind hydrophobic amino acids, particularly


amino acids containing nonpolar side chains (Flynn et aL,


1991).


This binding ability


is localized within the final 150 amino acids of the C-terminal region of HSP70.


This


region contains repeated uncharged amino acids such as proline, glycine and alanine
.-- 11 -.-- ....... _. _..T----.. ---. l. i. -_- --. A fo c .---..







24

hydrophobic domains of other binding proteins, such as histocompatibility antigens,


for example,


which bind to and present protein to lymphocytes (Rippmann et al,


1991).


Although


association


of HSC70


HSP68


with


proteins


is not


energy


dependent, dissociation of HSP70 molecules from substrates requires hydrolysis of


ATP (Flaherty et aL,


1991; McCarty and Walker, 1991).


Partial proteolytic digestion


studies on HSP70 molecules have determined that the ATPase activity resides within

a 44 kDa fraction within the N-terminal portion of the protein (Chappell et al, 1986;


Milarski and Morimoto, 1989).


This region displays sequence homology with ATP


binding sites of protein kinases (Walker et al.,


1982; Hannink and Donoghue, 1985)


and has structural similarities to hexokinase (Fletterick, 1975) and actin (Kabsch et


1990; McKay,


1993).


ATPase activity of HSP70 may also


increased


during heat shock,


to promote


association and


prevent


denaturation


cellular


components.


ATPase


activity


DNAk,


bacterial


counterpart


HSC70,


increases


70-fold following heat shock (Liberek et at,


1991; McCarty and Walker,


1991).


It is not known, however,


whether


ATPase activity of mammalian HSP70


proteins increases during heat.

HSP70 proteins utilize protein binding for constitutive roles such as aiding in


oligomeric disassembly and protein translocation within cells.

component of endocytosis by clathrin-coated pits. Clathrin


HSC70 is an essential


is composed of three


units, each


containing a heavy


chain and light chain


(Ungewickell and Branton,







25

coated pits and are responsible for the clustering and endocytosis of transmembrane


receptors (Pearse, 1988).


Following endocytosis, clathrin forms a polyhedral lattice


around the endocytosis vesicle (Crowther and Pearse, 1981).


HSC70 is responsible


clathrin


lattice


disassembly through


processes


dependent


on ATP


hydrolysis


(Ungewickell, 1985; Chappell et at,


1986).


HSC70 disassembles clathrin oligomers


by association with one of the two light chain regions of clathrin that contain a


glycine


proline


enriched


region


(DeLuca-Flaherty


et al


, 1990).


Following


clathrin disassembly, vesicles proceed through endosomal pathways and the clathrin


triskeleton is recycled (Rodman et at,


1990).


HSC70 also associates with proteins during translation on free ribosomes.


This


association may


targeting proteins


that are


not folded


correctly for


degradation or to allow for proper refolding (Welch, 1992).


HSC70 association also


aids in translocation of proteins to the mitochondrium and endoplasmic reticulum


(Pelham, 1989; Welch, 1992).


Since protein unfolding is an essential prerequisite for


translocation


from


cytosol


to the


mitochondrium


or endoplasmic


reticulum


(Schleyer


Neupert,


1985;


Eilers and


Schatz,


1986),


HSC70 binding appears


essential for translocation of proteins.


The specificity of HSC70 for translocated


proteins has not been determined but may involve N-terminal sequences of proteins.


These sequences serve to target proteins for the


mitochondrium or


endoplasmic


reticulum.


Additionally, these signal sequences may promote HSC70 binding, since


several signal sequences retard protein folding during translation (Park et al, 1988).







26

to allow for proteins to proceed through the mitochondrial membranes (Deshaies et


1988;


Pfanner


et al


, 1990).


proteins


pass


through


mitochondrial


membranes,


HSC70


localized


within


mitochondrium


binds


proteins.


Intramitochondrial association of HSC70 to proteins during translocation has been


shown to be essential for successful translocation (Kang et aL,

aids to inhibit protein folding within the mitochondrium. Fol


1990) and probably


lowing translocation,


HSC70 is dissociated from internalized proteins and proper folding of these proteins


occurs


with


of HSP60


(Ostermann et


1989).


Events


involved


with


translocation of proteins to the endoplasmic reticulum appear to be similar to that

of mitochondrial translocation events except that HSC70 and HSP60 are not involved

with binding and folding of proteins once proteins enter the endoplasmic reticulum

(Pelham, 1989; Welch, 1992).


HSC70


been


implicated


localization


some


proteins


to the


nucleus.


Nuclear localization signals for proteins consists of a pair of identical and


conserved seven basic amino acid residues, often separated by a ten to eleven amino


acid spacer (Adam and Gerace,


1991; Dingwall and Laskey,


1991


Robbins et aL,


1991; Shi and Thomas, 1992).


In some proteins, the spacer region contains proline


residues


which


promote


protein


folding


thereby


mask


localization


signals


(Dingwall and Laskey, 1992).


It has been postulated that HSC70 binds to the spacer


region


to inhibit


folding,


thus


maintaining


access


nuclear


localization


sequences to nuclear receptors. Indeed, motifs less than 10 amino acids in length can







27
nucleus localization sequences (Milarski and Morimoto, 1989; Yamasaki et at, 1989).


These proteins do not localize


to a great extent within


nucleus during non-


stressed conditions, but nuclear localization has been observed following heat shock


(Pelham, 1984; Velazquez and Lindquist, 1984; Welch and Ferisco, 1984


Welch and


Mizzen, 1988).

Recent studies have determined that HSC70 is a component of progesterone


receptor complexes in chickens and humans (Kost et at,


1989; Onate et at,


1991).


HSC70


maintains


association


with


receptors


in the


presence


absence


progesterone binding (Kost et al.,


1989; Onate et at,


1991


Smith et al


, 1992).


importance of HSC70 binding to steroid receptors is unclear.


Such association may


be required for stabilizing progesterone receptor complexes to optimize binding of

progesterone or to assist HSP90 molecules to prevent dimerization and/or DNA


binding


of non-steroid


bound


receptors.


contrast,


Sanchez et


(1990)


suggested th

performance


at association


the complex since


070 with steroid

HSC70 does


receptors


is not essential


not associate with


progesterone


receptors m mice.


Expression of HSP68,


synthesis (Milarski and


but not


Morimoto,


HSC70, increases coincidentally with


1986).


DNA


Functions of HSP68 during this time,


however, have not been determined.

associated with DNA replication. Ac


Perhaps HSP68 serves to stabilize proteins


additionally, synthesis of HSP68 increases with


cellular transformation or virus invasion (Pinhasi-Kimhi et al..


1986) and HSP68 can









et at


, 1991), implying that HSP68 may be


important during early viral invasion.


Interestingly, increased cellular sensitivity to heat shock ensues in virus-infected cells

(Li et at, 1990). Perhaps thermosensitivity occurs because of the preferential binding

of HSP68 to viral proteins rather than to other cellular components during heat

shock.


HSP70 and heat shock.


Heat shock induces a 10 to 20 fold increase in HSP68


synthesis


to 3 fold


increase


HSC70


synthesis


(Milarski


et at,


1989).


Increased expression of HSC70 and/or


HSP68 during heat shock appears


essential for conferring thermal resistance in many cell


types.


to be


With induction of


thermotolerance (Le., increased resistance to a severe heat shock after prior exposure


to a mild


heat shock),


translational activity


(Mizzen and


Welch,


1988)


survival (Li and Werb, 1982; Li, 1985; Mivechi and Li, 1985; Widelitz et at,


correlated positively with accumulation of HSP68.


1987) are


Additionally, HSP68 expression


is more highly correlated with cellular tolerance to heat shock than other classes of


HSPs in human fibroblasts (Mizzen and Welch,


1988) and several variants of cell


lines (Li and Werb, 1982; Laszlo and Li, 1985


1985


Mizzen and Welch, 1988;


Mivechi and Rossi, 1990).


More direct evidence also implicates that HSP70 proteins


are important in conferring cellular resistance to heat shock.


In murine oocytes,


which lack the ability to transcribe HSP68 and HSC70, microinjection of mRNA for


HSC70 caused enhanced resistance to heat shock (Hendrey and Kola, 1991).


Similar


nbservatinns~


haveP


hep.n


nh~eruedl


fnllnurina


nverePnrescimn


of HSC70


-~~~~~~ ~ ~ ~ -yr -Y V -W ~Vr .I~~ -i -ry w --t r e a u a aS a t.. raas


,


vrV









et aI,


1991).


Injection of antibodies to HSP68 and HSC70 (Riabowol et at,


1988)


or injection of DNA sequences which compete for cis-acting elements that regulate

HSP gene expression (Johnson and Kucey, 1988) decreased resistance of cells to heat


shock.


However, HSP68 may not be essential for all types of cells to confer thermal


resistance or undergo


thermotolerance.


Hatayama et


(1991)


concluded


thermotolerance


was


induced


Chinese


hamster


V79


cells


without


increased


synthesis of HSP68.


Perhaps the essential role of HSP68 in


conferring thermal


resistance may be determined by differential cellular expression of additional HSPs

or other biochemical mechanisms that may substitute for HSP68.

One mechanism by which HSP70 proteins induce cellular resistance to heat


shock likely involves association with malformed cellular components.


HSC70 and


HSP68 have increased affinity for denatured proteins and this binding persists longer


for denatured proteins than for non-denatured proteins (Liberik et at,


1991; Palleros


et at,


1991;


Palleros et at


, 1992).


However,


importance


of this activity


conferring thermal resistance is unknown, since the degree of cellular damage caused

by the existence of malformed proteins or the degree of alleviation exerted by HSP68

following association with malformed proteins has not been determined.

HSP70 may aid in conferring cellular resistance to heat shock by preventing


heat


shock


induced


damage


to ribosomal


components.


Although


rate


ribosomal


RNA synthesis


ribosome


assembly


decreases


during


heat


shock,


n n..nn ., A A a -J a 4.- n 4n an an Al ar nn~ an -t a a ar al,,,, rAI C .4I 1,r a ns a n...







30

nucleus after heat shock, particularly within the nucleolus (Pelham, 1984; Velazquez


and Lindquist, 1984;


Welch and Feramisco, 1984;


Welch and Mizzen,


1988).


presence of HSP68 and HSC70 within the nucleolus could aid in stabilizing ribosomal

components, possibly by binding to misfolded components, preventing aggregation


and inactivating denatured components.


Translational activity of HeLa cells can be


increased during and after heat shock with prior exposure


to a mild heat shock


(Mizzen and


Welch,


1988).


Induction


of thermotolerance


increases


the rate of


HSP68 localization to the nucleolus and exit from the nucleolus after heat shock

(Welch and Mizzen, 1988). Hence, induction of thermotolerance seemingly enhances

HSP68 complex formation with nucleolar structures and may hasten their protection


or repair during and after heat shock.


The protective role of HSP68 for ribosomal


components is also implied by findings that HSP68 accumulates in several additional


regions which


contain ribosomes,


particularly in


perinuclear regions,


plasma


membrane and within dense structures (Welch and Suhan, 1986).

The ability of HSP68 to protect translational machinery may, however, depend


on the stage of the


cycle.


As mentioned


previously,


synthesis of HSP68 is


increased during DNA replication, although induction of thermotolerance cannot be


achieved


in HeLa


cells


during


DNA synthesis


(Milarski


Morimoto,


1986).


HSP68 is not localized within the nucleolus during this time; instead the protein is


apparently


completed


with


other


cellular


components


(Milarski


et aL,


1989).


Translational machinery and possibly other cellular components that cannot complex









HSP90.


addition


to being


most


abundant


proteins


mammalian cells under non-stressed conditions, expression of this phosphoprotein (83


to 94 kDa molecular weight; pi of 5.1 to


5.8) increases with heat shock (Welch et at,


1983


Moore et at, 1987


lannotti et al.


1988


Iwasaki et at,


1989).


Also included in


this class of HSPs is GRP94, a protein localized in the endoplasmic reticulum whose


synthesis is enhanced by glucose starvation but not by heat shock (Lee, 1987


Liu and


Lee, 1991). As many as 12 isoforms for HSP90 can be observed by 2-dimensional

electrophoresis. These represent differentially phosphorylated proteins from two


genes that share


>70% protein sequence homology (Welch et aL,


1983


Rebbe et at,


1987


Iannotti et aL


1988


Hickey et aL,


1989).


HSP90 is distributed within


cytoplasm


under


non-stressed


conditions


maintains


primarily


a cytoplasmic


localization during heat shock, with some additional concentration of HSP90 around


the cell membrane and within the nucleus (Kelley and Schesinger, 1982


Carbajal et


1986


Collier and Schlesinger,


1986


Van Bergen en Henegouwen et at,


1987).


Although HSP90 binds to cellular proteins through hydrophobic interactions (Iwasaki


et at, 1989), HSP90 lacks intrinsic ATP hydrolysis activity (Hardesty and Kramer,

1989). With the use of coprecipitation studies, HSP90 has been observed to associate


with actin (Koyasu et at,


1986


Nishida et aL,


1986) and tubulin (Pratt et at.,


1989)


in a calmodulin-dependent


manner.


Perhaps


HSP90


binding


to other


cellular


components is regulated similarly.


Indeed the structural homolog, GRP94, exhibits







32

One constitutive role of HSP90 is completing with steroid hormone receptors


in the absence of steroid binding (Carson-Jurica et aL,


1990; Smith and Toft, 1993).


Upon steroid binding, HSP90 is dissociated and receptor dimerization and binding


of receptors to DNA occurs (Beato, 1989; Carson-Jurica et at,


1993).


1990; Smith and Toft,


HSP90 appears to be essential for regulating transcriptional activity of steroid


receptors


since


disruption


receptor/HSP90


complex


results


receptor


dimerization and DNA binding in the absence of steroid (Lindquist and Craig, 1988).

Inhibition of intrinsic receptor activity through HSP90 binding likely occurs because


the DNA binding site of receptors is masked, since


HSP90 contains a negatively


charged


a-helical


domain


which


may


associate


with


DNA


binding


domain


(Bilinski et aL,


1988) or because HSP90 presents a stearic hindrance for receptor


dimerization, which is a critical prerequisite for transcriptional activity (Pratt et at,


1989; Demarco et a.,


1991).


An additional role for HSP90 within cells pertains to the possible regulation


tyrosine


kinase


specific


enzymes.


HSP90


complexes


with


oncogenic


transforming protein pp60r


, which is a tyrosine


kinase oncogenic product of the


Rous sarcoma virus (Sefton et at, 1978; Brugge et at,


1981; Oppermann et al.,


1981).


When the kinase was completed with HSP90 and an associated 50 kDa protein, it

was inactive; however full activity of pp60r was achieved by dissociation of HSP90


and associated proteins.


It has been speculated by


Brugge (1986)


that complex


tnrtTma~nn; 1 Qnc canl n o C ACld lmnr nflirnrnn.nntha *nrneina tnin n e ,-d' .b4 +r i j







33

Several additional retrovirus-encoded oncogenic products that contain tyrosine kinase

activity likewise complex with HSP90 (Brugge, 1986), suggesting that HSP90 binding

assists in the transport of oncogenic and possibly inherent cellular tyrosine kinases

throughout the cell.


HSP90 is


important


conferring


thermal


resistance;


reducing levels of


cellular HSP90 by antisense treatment resulted in reduced growth and survival of


heat-shocked L-cells (Bansal et al., 1991).


Since HSP90 associates with cytoskeleton


components (Nishida et at, 1986; Koyasu et at,


1989; Pratt et al.,


1989), it is possible


that the protein serves to stabilize the cytoskeleton during heat shock. Indeed, severe

heat shock promotes cytoskeleton disassembly, which can be inhibited with induction


of thermotolerance (Welch and


Mizzen,


1988


Shyy et at,


1989).


Alternatively,


HSP90


conferring


cellular


resistance


to heat


shock


decreasing


translation rate


within


heat shock


cells.


Such


an action


been


observed


reticulocytes, as association of HSP90 with eukaryotic initiation factor


increases the enzymes ability to inhibit translation (Rose et aL,


2a kinase


1987).


HSP27


. HSP27 is represented by proteins of


to 30 kDa with pi range of


.9 to 6.3 which are usually encoded by a single gene in mammalian cells (Hickey et


aL, 1986; Arrigo and Welch, 1987


Faucher et aL, 1993).


Most proteins in the HSP27


family


characterized


methionine


content


high


degree


phosphorylation (Kim et at, 1983b; Arrigo and Welch, 1987).


The level of serine and


thrnnins rnhncnhrrulatinn fr T-T-P77 i hiohlv unnrinalh 2nd mav he denendrnnt in









1983b; Arrigo and Welch, 1987).


There is considerable sequence variation between


HSP27 of different organisms, although hydrophilic and hydrophobic domains within

the C-terminus are highly conserved and related to domains found on a-crystallin


(Neumann et aL,


1989).


possible


function


of HSP27


during non-stressed


conditions


may


regulate RNA activity.


HSP27


forms aggregates, like a-crystallin,


which contain


mRNA (approximately 400 kDa) and localize around the Golgi under non-stressed


conditions (Collier and Schlesinger,


1986; Arrigo and Welch,


1987


Arrigo et aL,


1988).


HSP27 may also be involved in developmental processes in certain organisms.


In Drosophila, for example, expression of HSP27 is altered during development and


differentiation (Cheney and Shearn, 1983; Pauli et at,


1990).


Synthesis of HSP27


occurs at low


levels


under unstressed conditions and


increases 10 to 20 fold upon exposure to heat shock (Kim et al.,


1983b


Welch, 1985).


HSP27 is capable of conferring thermotolerance to cells; transfection of murine cells

with the HSP27 gene to induce overexpression increased thermal resistance of cells


(Landry


et aL,


1989).


However,


functions


of HSP27


during


heat shock remain


speculative.


During


heat


shock,


HSP27


localizes


within


nucleus


to form


aggregates as large as 2000 kDa (Collier and Schlesinger, 1986; Arrigo et at,


1988).


The presence of this protein may aid in stabilizing or regulating activity of RNA


transcripts,


given


constitutive


RNA binding


to HSP27


aggregates


been


observed (Nover et aL.


IQRQV.









Other HSPs.


A single


110 kDa protein with a pi of 5.5 has been identified


as a heat-induced protein in mammalian cells that is also expressed constitutively at


low levels (Subjeck et at,


1982; Subjeck et at,


1983; Shyy et at,


1986).


Under non-


stressed


conditions,


HSP110


found


throughout


localizes


to the


nucleolus during heat shock (Subjeck et aL,


1983; Shyy et at,


1986).


Depletion of


yeast HSP110 abolishes


ability of


cells


to undergo induced thermotolerance


(Sanchez and Lindquist, 1990), implying that at least in yeast, HSP110 is essential for

conferring thermal resistance.


HSP60 is a heat-inducible


protein


that is also


constitutively


expressed


mammalian cells.


This protein has an apparent molecular weight of 58 to 64 kDa,


pi of 5.8 and is localized within the mitochondria during both non-stress and heat


shock conditions (McMullin and Hallberg, 1988; Waldinger et al., 1989).


Monomers


and oligomers of this protein function as chaperones within the mitochondria.


particular, HSP60 is involved in assembly of monomeric proteins following transport


through


mitochondrial


membranes


formation


polymeric


complexes


(Ostermann et al,


1989).


Potential functions of HSP60 during heat shock are not


defined.


One possibility is that HSP60 may limit or correct altered protein structure


that may occur within the mitochondria during heat shock.


The mitochondria may


be particularly susceptible to heat shock because free radical production may increase

within the mitochondria during heat shock.

Ubiquitin (HSP8.5) is a 8.5 kDa protein that covalently binds to proteins and







36
protein degradation is likely responsible for selective intracellular protein degradation


(Chin et at,


1982; Hershko et at,


1982; Bachmair et al., 1986).


Ubiquitin activating


enzyme (El) utilizes ATP to modify ubiquitin conformation and increase affinity for


proteins (Ciechanover et at,


1984; Finley et al, 1984).


Following activation, ubiquitin


binds to lysine residues of proteins targeted for degradation (Hershko et at,


1984).


This binding is regulated by ubiquitin's


association with ubiquitin


carrier protein


(E2),


which aids in targeting proteins, and by ubiquitin protein


igase (E3),


which


initiates ligation of ubiquitin to the protein (Hershko et al.,


Schwartz, 1989).


1986; Ciechanover and


Following binding of a single ubiquitin, poly-ubiquitination of the


protein occurs, which targets proteins for degradation by an ATP-dependent protease

to yield free amino acids and reusable ubiquitin (Ciechanover and Schwartz, 1989;


Ciechanover et aL,


1990).


Binding of ubiquitin is regulated by the N-terminal amino acid of targeted


proteins.


While


absence


methionine


at the


N-terminus


usually


confer


ubiquitination (Ciechanover et al, 1990), ubiquitination is more prevalent in proteins

containing basic N-terminal residues (histidine, arginine or lysine) or hydrophobic N-

terminal residues leucinee, tryptophan, phenylalanine or tyrosine; Reiss et al., 1988).

Since most proteins contain methionine as the N-terminal residue, ubiquitin mediated

proteolysis is likely a regulatory mechanism involved with degrading proteins that


have been translated incorrectly.


Additionally, translation of proteins containing N-


terminal sequences that promote ubiauitination mav also represent a mechanism to







37
Ubiquitination of proteins that are damaged during heat shock may be an


important mechanism to increase sensitivity of cells to heat shock.


Indeed, heat-


induced synthesis of ubiquitin has been observed in a number of species (Bond and


Schlesinger, 1985; Ovsenek and Heikkila, 1988; Forance et at,


1989b).


However, the


importance


of this system may


questioned


since


rate of protein


degradation


decreases during heat shock


HeLa


cells (Carlson et at,


1987),


possibly


as a


consequence of decreased activity of proteolytic enzymes.


HSP


gene


regulation.


Increased synthesis of HSPs


heat shock and a


number


other


cellular


stresses


is regulated


primarily


increased


transcription.


Expression of HSPs following heat stress is induced by interaction of


a trans-activating factor,


termed heat shock factor (HSF),


with specific cis-acting


elements termed heat shock elements (HSE).


The HSE consists of at least two


continuous inverted repeats of nGAAn nucleotide sequences arranged either head-to-

head (nGAAnnTTCn) or tail-to-tail (nTTCnnGAAn) and usually located within the


first 300 bp upstream of the


transcription start site


genes encoding HSPs


presented in this section (Perisic et al, 1989; Nover, 1991) and of other heat-induced


genes such as heme oxygenase and interleukin-7 (Mitani et at,


1991


Wathelet et al,


1987


Lupton et aL, 1990).


Transcriptional activation studies have determined that


one HSE is adequate for transcription, but two or more elements are needed for


maximal transcription (Pelham, 1982; Dudler and Travers, 1984;


Topol et at,


1985;


Kav et at.


1986: Klemenz and Gehrinp.


1986: Amin at al


10R71


At with nther







38

higher at the HSE most proximal to the transcription start site and initial binding to

this site promotes cooperative binding of distal sites to HSF (Topol, 1985; Kay et at,


1986;


Amin et


1987).


However,


ability


of HSE


sequences


to promote


transcription decreases with increased distance from the transcriptional start site


(Amin et at,


1987).


Although the possibility remains that low level HSF interaction with HSE

could cause some expression of HSPs in the absence of cellular stress, constitutive

expression of HSPs is mainly conferred by additional cis-acting elements and trans-


activating factors within the


promoter regions of genes encoding HSPs (Tanguay,


1988).


For example, the


flanking region of the human HSP68 gene contains a


serum


response


element


which


probably


regulates


growth


factor


or cell


cycle


dependent expression (Wu et at,


1987).


The trans-activating protein factor, HSF, interacts with HSE motifs to promote


gene expression.


In unstressed cells, HSF is found throughout the cytoplasm and


nucleus in a monomeric form with low binding affinity to DNA.


In response to heat


shock, HSF forms trimers, localizes within the nucleus, and binds to HSE with high


affinity (Wu, 1984; Sorger and Nelson, 1989;


1992).


Westwood et al.


, 1991; Jurivich et at,


However, HSF binding to HSE alone does not induce transcription.


In yeast,


trimerization and DNA binding occurs innately, but


transcription is not initiated


(Gross et


, 1990;


Jakobsen


Pelham,


1991).


This


phenomenon


was


observed following microiniection of veast HSF into Xenonus oocvtes (Clos et al.,







39

HSF bound DNA, HSP gene expression did not occur in Xenopus or mammalian


cells.


Phosphorylation of HSF


which may alter HSF conformation, is a possible


mechanism by which HSF-induced transcription is activated.


This has been proposed


since initiation of transcription for


HSPs


in yeast and other mammalian


cells is


correlated with serine/threonine phosphorylation of HSF (Krishnan and Pueppke,


1987


Sorger, 1990).


The structure of HSF


, derived from DNA sequence analysis, has provided


much information pertaining to the nature of HSF trimerization, DNA binding and


activation of transcription.


Cloning of HSF genes has revealed that HSF is expressed


by a single gene in yeast and Drosophila (Clos et at,


1990; Jacobsen and Pelham,


1991), by two genes in humans and mice (Sarge et al.,


1991


Schuetz et aL


,1991) and


by three genes in tomatoes (Scharf et at,


1990).


Two highly conserved regions persist


for HSF molecules among organisms.


The first is a 188 amino acid motif in the N-


terminal region that is responsible for DNA binding.


Although this region contains


no known binding motifs used by eukaryotic cells (Wiederrecht et at,


1988; Clos et


1990), it is considerably homologous to bacterial sigma DNA binding factors


(Clos et


1990).


Perhaps


a novel


eukaryotic motif


is utilized


trans-


activating factor.


The second conserved region, located in the C-terminal region, is


responsible for HSF trimerization (Rabindran et at,


1993).


This region contains


coiled-coil motifs that serve as a flexible hinge to promote binding of all three N-


terminal


regions


to DNA


regions


(Snrp.er


NePlnn


I- -' ir y U- r r -. -( -IhW *-- w / V I- a / LS J t.'* -. -


1989


rlnc: Pt


1 osn







40

revealed that a region of HSF maintains transient activation since alteration of this


region


induces


constitutive


transcriptional


activation


(Nieto-Sotelo


et al.,


1990;


Sorger,


1990).


However, the mechanisms by which this region regulates transient


transcriptional activity is not known.

Distinct HSFs, produced from different genes, appear to possess divergent


roles in the heat shock response.


Through use of antibodies, one factor, HSF1,


was


determined to be involved in transcriptional activation in response to heat shock,


oxidative stress, heavy metals and amino acid analogues (Sarge et al.,


1993) whereas


second


factor,


HSF2,


was


responsible


hemin-induced


differentiation


erythroleukemia cells (Sistonen et at,


1992).


The third HSF found in tomatoes,


HSF3, does not initiate transcription following any of the above stimuli (Morimoto,


1993).


Therefore, specific signals, some of which may not be yet discovered, induce


activation of transcription by specific isoforms of HSF.


Signalling


systems


trimerization,


DNA


binding


transcriptional


activation of genes encoding HSPs by HSF have not been completely determined.

Much evidence lends support to a theory for HSF regulation by the constitutively


expressed protein, HSC70 (Sorger, 1991; Lis and Wu, 1993; Morimoto, 1993).


HSF


binding to DNA can be induced in cytoplasmic extracts with heat shock, exposure to


detergents or low pH (Larson et al.,


1988; Mosser et al.,


1990; Abravaya et at,


1992;


Mosser et at,


1993) but addition of HSC70 blocks this effect (Abravaya et al.,


1992;


Mosser et aL, 1993).


This effect can be reversed with addition of ATP (Abravaya et







41

underexpression of HSC70 results in enhanced synthesis of other HSPs under non-


stress conditions


in Drosophila


(Solomon et


, 1991).


been speculated


(Sorger,


1991; Morimoto et aL,


1992; Morimoto,


1993) that HSC70, and possibly


other constitutively produced HSPs, make up an abundant pool of excess HSPs which

will associate with HSF under non-stressed conditions and inhibit HSF activation.

During heat shock, HSC70 association with HSF becomes limiting since other cellular

proteins that have been adversely affected by heat shock would compete with HSF


for associating with HSC70.


Consequently, unbound HSF would then be able to


trimerize, become activated and initiate HSP synthesis.


The expression of HSPs


would then continue until an abundant pool of HSC70 and possibly other HSPs is re-


established.


However,


researchers


have


been


unable


to determine


whether


association between HSC70 and HSF exists in non-stressed cells.


Therefore, it is also


possible


other


regulatory


mechanisms


involved


with


signalling


HSF


activation.

An intriguing event that has prompted investigation is the speed at which

HSPs are transcribed following initiation of heat shock; mRNA encoding HSPs have

been observed to increase within minutes after heat shock (Wu, 1980; Sorger, 1991).

In non-stressed Drosophila cells, regions of DNA encoding HSPs are maintained in

a chromatin structure depleted of nucleosomes, where DNA unwinding has already


occurred (Nacheva et al.,


1989).


Transactivating factors bind to TATA boxes of these


HSP genes during non-stressed conditions, promote RNA polymerase binding and









1993).


The mechanism by which transcription is halted has not been elucidated.


Upon HSF binding and activation, transcription resumes, likely as a result of DNA

folding to make downstream DNA sequences accessible to polymerase. Alternatively,

HSF binding may aid in recruiting additional RNA polymerases which take over for

the stalled polymerase.


Translational processing is also involved in regulation of HSP synthesis.


HSP


transcripts are preferentially translated during periods of heat shock (Storti et aL,


1980; Scott and Pardue, 1981).


defined.


However, mechanisms for this process have not been


In Drosophila, stability of mRNA for HSPs is increased during heat shock


(DiDomenico et aL,


1982) and this may result in preferential translation during heat


shock.

Glutathione


Antioxidants protect cells from secondary damage caused by free radicals


generated by heat shock, other cellular insults and normal metabolism.


Antioxidants


can act in two ways; by reacting directly with free radicals through electron transfer

to neutralize free radicals or by acting through enzymatic processes to remove free


radicals or correct damage to cellular macromolecules caused by free radicals.


antioxidant, glutathione (GSH), is a prominent water-soluble intracellular antioxidant


that acts through both of these processes.


Glutathione is a tripeptide (7-glutamyl-


cysteine-glycine) present intracellularly at concentrations of 500 MM to 10 mM while


eiTnuC iin nd+P~tsrti svt-rallilrl'T, avpr-nn in the.. l7rnr (kncnrxFar NTnct


1O'76


1IAa;rt~PF anrl









form (GSH) or as a dimer formed from


disulfide


bond formation between


oxidized molecules (GSSG). An overall summary of GSH metabolism, transport, re-

cycling and functions are presented in Figure 2-1.


GSH synthesis.


transport


recycling.


GSH


synthesis


is dependent


transport


precursor


amino


acids


into cells.


Cysteine,


glycine


glutamine


residues are transported into cells through amino acid transport systems (Griffith et


1979;


Meister


Anderson,


1983).


Following


transport,


glutamine


metabolized to glutamic acid by a two-step enzymatic process (--glutamyl


cycle)


requiring


hydrolysis


(Meister


Anderson,


1983).


Reduced


GSH


synthesized by a two-step process which is positively regulated by the availability of


cysteine (Meister and Anderson, 1983).


Cysteine and glutamic acid react with 1-


glutamylcysteine synthetase


to yield -y-glutamylcysteine (Gipp et at,


1992).


This


reaction is rate limiting in the GSH synthesis process, requires ATP hydrolysis and

is feedback-inhibited by GSH (Richman and Meister, 1975; Wirth and Thorgeirsson,


1978).


GSH is formed by coupling glycine to --glutamylcysteine in an ATP-requiring


reaction


catalyzed


GSH


synthetase


(Richman and


Meister,


Wirth


Thorgeirsson,


much as 99


1978).


GSH is maintained predominately in the


Carlberg and Mannervik, 1977


Griffin and Meiste


reduced form (as

:r, 1979a; Griffith


and Meister, 1979b) by the actions of GSH reductase, which uses NADPH derived


primarily from oxidative processes of glycolysis to reduce GSSG (Thieme et al.,


1981;


Williams et at


, 1982; Chung et at,


1991).





































-1. Synthesis, utilization and recycling of GSH within cells.
involving -y-glutamylcysteine synthetase (1) and GSH synth


responsible for synthesis


GSH
electr
GSH
form,
Some


is to reduce free ra
ophilic compounds
and via enzymatic-


GSS(
GSH


membrane
(8). Consti
GSH (9).


of GSH within cells. The major function of
dicals or other electrophilic compounds (3) or
(4). These processes occur through direct i
*driven reactions. Reduction events produce


3 (5), which is readily converted to a reduced state by GSH
[ and GSSG is lost from the cell by passive diffusion (7)
and degraded on the extracellular surface by membrane-b
tutive amino acids are then transported back into the cell f
Conjugates of GSH are transported out of the cell (10).


A two step
etase (2) is
intracellular
to conjugate
action with
the oxidized


reductase (6).
across the cell
ound enzymes
or synthesis of
Subsequently,


glutamine and glycine residues are released by cleavage (11) and transported into the
cell (9) whereas the remaining cysteine conjugate is targeted for excretion in urine
4J4 a'


Figure 2
process







45

Loss of intracellular GSH occurs as a result of transport of GSH, GSSG and


GSH conjugates out of the cell through undefined systems.


Loss of GSSG exceeds


that of GSH because of its increased


membrane


permeability (Griffith and


Meister,


1979a;


Griffith


Meister,


1979b;


Rouzer


et at,


1982).


Following


transport, GSH and GSSG are readily metabolized by 7-glutamyl transpeptidase and

dipeptidase enzymes; these are soluble, membrane-bound proteins localized on the

extracellular surface of cells (Griffith et at, 1978; Hughey et al, 1978; Meister, 1981;


Okajima et


1981).


Glycine, glutamine and


cysteine can


then be utilized for


resynthesis of GSH upon transport back into the cell.


Direct


reactions


GSH.


ability


GSH


to donate


hydrogen


reduction of free radicals or other electrophilic compounds can occur without the aid


of enzymes (Figure 2-1; Kosower, 1976).


One reaction involves conversion of H202


and other peroxides (R202) to H20 or ROH and GSSG (Mills, 1960; Pirie, 1965).


The major source of H202 in cells is as a result of dismutation of O,


by superoxide


dismutase (Chance et at,


1979).


Since


*,


is produced as a result of


electron


transfer, superoxide dismutase is localized within the mitochondrial membrane as


well as in the endoplasmic reticulum and peroxisome (Chance et al.,


1979).


Lipid


peroxides


are formed


from


reaction


*OH


with


unsaturated


fatty


acids


membranes.


Secondly, GSH reacts directly with disulfide bonds of other compounds


to yield


reduced


sulfhydryl


residues


GSSG


(Schdberl


Gr~tife,


1958;


Thaland Ir and Pdaihard 10"70- Moannnarl antd Avslccnn 1 OR\v


A third reanrtinn nf







46

partially oxidized molecules such as heavy metals (Dierickx, 1982), ethanol (Hetu et


at, 1982), steroid derivatives (Benson et at,


1977) and exogenous drugs (Chasseaud,


1979).


Following GSH conjugation, transport out of the cell


occurs by an ATP-


dependent transport system (Ishikawa, 1989; Kobayashi et alt,


Within the extracellular milieu,


1990; Ishikawa, 1992).


7-glutamyl and glycine residues of GSH are rapidly


removed


from


conjugate


y-glutamyl


transpeptidase


dipeptidase,


respectively (Griffith et aL,


1978; Hughey et at,


1978


Meister, 1981


Okajima et aL,


1981).


Metabolism of the conjugate results in the formation of mercapturic acids,


which are targeted for excretion in urine.


In addition to its intracellular functions,

conjugate molecules extracellularly. This active


GSH may also directly reduce or


ity is probably limited to the liver,


because GSH concentrations range from 1 to 20 MM in liver blood plasma and 1 to

6 mM within bile, whereas extracellular concentrations of GSH are undetectable in


other extracellular locations (Anderson et at,


1980; Meister, 1984).


The proposed


role for extracellular GSH in the liver is reduction and conjugation reactions with


toxic electrophilic compounds (Meister and Anderson,


1983; Avissar et aL,


1989).


Increased extracellular GSH concentrations in liver result from low activity of y-


glutamyl transpeptidase and dipeptidase (Griffith and Meister,


Meister, 1979b).


1979a; Griffith and


In contrast to the liver, the activity of these catabolic enzymes is


high in extracellular compartments of other tissues, particularly, those which contain


hioh c rratnrv nr nhcnrntive fnnrtinnc /(riffith and Mkictor


107Q0a


friffith and








Meister, 1979b).


High levels of y-glutamyl transpeptidase and dipeptidase probably


ensure that GSH and GSSG concentrations remain low extracellularly.


Enzyme-mediated reactions of GSH.


Reduction of H202 and other peroxides


by GSH is catalyzed by GSH peroxidases.


Several isoforms of GSH peroxidase have


been characterized, most of which require selenium as an electron donor (Forstrom


et at, 1978; Zakowski et at,


1978). However, selenium-independent peroxidases have


also been identified which, while not reacting with H202, can reduce other peroxides,

particularly from the lipoygenase pathway of arachidonic acid metabolism (Lawrence


and Burk, 1976; Burk et at,


1978).


Also, GSH peroxidase-mediated reactions have


also been implicated in reducing molecules and other antioxidants that have reacted


with free radicals (Wayner et aL,


1985


Frei et aL


, 1988).


Thiol-disulfide bond exchanges of proteins with GSH is regulated by GSH


transhydrogenases.


These enzymes,


of which at least two classes exist, ensure that


the intracellular GSH pool acts as a thiol redox buffer within cells (Chance et at,


1979; Anderson and Meister, 1980; Meister and Anderson, 1983).


Protein disulfide


isomerase is a GSH-dependent enzyme localized within the endoplasmic reticulum

which serves to reduce disulfide bonds of proteins, reversing protein thiol oxidation

and aiding in regulating tertiary protein structure (Mannervik and Axelsson, 1980).

A second class of transhydrogenase enzymes, ribonucleotide reductase enzymes, aid


in conversion of RNA to DNA.


The proteins thioredoxin and glutaredoxin, rather


than GSH, are the preferred electron donors for this enzyme.


In turn, GSH aids in







48

reduction of oxidized thioredoxin and glutaredoxin (Thelander and Reichard, 1979;


Hoog et at,


1982).


Conjugation of sulfhydryl linkages between GSH and other molecules can be

catalyzed by GSH S-transferases both intracellularly and extracellularly (Boyland and


Chasseaud, 1969; Avissar et al.,


1989).


Conjugation of GSH, as mediated by GSH


S-transferase, also plays a role in physiological responses to stress.


For example,


leukotriene C4 is formed from conjugation of GSH to leukotriene A4 and is a local


mediator of inflammation within tissues (Rouzer


et al.,


1982; Bach et at,


1984).


Following export of leukotriene C4 from the cell, removal of "y-glutamyl and glycine

residues from GSH results in the formation of leukotriene D4 and E4, respectively.


Importance


GSH


stressed


cells.


essential


GSH


maintenance


function


observed


several


tissues.


Decreased


intracellular concentrations of GSH causes damage to skeletal muscle (MArtensson

and Meister, 1989), lung (Mrtensson et al., 1989) and intestinal mucosa (MArtensson


et at,


1990) and has been associated with numerous diseases (Uhlig and Wendel,


1992).


most prominent


effect


decreased


GSH


concentrations


kidney


damage.


The kidney is probably more sensitive to decreased GSH concentrations


because of its high rate of GSH metabolism and synthesis. Nephrotoxicity can be

induced by treatment with D,L-buthionine-S,R-sulfoximine (BSO), an inhibitor of y-


glutamylcysteine synthetase (Griffith et at,


1979; Griffith and Meister, 1979c), or by


administration of edlnitin n wideiv iinpd nntiennTrr aoent (Harder and Rn;enhero









requiring thiol cofactors (Aull et at,


1979; Smith and Douglas, 1989).


Detrimental


effects of BSO and cisplatin can be reversed by oral or intraperitoneal administration


of GSH (Aw et aL,


1991; Bump et aL,


1992).


Exogenous administration of GSH


probably affects intracellular GSH only after being metabolized extracellularly and


resynthesized


intracellularly


after


transport


amino


acids


membrane-permeable form of GSH, monoethy


GSH ester, is a more effective form


of GSH for increasing delivery to cells because it is readily transported into the cell


(Anderson and Meister, 1989).


Although intraperitoneal injection of both GSH and


monoethyl GSH ester reduced cisplatin-induced nephrotoxicity in mice, monoethyl


GSH ester was effective at lower doses than GSH (Anderson et at,


1990).


Intracellular GSH has been proposed to increase thermal resistance of cells.

Variants of Chinese hamster fibroblasts containing higher concentrations of GSH at


normal


temperatures


were


more


resistant to


heat shock


compared with variants


containing less GSH (Shrieve et at,


of GSH with BSO (Shrieve et at,


1986).


1986).


This effect was diminished by depletion


During heat shock, GSH concentrations are


greatly increased within the mitochondrion (Freeman and Meredith, 1988), a primary

site of free radical production.

Additionally, increased synthesis of GSH occurs in association with induction


of thermotolerance.


Intracellular GSH concentrations increased


2 to 3 fold following


exposure


initial


heat


shock


made


cells,


murmne


mammary


adenocarcinoma cells and Dostimolantation rat embryos resistant to a subsequent









Harris et at


, 1991).


Induction of thermotolerance


by administration of ethanol,


instead of a mild heat shock, likewise increased intracellular GSH concentrations


(Mitchell et aL,


1983).


Moreover, induction of thermotolerance was inhibited by


BSO (Mitchell et at,


1983; Russo et aL, 1984; Jones and Douple, 1990; Harris et at,


1991)


Chinese


hamster


ovary


cells


gained


resistance


heat


shock


microinjected


with


GSSG


(Lumpkin


et at,


1988)


or GSH


(Kapiszewska


Hopwood, 1988) prior to heat shock.


mouse embryos.


Similar observations have also been made in


Ar6chiga et al (1992) reported that induction of thermotolerance


murmei


morulae


was


abolished


with


administration


BSO


whereas


thermotolerance was increased by increasing intracellular GSH concentrations.


mechanism for induction of GSH synthesis during heat shock has not been defined

but possibly is caused by increased activity of enzymes involved in GSH synthesis or

by decreased GSH transport from the cell.

Enzymes which utilize GSH for removal of free radicals are also affected by


heat shock.


In a thermally resistant mouse embryonic cell line, activity and synthesis


of superoxide dismutase and GSH peroxidase were increased


to 3 fold by heat


shock (Omar et at,


1987).


GSH may also regulate HSP synthesis, although this has


not been established with certainty.


Russo et at (1984) found that GSH depletion


in V79 cells diminished HSP68 synthesis in response to heat shock.


In contrast, heat-


induced synthesis of HSP68 and other HSPs was not affected by GSH depletion in


rat nostimnlantation emhrvns (T-Irri pt na


1001\









Taurine


Taurine ( NH3-CH2-CH2-SOj; 2-aminoethanesulfonic acid) is a B-amino acid


synthesized by metabolism of cysteine.


Taurine is a weak antioxidant which reacts


with electrophilic compounds through reactions involving its sulfonic acid (Aruoma


et al


,1988).


While only a weak antioxidant, concentrations of taurine are very high


in specific cells and tissues, and at these sites an antioxidant role for taurine or its


precursor molecule, hypotaurine may be important.


Taurine and hypotaurine may


play a role during embryonic development since millimolar concentrations of these


amino acids are present in uterine fluids and oviductal cells (Fahning et al.,


Van der Horst and Brand, 1969; Cassl6n, 1987).


1967


Taurine is a non-essential amino


acid in most species; cats appear to be the exception because of low activity of


enzymes required for taurine synthesis (Hardison et at,

Taurine synthesis, transport and localization. Tv


1977).


vo primary routes of taurine


biosynthesis exist:


1) sequential oxidation of cysteine to produce 3-sulfinoalanine


followed


cysteic acid


and subsequent


decarboxylation


to form


taurmne


, or 2)


decarboxylation of 3-sulfinoalanine to produce hypotaurine followed by oxidation to


produce taurine (Wright et at, 1986).


Taurine is present in serum at concentrations


of 100 MM but can be transported into cells to produce intracellular concentrations


of up to 50 mM (Pasantes-Morales et al.,


1972; Cohen et at,


1973).


Such transport


achieved


through


a sodium-


energy-dependent


transport


system


with


apparent Km of 15 to 20 uM (Schmidt.


1980:


Tallan et al


,1983).


This transport







52

system can be inhibited by precursors of taurine, particularly by hypotaurine and


alanine (Tallan et at,


1983).


Intracellular concentrations of taurine are usually high in cells which produce

large quantities of free radicals, suggesting taurine serves as an antioxidant in these


cells.


example,


taurine


is present in


high


concentrations within


retina


(Pasantes-Morales et at,


1972; Cohen et al.,


1973), where it protects photoreceptors


from free radical- or illumination-induced damage (Pasantes-Morales et al.,


1984).


Likewise,


taurine


represents


as much


as 60%


amino


acids


within


phagocytotic cells (Fukuda et al.,


1982).


Taurine has also been shown to protect


skeletal


cardiac


muscle


from


exposure


to external


agents


(Huxtable


Lippincott,


1981; Kramer


et at


, 1981), protect cell membranes from free


radical


damage (Nakamori et at, 1990), and protect bovine lymphocytes from damage caused


by heat shock (Malayer et aL,


1992).


Free radical-scavenging properties of taurine.


The antioxidant capabilities of


taurine do not appear to involve highly specific scavenging of


* 02, H202 or


*OH


radicals.


Aruoma et at (1988) demonstrated that taurine does not readily react with


these free radicals, probably because the sulfonic acid group of taurine is not an


optimal substrate for such free radicals.


In contrast, because of its highly reactive


sulfinic acid group, hypotaurine


is highly reactive with all


of these


radicals


(Aruoma et aL,


1988


Green et aL


, 1991).


Taurine can readily scavenge the free


radical hvoochlorous acid (HOCI:


Thomas et aL


1986).


This reactive


molecules







53
(Harrison and Schultz, 1976; Morrison and Schonbaum, 1976) and causes formation

of toxic aldehyde derivatives upon reaction with cellular components (Wright et aL,


1986).


In contrast, chlorination of taurine by HOCI yields a stable chloramine with


a half-life of


-2.5


d (Weiss et al,


1982;


Thomas et al


, 1983).


Although taurine-


chloramine still contains reactive properties, its degree of reactivity is greatly reduced


compared with HOCI (Wright et at,


1986).


Additional properties of taurine.


Taurine is a prominent conjugate of bile


salts.


Its proposed role in the bile is conjugation and detoxification of potentially


damaging components in biliary fluid, rather than affecting the absorption of lipids


(Roy et at, 1982; Dorvil and Yousef, 1983; Emudianughe et aL,


1983).


Taurine may


regulate


osmotic


pressure


cells,


particularly


where


taunne


administration has been observed to inhibit swelling (Pasantes-Morales and Cruz,


1983).


This amino acid may also be a neurotransmitter molecule, since taurine is


released


after


photoexcitation


(Pasantes-Morales


Quesada-Carabez,


1981).


Calcium homeostasis may be regulated by taurine in some cells.


In retina, taurine


stimulates calcium influx in the presence of low intracellular calcium concentrations,


whereas


at high


calcium


concentrations,


uptake


inhibited


taurine


(Lopez-


Colome and Pasanto-Morales, 1981).


Taurine is also an important amino acid during development.


Taurine


present in high concentrations in milk, including colostrum in dairy cows (Sturman,


1986). I


*YC t*S Wa-


rats.


taunne


deficiency


increased


the incident


e of stillborn


I







54

incidence of photoreceptor degeneration (DeLa Rosa and Stipanuk, 1984; Bonhaus


et aL,


1985; Jacobsen et aL,


1987


Rapp et at,


1988).


Taurine and hypotaurine also enhance spermatozoa viability.


These amino


acids are present in millimolar concentrations in semen from bulls, boars, guinea


pigs, and humans (Van der Horst and Grooten, 1966; Johnson et al.,


1972; Meitzel


et al


, 1980; Holmes et al.,


1992).


Administration of hypotaurine increased motility


of sperm (Leibfried and Bavister, 1982; Boatman et at,


1990) and administration of


hypotaurine


Taurine


or taurine


hypotaurine


stimulated


probably


acrosome


serve


reaction


antioxidant


(Mrsny


roles


et aL


semen


, 1979).


since


administration of hypotaurine and taurine inhibited lipid peroxidation of spermatozoa

(Alvarez and Storey, 1983).

Taurine is present in uterine fluid at concentrations of 4 to 11 mM in humans


(Cassl6n,


1987) and 1


to 2 mM in cattle (Fahning et al.,


1967).


Although taurine


concentrations have not been defined in oviductal tissue


tissue concentrations of


hypotaurine are present in millimolar concentrations in ewe oviducts during the first


few d following estrus (Van der


Horst and Brand,


1969).


Perhaps, as in semen,


oviductal


uterine


taunne


hypotaurine


serves


as important


antioxidant


molecules for the protection of spermatozoa, oocytes or embryos.


Thermoprotective property of taurine

free radicals produced during heat stress.


It is possible that taurine can scavenge


Malayer et al. (1992) found that taurine


and alanine nrotected ~nltnred hnvine Ivmnhnrvtpe and miirine emhrvna frnm heat









shock.


Additionally, alanine reduced cytotoxic effects of heat shock on Chinese


hamster ovary cells (Vidair and Dewey, 1987).

Other Antioxidant Molecules


In addition to GSH and taurine,

radicals or electrophilic compounds fro


Vitamin A, C and E aid in scavenging free

m cells. In contrast to GSH and taurine,


however, these antioxidants have not been examined for ability to protect cells from


heat shock effects.


Hence, this section will review antioxidant functions of vitamin


A, C and E under situations other than heat stress.


Carotenoids (vitamin A).


Carotenoids are a class of lipid-soluble molecules,


some of which are precursors of vitamin A, which must be provided by the diet in


most animals.


B-carotene, retinol and other carotenoids are present throughout the


body at tissue and plasma concentrations of 100 to 600 nM (Lehman et at,


1988;


DiMascio et at,


1989).


Carotenoids readily react with free radicals produced either


by enzymatic or photochemical processes to yield formation of stable carbon radicals


on methyl groups (Sies et at,


1992).


Carotenoids which react with


*02.


radicals


include B-carotene


, retinol, lycopene (an abundant-open-chained analogue),


and the


bile pigments bilirubin and biliverdin (Stocker et at,


1987


DiMascio et al.,


1989;


Conn et alt,


1991).


The lipid solubility of this class of antioxidant suggests that they


are able


to protect


membranes


from


lipid


peroxidation.


P-carotene


other


carotenoids reduced


peroxidation


of lipids in


vitro


(Terao,


1989)


are more


reactive with


radicals than tocooherols (McDonagh, 1972).


O,







56

Deficiency of f-carotene or retinol in dairy cattle has been associated with


decreased


pregnancy rates (Kuhlman and


Gallup,


1942),


increased


incidence of


spontaneous abortions and dead calves (Ronning et at, 1959), and decreased growth


rate (Ganguly et aL,


1980).


Additionally, rate of spermatogenesis was reduced for


bulls deficient in vitamin A (Hodgson et aL,


1946; Erbman et al.,


1984).


Although


mechanisms by which carotenoids aid in reproductive performance and growth rate

are not defined, such consequences are probably caused at least in part by decreased

antioxidant status.

Vitamin A has likewise been associated with fertility in pigs; administration


vitamin


or a-carotene


around


time


of breeding


early


pregnancy


decreased embryonic mortality (Brief and Chew, 1985


Coffey and Britt, 1989).


Such


beneficial effects are probably caused by beneficial effects of retinol and retinoic acid


during embryonic development.


Uterine concentrations of retinol and its associated


binding protein (retinol-binding proteins) increase 7 to 8 fold during the second week


of gestation in pigs (Trout et at,


1992).


Perhaps retinol and retinoic acid serve to


limit


detrimental


effects of


electrophilic compounds


on embryonic development


during this period.


Vitamin A may also


influence embryo development through


additional


mechanisms,


such


as promoting


differentiation


proliferation


(Schindler,


1986), regulation of gene expression (Chiocca et at,


1988; Bedo et al.,


1989) and regulation of steroid synthesis (Talavera and


Chew,


1988).


It is also


possible


cows


require


retinol


-.- --- C -- -----2 r-- fl-1--


during


early


pregnancy


since


retinol-binding









Ascorbic acid (vitamin CL


Ascorbic acid, or vitamin C, is a water-soluble


molecule which is an important antioxidant of extracellular fluids, being present in


serum at concentrations of 30 to


150 MM (DiMascio et at,


1989).


Ascorbic acid is


an efficient scavenger of O,, H202,


*OH, HOCi and lipid peroxides with reaction


rates similar to carotenoids and higher than tocopherols (Nishikimi, 197


Halliwell


et at,


1987


Frei et at,


1989; Sies et at,


1992).


Ascorbic acid probably serves as an


important antioxidant molecule for spermatozoa.


Ascorbic acid is present in seminal


fluid at concentrations of 200 to 400 MM and has been shown to block oxidative


damage of spermatogonal DNA (Fraga et at,


1991).


Ascorbic


acid


probably


as an intracellular


antioxidant


because


intracellular concentrations are similar to those in serum (DiMascio et at,


1989).


Ascorbic acid enhances the antioxidant status of membranes, in conjunction with

GSH, by salvaging oxidized tocopherols and other electrophilic compounds (Packer


et at,


1979).


Ascorbic acid is oxidized to dehydroascorbic acid upon reaction with


tocopheroxyl radicals or other electrophilic compounds.


This compound is


then


readily reduced to its reactive state by GSH transhydrogenase enzymes (Meister,

1992).

Reports of ascorbic acid deficiency related to reproductive performance in

dairy cattle are lacking since cattle do not require dietary supplementation of vitamin


However, ascorbic acid has been observed


renrndirrtivu nrnhlm m c


to promote fertility in cattle with


Acrnrhir arid anrlmnictrntrnn imnrnved nreonnrvn ratPs in









bulls with low fertility (Phillips et at, 1940).


Moreover


ascorbic acid concentrations


in semen have been correlated positively with viability of bull spermatozoa (Phillips


et ai


, 1940).


Tocopherols (vitamin E).


Tocopherols, or vitamin E molecules, encompass


a group of lipid-soluble molecules that are considered to be the major antioxidant


for protection of membranes from


lipid peroxidation (Burton and


Ingold,


1984;


Horwitt, 1986).


Although reactivity of tocopherols with free radicals is lower than


for carotenoids and ascorbic acid (McDonagh,


1972; Sies et at,


1992), tocopherols


are present in tissues and serum at higher concentrations (2 to 40 MM; Lehman et at,


1988; DiMascio et at,


1989).


Similarly to carotenoids, methyl groups on aromatic


rings of tocopherols are responsible for reactions with 02, H202,


metals (Pascoe and Reed, 1987).

stable tocopheroxyl radical, whi


*OH and heavy


Oxidation of tocopherols produces formation of a


ch can be reduced by reaction with ascorbic acid


(Meister, 1992).


vitamin


reproduction


cattle


not been


clearly


established.


Several


studies


suggest


vitamin


deficiency


does


not affect


reproductive performance in cattle (Guillickson et al, 1949; Schingoethe et at,


1978).


Prepartum administration of vitamin E and selenium improved fertility of cows in


some studies (Segerson et al.,


1977


Shubin, 1988; Ar6chiga et at,


1994b) but not in


other studies (Schingoethe et a.,


1982; Segerson and Libby,


1982; Kappel et al.,


-t nnA'\


AS1 -ai'1I







59

decreased the incidence of retained placentae (Segerson et at, 1981; Harrison et at,


1984; Eger et aL,


1985), metritis (Harrison et aL,


1984) and cystic ovaries (Harrison


et at


, 1986).


Beneficial


effects


vitamin


and/or


selenium


during


periparturient period is probably caused by increased uterine contractility (Segerson


and Libby,


1982) or by enhanced uterine neutrophil activity (Grasso et at,


1990;


Gilbert et al


, 1993).


Presence of Protective Mechanisms in Mammalian Embryos


Maternal heat stress may alter embryonic development and viability either


directly or indirectly.


Indirect effects of maternal heat stress, such as effects of heat


stress on hormonal patterns and uterine secretions, have been described earlier in


review.


Elevated


uterine


temperatures


are likely


to also


directly


affect


embryonic


development


through


alterations


lipid,


protein


nucleic


structure.


The relative importance of embryonic versus reproductive tract effects


during heat stress were assessed by Alliston and Ulberg (1961).


pregnancy rates were


In that experiment,


reduced by transfer of embryos from heat-stressed ewes to


nonstressed recipients, suggesting that heat stress compromised embryonic survival


during early development.


Additionally, transfer of embryos from nonstressed ewes


into heat-stressed recipients reduced pregnancy rates to a lesser extent; suggesting

that heat stress, in addition to directly influencing embryonic survival, exerts adverse


effects on the uterus as well.


This section will review available knowledge regarding


direct effects of heat shock on embryonic function and discuss the mechanisms that









Effects of elevated temperature on cultured embryos.


Cultured mammalian


embryos


have


been


observed


to be


adversely


affected


exposure


to elevated


temperature. Alliston et aL (1965) determined that exposure of 1-cell rabbit embryos


to a heat shock of


40 C for 6


h decreased postimplantation


development when


embryos were subsequently transferred to recipients.


Similarly, Gwasdauskas et aL


(1992)


determined


exposure


1-cell


mouse


embryos


to 39


decreased


subsequent in vitro development.


Viability and development of murine morulae were


decreased following exposure to 42 C or 43 C heat shock for


1992; Malayer et aL,


2 h (Ar6chiga et at,


1992).


Adverse effects of heat shock on embryos in culture are probably caused by


direct effects of elevated temperatures on cellular components.


Instability of lipids


(Overath et at,


1970; McElhaney,


1974;


Yatvin,


1977


Bowler,


1981), denaturation


of proteins (Privalov,


1979; Lepock et at,


1983)


and altered activity


enzymes


(Ashburner and Bonner, 1979; Penafiel et al.,


1988;


Walton et al.


, 1989) occurs at


temperatures of 40 to 45 C.


These effects would adversely affect ion transport, signal


transduction,


metabolism


energy


substrates,


growth


factor


regulation


cytoskeleton integrity within embryos.


Adverse effects of heat shock on cultured


embryos may also


include effects caused by free


radicals.


Several


reports have


observed


radicals


limit


embryonic


development


under


thermoneutral


conditions.


For murine embryos, free radical production can be observed during in


i3-9t,- Ani ol nnin Tant /MTr- l 1 tnj n I-,1


I1 n.an\


1 nnnl (rnCn nl nl


In nnmn mn, rnn









Pratt,


1983; Noda et at,


1991).


This block in development can be prevented by


administration


antioxidants


such


as GSH


(Legge


Sellens,


1991)


thioredoxin (Goto et at, 1992), by administration of heavy metal chelators (Nasr-

Esfahani and Johnson, 1992) or by administration of scavenging enzymes such as


superoxide dismutase (Noda et at, 1991; Goto et at,


1992; Umaoka et at,


1992).


addition, administration of taurine


to mouse embryos from strains which do not


undergo a developmental block promoted development to blastocyst stages in culture


(Dumoulin et aL,


1992).


Likewise, administration of hypotaurine in cultured hamster


embryos improved survival of embryos following transfer to recipients (Barnett and

Bavister, 1992).


Ontogeny of thermotolerance in embryos.


Embryos gain resistance to heat


shock


as they progress


in development.


Alliston et


(1965)


determined


exposure to 40 C for 6 h decreased subsequent development of 1-cell rabbit embryos


but had no effect on 2-cell embryos.


Similarly, development of 1-cell mouse embryos


exposed to 39 C for 96 h was decreased compared to controls maintained at 37 C,

whereas 2-cell embryos were not affected by this heat shock (Gwasdauskas et at,


1992).


Similar observations have been made in vivo; embryonic development was


decreased to a greater extent by maternal heat stress on d 1 of pregnancy than with


heat stress on d 3 or later in sheep (Dutt, 1963).


Similarly,


maternal heat stress on


d 1 of pregnancy decreased embryonic viability to a larger degree than with heat


nn d 90


nrePonnnrv


in nuon


(Tmrnnl-nc


at nai


1Q0t7\


;nrrs9tcsA


__1 aV WV.l. aa -V VI UII*IV Wl **t** ***Ilull LCAa U~k aI t'Afttt. t.& *1~ A.A L A *Al L


atrp.c~









cells


provided


some


insight


to the


underlying


cause


acquisition


thermotolerance during development.


HSP synthesis


in embryos.


outline


for the current knowledge


of the


ontogeny of induced thermotolerance, ontogeny of HSP synthesis and efficacy of


antioxidants as thermoprotectants in murine embryos is presented in Figure


described previously, the presence of thermoprotective mechanisms in cells can be

determined by evaluating ability of cells to undergo induced thermotolerance. Muller

et al (1985) reported that exposure to a mild heat shock made mouse blastocysts


more resistant to a subsequent, severe heat shock. There was no beneficial effect of

exposure to a mild heat shock on 1-cell embryos, however. Further characterization


of the ontogeny of induced


thermotolerance


has not


been completed for mouse


embryos.


It is also not known whether induced thermotolerance occurs for embryos


of other species.

Induced thermotolerance in cells is associated with increased production of


HSPs; this may be true for embryos as well.


Constitutive synthesis of HSC70 occurs


in murine oocytes until the onset of oocyte maturation,


when mRNA and protein


levels decrease (Curci et at,


1987


Curci et al


1991


Manejwala et a.,


1991).


HSC70


mRNA and protein levels remain low until onset of transcription of the embryonic


genome at the 2-cell stage.


Constitutive synthesis of HSC70 and HSP68 resumes at


the 2-cell stage in murine embryos but heat-induced synthesis of HSP70 has not been


observed at the


or 8-crll staoe althnnloh


hlantnrvcts nnuperon in rpn2cpd T-TS.P7n


L-












tiul


S qt
sta
^E

c'b
at


4


4)
*1-


cc4)

cn-
'to


Ea


I- -Y ax a-rl I.








et at,


1984;


Muller


et at,


1985; Hahnel et


1986).


Stem


cells were


able


synthesize


HSP70


molecules


m response


to heat


shock


only


after


undergoing


differentiation to inner-cell mass or trophectoderm-like cells (Wittig et at,


1983;


Morange et at,


1984).


Taken together, these studies suggest that HSP70 proteins


become heat-inducible at the morula to blastocyst stage.


Since HSP68 and HSC70


have been observed to confer thermal resistance in many cell types (Johnson and


Kucey,


1988


Riabowol et al.


, 1988; Angelidis et aL.,


1991


Hendrey and Kola, 1991;


Li et at


, 1991),


these


HSPs


responsible,


at least


in part,


increased


resistance to heat shock as murine embryos proceed through development.

Heat-induced production of HSP70 is probably not the only mechanism by

which embryos gain resistance to heat shock, because the increase in resistance to


heat shock that occurs between


1-cell and 2-cell stage (Alliston et at,


1965;


Gwasdauskas et al., 1992) occurs before the embryo can undergo heat-induced HSP70


synthesis.


One possibility is that thermal resistance of murine 2-cell embryos involves


constitutive production of HSP70.


Protein synthesis from the time of resumption of


meiosis in oocytes until the 2-cell stage in mouse embryos is controlled by maternally

derived mRNA molecules and not by transcription from the cellular genome (Flach


et al.


1982


Bolton et aL


, 1984).


HSP68 and HSC70 represent some of the first


constitutive proteins synthesized following genome activation (Bensaude et aL,


1983:


Manejwala et at,


1991).


Since activation of the embryonic genome and constitutive


production of HSP68 and HSC70 is coincidental with increased thermal resistance









of other species also occurs at the time of genome activation.


Results of Hendrey


and Kola (1991) support this hypothesis because microinjection of mRNA for HSC70

to murine oocytes increased resistance to heat shock.


It is


possible


that other


HSPs are


involved


with


conferring


thermal


resistance in embryos.


In marine embryonic stem cells, heat-induced synthesis of


HSP110, HSP90 and HSP60 occurs (Lindquist and Craig, 1988; Burel et at,


1992).


HSP27 synthesis may also be heat-induced in these cells, although such synthesis

could not be observed through labelling with radiolabelled methionine (Kim et aL,


1983b; Arrigo and Welch, 1987).


Any or all of these proteins may


regulate thermal


sensitivity in


embryos during


early


development.


HSP90


HSP27


are likely


candidates because these proteins have been reported to increase thermal resistance


in other cell types (Landry et aL,


1989; Bansal et al.,


1991).


Other thermoorotective mechanisms.


also play a role in thermal resistance of emb


The intracellular antioxidant, GSH, may

)ryos. Concentrations of GSH are very


high in murine and porcine oocytes, ranging from 1 to


15 mM (Calvin et at,


1986;


Yoshida et aL,


1993).


Ar6chiga et alt


(1992) reported that intracellular GSH was


essential


induction


thermotolerance


munne


morulae.


Induction


thermotolerance was abolished by depletion of intracellular GSH and resistance to


heat shock was enhanced by increasing intracellular GSH


heat shock.


concentrations prior to


These observations of Ar6chiga et aL (1992) also imply that free radical


Production is increased during embrvonic heat shock.


Conseouentiv_ administration









shock.


In murine morulae, administration of taurine (Malayer et at,


(Malayer et al.,


1992) and vitamin E (Ar6chiga et at,


1992), alanine


1994a) partially prevented


detrimental effects of heat shock on embryonic viability.


Strategies for Limiting Deleterious Effects of
Heat Stress on Embryonic Survival in Cattle


Studies in the cow (Dunlap and Vincent, 1971; Putney et aL,


1988a; Putney et


1989a), sheep (Dutt, 1963) and pig (Tompkins et at,


1967


Omtvedt et al.,


1971)


have determined that the maturing oocyte and early developing embryo are highly


sensitive to heat stress effects.


It may be possible, therefore, to improve pregnancy


rates in heat-stressed cattle by limiting heat stress effects on the maturing oocyte and

early developing embryo. Several schemes have been utilized to accomplish this task.

Long-Term Cooling

Solar radiation can be a major contributor of heat to the heat-stressed cow


and this heat flow can be reduced by provision of shade.


Body temperatures were


lower in cows given access to shade structures during heat stress (Roman-Ponce et


, 1977; Buffington et at,


1981


Gwasdauskas et aL


1981


Roman-Ponce et aL,


1981). In one study (Roman-Ponce et aL, 1977), pregnancy rates were increased from


to 44.4


by provision


of shade.


In addition


to shade


heat


loss may


increased in cattle through convective systems that increase heat transfer from the


cow to the surrounding.


Rectal temperatures were decreased and pregnancy rates







67
Convective heat loss decreases as dry bulb temperature increases (Berman and


Meltzer,


1973), and at high temperatures a majority of heat loss occurs


through


evaporative heat exchange (McLean, 1963).


Flamenbaum et al (1986) found that


homeothermy was maintained for cows exposed to repeated sprinkling (20 to 30 sec)


and forced ventilation (3 to


5 min).


Pregnancy rates were improved from 17% to


59% with exposure to repeated cooling for the first 150 d of lactation (Wolfenson et


1988).


Similarly, pregnancy rates were increased for cattle housed in an air-


conditioned facility (Stott et at,


1972;


Thatcher et al


1974).


Systems such as these,


therefore, are effective in limiting heat stress effects on reproduction in dairy cattle.

Short-Term Cooling

A more economical scheme by which pregnancy rates may be increased during


heat


stress


is provision


cooling


limited


periods


during


early


embryonic


development.


In one such study (Gauthier,


1983),


there was a large increase


pregnancy rates for heat-stressed cows cooled for the first 10 d following breeding (13


to 53


pregnant), although low numbers of cows were used (n


= 15).


Stott and


Wiersma (1976) found a marginal increase in pregnancy rates by cooling cows for the


first 4 to 6 d following breeding (22 to


30% pregnant) and Her et al. (1988) found


no benefit to cooling cows from


d before until 8 d following breeding.


In this


study, however, the difference in body temperature between controls and treated


cows was small (38.5 to 39.4 C).


In summary, short-term cooling is a possible method


for improving pregnancy rates during heat stress but further investigation is needed









more successful if cows were also cooled for


2 to 3 d before breeding,


when final


oocyte maturation occurs.


Embryo


Transfer


Pregnancy rates may also be improved during periods of heat stress by embryo


transfer.


Transfer of embryos on d 6 to


7 after estrus may result in a bypass of


detrimental effects of heat stress on oocyte maturation and embryo development.

Putney et al (1989b) observed that pregnancy rates of lactating dairy cows exposed


to heat


stress


conditions


were


higher


recipients


of high


quality


morula-


blastocyst-stage


embryos


on d


postestrus


than


cows


bred


artificial


insemination.


Additionally,


no depression


in pregnancy rates were observed


lactating and nonlactating embryo transfer recipients throughout summer months in


the Southwest United States (Putney et at,


1988c).


Manipulation of Embryonic HSP Synthesis

A third approach is to protect the developing embryo from direct effects of


heat stress.


Manipulation of HSP concentrations within oocytes and embryos may


be one way to increase resistance to heat.


HSP70, HSP90 and HSP27 have been


reported to confer thermal resistance in a number of cells (Johnson and Kucey, 1988;


Riabowol et at, 1988; Angelidis et al., 1991; Li et al, 1991).


Resistance to heat shock


also was


increased in murine


oocytes with


microinjection


of mRNA for


HSC70


(Hendrey


Kola,


1991).


such


manipulations


to be


used


improving


Dreenancv rates during heat stress. however. gene expression must be altered.


This









Thermoprotection with Antioxidants


Effects of elevated temperatures may also be minimized by supplementation

of antioxidants to decrease damage caused by free radicals during heat stress (Loven,


1988).


Effects of heat shock have been reduced in various cultured cells by provision


GSH,


taurine


or alanine


(Vidair


Dewey,


1987


Lumpkin


et aL,


1988;


Kapiszewska


embryos


gained


I Hopwood,

resistance t


1988


o heat


Malaye

shock


e al.


effects


, 1992).


with


Additionally,


administration


munne

alanine


(Malayer et at,


1992), taurine (Malayer et at,


1992) and vitamin E (Ar6chiga et aL,


1994a).


In order for such a system to be successful, it will be necessary to identify


antioxidants that are effective in preventing effects of heat stress during early stages


of development, when embryos are highly sensitive to heat stress effects.


It is also


necessary to develop delivery systems that increase concentrations of antioxidants in

the oviduct sufficient to achieve protection.

Summary


Deleterious effects of heat stress on reproductive performance may be exerted


through


alterations


a plethora


reproductive


processes,


including


follicular


development,


oogenesis,


spermatogenesis,


preimplantation


postimplantation


embryonic development, uterine and oviductal function, and hormonal patterns.


maturing oocyte and early developing embryo appear to be particularly susceptible


to heat stress.


Exposure


cattle


to heat stress


conditions during


final


oocyte


maturation (Putnev et at..


1989b) or for the first 3 to


7 d of nre nancv (Dunlan and









viability.


However, after the first few d of pregnancy,


pregnancy rates were less


affected by maternal heat stress.


Transfer of embryos to lactating dairy cows at d 7


after


estrus


improved


pregnancy


rates


during


heat


stress


reduced


seasonal


variation in pregnancy rate (Putney et al.,


1988c; Putney et at,


1989b).


In sheep,


changes in embryonic resistance to heat stress have been described in detail through

experiments that involve exposure of females to heat stress for a single day during


early pregnancy (Dutt, 1963).

heat stress occurred on d 0


occurred on d 3, 5 or 7 of pregnancy.


Embryonic viability and development were lower when


(breeding) or d 1 of pregnancy than when heat stress


Similar experiments have not been performed


in cattle.


Filling


gaps


information


about


developmental


changes


embryonic


sensitivity to heat may result in development of management schemes to improve

pregnancy rates during periods of heat stress in cattle through provision of maximum


cooling during critical periods of early pregnancy.


Deleterious effects of heat stress


can be limited by provision of cooling systems.


For example,


Wolfenson et al. (1988)


found that provision of shade, sprinklers and forced ventilation for the first 150 d of


lactation


during


summer


months


Israel


improved


pregnancy


rates


to levels


observed during of winter months.


It may be more practical under certain situations


to provide maximum environmental modification for only a limited time during early


embryonic development.


Such an approach has resulted in large (Gauthier, 1983),


small


(Stntt


Wiersma.


1976)


or no (Her


et al


. 1988)


beneficial


effect


V-..


ururn \ru rr+r







71
by Hansen et at (1992), might be made more effective if a better understanding of

critical periods of embryonic sensitivity to heat stress was acquired.

While it has been shown in several mammals that embryos become more

resistant to heat stress as development progresses, there is no information for any


species


regards


cellular


biochemical


basis


phenomenon.


Resistance of many cultured cells to heat shock can be improved by prior exposure

to a mild heat shock (Gerner and Schneider, 1975; Henle and Leeper, 1976; Li and


Werb, 1982; Mirkes, 1987


Welch and Mizzen, 1988; Li and Mak, 1989; Maytin et at,


1990;


Hatayama


et aL


, 1991).


This


phenomenon,


called


thermotolerance,


associated with changes in synthesis of HSPs (Li and Werb, 1982; Li, 1985


Mivechi


1985;


Widelitz


eta


1987


Mizzen


Welch,


1988)


antioxidant


molecules (Mitchell et al.,


1983; Russo et at,


1984


Jones and Douple,


1990; Harris


e al.


, 1991),


which may confer thermal resistance.


Establishing the


relationship


between induced thermotolerance and ontogeny of thermal resistance in mammalian

embryos, and identification of specific intracellular processes involved, may lead to


development


novel


approaches


increase


fertility


heat-stressed


embryos


through biochemical modification of the embryo.


One biochemical system that may be beneficial


to modification to protect


embryos from adverse effects of heat stress is the antioxidant system.


Loven (1988)


proposed that heat shock increases free radicals in cells, which then causes cellular


damage.


Various antioxidants have been shown to reduce effects of heat shock on









Kapiszewska


Hopwood,


1988;


Malayer


et aL,


1992)


in two


studies,


preimplantation


mouse


embryos


(Malayer


et aL,


1992;


Ar6chiga


et aL,


1994a).


However, further investigation of such antioxidants is needed before this type of an


approach


can be considered a valid means


to protect embryos from heat stress


effects.


There were two major objectives of the experiments in this dissertation.


first objective involved characterization of the ontogeny of induced thermotolerance

in embryos and exploitation of this information to improve fertility in heat-stressed


cows.


Specific objectives were to identify the period in early pregnancy when the


embryo is most susceptible to heat stress, use cultured bovine embryos to evaluate

whether developmental changes in susceptibility to maternal heat stress are due to

changes in resistance to elevated temperatures, use mouse embryos to evaluate the

ontogeny of induced thermotolerance response and finally to test whether cooling

cows during critical periods of early pregnancy improves pregnancy rates of heat-


stressed cows.


The second major objective was to evaluate the efficacy of providing


antioxidants to increase resistance of embryos to heat shock.


The approach used


cultured bovine and murine embryos to identify beneficial antioxidant molecules, with

the long-term goal of testing these molecules for thermoprotective effects under field

conditions.













CHAPTER III
DEVELOPMENTAL CHANGES IN EMBRYONIC RESISTANCE TO
ADVERSE EFFECTS OF MATERNAL HEAT STRESS IN COWS


Introduction


In hot climates, fertility of dairy cattle is depressed during the summer (Poston


et at


, 1962; Stott and Williams,


1962; Rosenberg et alt,


1977


Badinga et aL,


1985;


Monty and Racowsky, 1987).


Heat generated from metabolic functions associated


with


lactation,


growth,


maintenance


exchanged


readily


environments, and cows often become hyperthermic when they are exposed to heat


stress.


A major source for reduction in embryonic survival induced by heat stress


may be adverse effects of elevated body temperatures on developing zygotes and


embryos.


Exposure of cattle to elevated temperatures during oocyte maturation and


ovulation (Putney et aL, 1989a) or during the first 3 or


Vincent; Putney et at,


7 d of pregnancy (Dunlap and


1988a) decreased embryonic viability and development.


other


species,


embryos


become


more


resistant


elevated


temperature


development


progresses.


particular,


ovine


embryos


most


sensitive


deleterious effects of maternal heat stress during


the first


2 d of pregnancy but


become more resistant to maternal heat stress effects by d 3 to


(Dutt, 1963).


after breeding


The increased resistance may be due to development of biochemical







74

responses within embryos that limit deleterious effects of elevated temperature, i.e.,

the heat shock response (Lindquist, 1986; Mirkes, 1987).


objective


current


study


was


to test


whether


embryos


from


superovulated cows become more resistant to adverse effects of maternal heat stress

as embryonic development progresses. Superovulated cows were used to increase the

number of embryos examined per cow and thereby to improve the efficiency of the


experimental design.


Identification of stages at which embryos are most susceptible


to heat


stress


contribute


to the


knowledge


developmental


changes


embryonic responses to stress and is of practical importance because pregnancy rates

during periods of heat stress may be improved by cooling cows during critical periods

of early pregnancy.


Materials and Methods


Synchronization of Estrus and Superovulation


The experiment was conducted from June to September over

years at the University of Florida Dairy Research Unit in Hague. G


consecutive


roups of 10 to


20 lactating, nonpregnant Holstein cows (50 to 150 DIM) were housed in a free-stall


barn containing fans and sprinklers.


Fans operated continuously from 0700 to 2000


h, and sprinklers operated for 3 min at 20-min intervals from 0700 to 2000 h daily.


Estrous cycles were synchronized by administration of PGF, (25 mg; Lutalyse


Upjohn Co., Kalamazoo, MI) twice at


11-d intervals.


From 48 to 96 h after the


second infection of PGF,.. cows were observed for estrus twice daily.


Cows observed







75
follicle-stimulating hormone (FSH-P; Schering Corp., Kenilworth, NJ) twice daily on


d 10 (14 mg/d), 11 (12 mg/d), 12 (10 mg/d), and 13 (8 mg/d) postestrus (23).


d 12 postestrus, PGF~ (25 mg) was administered twice and cows were inseminated

artificially three times at 12-h intervals from the onset of standing estrus (onset of


estrus


= d 0 of pregnancy).


A majority of cows demonstrated standing estrus on the


morning


cows


not demonstrating


standing


estrus


time


were


administered 4 mg FSH-P and observed for estrous behavior for an additional 24 h.

Treatments


For yr 1,

stress (control).


treatments were heat stress on d 1


For yr


3, 5, or 7 of pregnancy or no heat


treatments were heat stress on d 1 or 3 or control.


induce heat stress, cows were placed in an unshaded lot from 0800 to


1500 h.


cow experienced rectal temperatures >42 C, she was removed from the heat stress

lot and placed under a shade structure until 1500 h. At all other times, except during


milking (0700 and


1600 h for yr


1; 0200,


1000, and


1600 h for yr


cows were


housed in a free-stall barn to maintain thermoneutral conditions.


Cows


were


assigned


randomly


to treatments


at the


onset


estrus.


environmental conditions on the assigned day of treatment apparently would not be


conducive to impose heat stress (for example, rain or cool air temperatures), cow


were


not placed


were


reassigned


randomly


to other


available


treatments.

Environmental measurements (black globe temperature, dry bulb temperature,








heat


stress


(both


years)


free-stall


barn


Rectal


temperatures were measured at 1200 and


1500 h on the day of heat stress for all


heat-stressed cows (both years) and for control cows at either d 1 or 3 (yr

Determination of Embryonic Survival


d 8,


uteri


were


flushed


nonsurgically


to retrieve


embryos


were


classified according to stage of development (Drost, 1986).


Viability was determined


using the vital stain 4',6'-diamidino-2-phenylindole (DAPI; Sigma Chemical Co., St.


Louis, MO).


Embryos were incubated in Dulbecco'


PBS (DPBS; pH 7.4,


containing


0.0001


DAPI


to 20


room


temperature,


washed


Dulbecco's


PBS and examined using an epifluorescence microscope with a 490-nm


emission filter (Schilling et al, 1979).


Embryonic viability was scored on a four-point


scale according to the proportion of cells within embryos that stained positive for


DAPI: DAPI score was 1 when no cells stained,


2 when fewer than one-third of the


cells stained, 3 when one- to two-thirds of the cells stained and 4 when more than


two-thirds of the cells stained.


Embryos were considered to be live when fewer than


one-third of the cells stained positive for DAPI (scores of 1 and


Statistical Analysis


Data were analyzed using both categorical procedures (CATMOD) and least


squares ANOVA (GLM) through procedures of SAS (1989).


One-cell embryos were


considered to be unfertilized oocytes and were removed from all analyses except for


stage


embryonic


development


at d 8 and


percentage


embryos at









embryos/unfertilized


oocytes


are presented


Table


categorical


procedures (DAPI score, percentage of embryos at each stage of development, and

distribution of embryos within stage), the model included components of treatment,


year, and treatment x year interactions.


Stages of embryonic development included


1-cell, 2- to 8-cells, 9- to 16-cells, morula and blastocyst.


Data were analyzed using


all treatments (complete data set) and then reanalyzed after excluding treatments on

d 5 and 7 (reduced data set), since these treatments were not represented during yr

2. For ANOVA (rectal temperature, DAPI score, percentage of live embryos, and


percentage of blastocysts),


cow was used as


the experimental


unit for


effects of


treatment, year, treatment x year, and experiment(treatment x year).


These analyses


were


accomplished


analysis


average


embryonic


responses


each


cow.


Preplanned orthogonal contrasts were performed to separate treatment effects and


consisted of control, d 1 and 3 versus d


and 7


d 5 versus 7; control and d 3 versus


d 1; and control versus d 3.


For the reduced data set, contrasts were control and d


3 versus d


1; and control versus d 3.


For rectal temperature, Duncan'


multiple


range test was used to evaluate differences among treatments.

Results


Environmental Conditions and Rectal Temoeratures


Peak black globe temperature, dry bulb temperature,


and relative humidity in


the unshaded lot averaged 42.1 C, 34.3 C and 53.


for yr 1 and 41


C, 34.7 C and


64.4%


for yr


respectively.


During


black


- .


globe


temperatures,


bulb








C and 64.4%, respectively.


Rectal temperatures were higher (P


< 0.05) for cows


placed in the unshaded lot than for controls (40.9 to 41.7 versus 39.1 C;


Table


and are comparable to rectal temperatures observed in previous studies (Putney et


1988a; Putney et at,


1989a).


Variation in rectal temperatures among cows was


not a significant factor in embryonic responses since use of rectal temperature as a

covariate did not affect results.

Embryonic Survival

A CATMOD analysis revealed an effect of treatment on DAPI score when


all data were analyzed (P


= 0.07) or after embryos from cows heat stressed on d


and 7 were excluded (P


= 0.03).


As shown in Figure


maternal heat stress on d


1 resulted in fewer embryos with DAPI scores of 1 and


DAPI scores of 4.


2 and more embryos with


Least squares means for DAPI scores are presented in Table 3-1.


As determined by


ANOVA of


orthogonal contrasts,


DAPI score was greater for


embryos from cows heat stressed on d


than for embryos from control cows and


cows heat stressed on d 3 (complete data set, P


= 0.07


reduced data set, P


= 0.05).


Day of heat stress also affected the proportion of embryos classified as live or dead


based on CATMOD analysis of DAPI scores (Table


reduced data sets).


= 0.03 for complete and


The percentage of live embryos was also calculated for each cow,


and data were analyzed by least squares ANOVA to consider variation among cows


in the analysis.


Least squares means for the percentage of live embryos were 70.9%


for embryos from control cows and 54.9, 60.3, 62.6, and 82.0% for embryos from cows

























ennv
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O\ OooVtr


0
00


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O4
I-.


h0


C3'00 E

-" I
rt0


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0)
In


4o ~q
U


rl0~
'04-


'.4 t

En


4)


tAZA -. ~-'P




0,

In














DAPI=1


~LAPI=2


DAPI=3


flkPI=4


Control 1 3 5 7
Day of Heat Stress


Figure 3-1. Effect of maternal heat stress on 4',6'-diamidino-2-phenylindole
(DAPI) score of embryos (2-cell). Results represent the percentage of embryos
within each treatment with DAPI scores of 1 (no cells stained), 2 (less than one-
third of the cells stained), 3 (one-third to two-third of the cells stained) and 4
(more than two-third of the cells stained).








for the reduced data set; SEM


= 12%).


No year x treatment interactions were


detected for any of the models used to analyze mean DAPI score or percentage of

live embryos.

Embryonic Development

Alterations in the distribution of stage of embryonic development (Table 3-2)


were


evident


among


treatments


as determined


CATMOD


analysis


treatments (P


= 0.10), or after exclusion of embryos from cows heat stressed on d


5 and 7(P


= 0.03).


Individual analysis of the percentage of embryos at each stage


showed that heat stress on d 1 decreased the percentage of embryos at the blastocyst


stage of development (P


= 0.02 for the complete data set, P


= 0.05 for the reduced


data set) and increased


the percentage of


embryos at


to 16-cell stage of


development (P


= 0.04 for the complete data set, P


= 0.01 for the reduced data set).


In addition, day of heat stress affected percentage of 1-cell embryos/unfertilized


oocytes (P


= 0.03 for complete data set; P


= 0.05 for the reduced data set), being


lower for cows treated at d 3.


No treatment effects were observed at other stages.


Least squares means for the percentage of blastocysts,


when


1-cell embryos were


removed from the data sets, were 60.6


for embryos from control cows and 37.4,


54.8,


62.6, and 64.5


for embryos from cow


heat stressed on d


and 7,


respectively; the percentage of blastocysts was decreased only on d 1 (P


= 0.07 for


complete


data set, P


= 0.06


for reduced


data set


when


results


from


were


compared with those for controls and d 3; SEM


= 13%).


When


1-cell embryos/























































































U K...


~Otd~ o


cm~


-o


O\ tt
~ Ic~










1/1 ~O
r( rl


II
I~q


~SM








percentage of blastocysts were 42.1


for embryos from control cows and 28.4, 54.8,


63.0, and 58.5


for embryos from cows heat stressed on d 1,


3, 5, and 7, respectively.


With this analysis, heat stress on d 1 decreased percentage of blastocysts compared


to embryos from control cows and from cow


complete data set; P


heat stressed on d 3 (P


= 0.05 for reduced data set; SEM


= 0.03 for


Year x treatment


interactions were not significant for any statistical analysis of embryonic development.

Discussion


These


results demonstrate


that bovine embryos become


more


resistant to


deleterious effects of maternal heat stress as they proceed through development.


Thus, the cow is similar to the sheep (Dutt,


1963) and pig (Tompkins et al.,


1967


Omtvedt et al.,


1971) in this regard.


A minimum period after heat stress before


evaluation


embryonic viability


and development


could


preclude


the ability to


detect adverse effects for embryos on d


and 7 treatments.


Since no effects of heat


stress on embryos were observed on d 3, however, it was apparent that embryos


become more resistant to heat stress as development progresses.


The magnitude of


adverse effects of maternal heat stress on embryonic survival was less severe in the


present study than for studies in other species.


Differences may be attributed to


method of heat stress; studies in sheep (Dutt, 1963) and pigs (Tompkins et al., 1967


Omtvedt et al.


, 1971) were performed in environmentally controlled chambers for 17


to 24 h, whereas the present study was performed under more variable


conditions for 7 h.


environmental


Present findings do not imply that bovine embryos are completely







84

severity or duration than that used in this study could possibly decrease embryonic


survival before or after d 1.


Maternal heat stress during final oocyte maturation and


ovulation has deleterious effects on subsequent embryonic development that is more


severe than was observed in the present study (Putney et aL,


1989a).


In addition,


concepts development was decreased by exposure of cows to heat stress from d 8


to 16 of pregnancy (Biggers et aL,


1987). Nonetheless, these results demonstrate that


embryos respond differentially to maternal heat stress depending on their stage of

development, and, by d 3 of pregnancy, embryos have acquired some resistance to

adverse effects of maternal heat stress.

Mechanisms that are responsible for the ontogeny of embryonic resistance to

thermal stress are not defined but could reflect changes in embryonic function or in


the microenvironment of the embryo.


Embryos may develop the capacity to produce


molecules that limit effects of heat on cellular function.


In many cells, the synthesis


HSPs


during


elevated


temperature


limited


deleterious


effects


elevated


temperatures (Li and Werb, 1982; Riabowol et at,


1988; Landry et at,


1989; Bansal


etaI


1991; Hendrey and Kola, 1991).


In mouse embryos, thermal resistance was


increased for 2-cell embryos compared with


1-cell


embryos (Gwasdauskas et


1992), coincident with the partial activation of the embryonic genome (Prather and


First,


1988) and constitutive synthesis of HSP70 molecules (Bensaude et at,


1983;


Manejwala et


1991).


development


of bovine


embryonic


resistance


maternal heat stress in cattle may be due to the ability of embryos to produce HSP








85
bovine embryonic genome is activated between the 4- to 8-cell stage (Barnes and


Eyestone, 1990; Barnes and First, 1991), i.e.,


d 2 to 3 of pregnancy (Betteridge and


F16chon, 1988).

Developmental resistance of embryos to maternal heat stress may also involve


interactions between the embryo and reproductive tract.


Heat stress altered protein


secretion from the oviduct and uterus (Malayer et alt,


1988; Geisert et aL,


1988;


Putney et al,


1988b;


Malayer and Hansen,


1990).


increase


in resistance of


embryos to heat stress is not likely changed by a shift in the location of embryos from


oviduct


to uterus


because


embryos


are present in


oviduct


at d 1


pregnancy (Betteridge and F16chon, 1988).


This


study


have


practical


implications


improving


fertility


during


summer in hot climates.


Hansen et aL


(1992) proposed


that,


while cows should


receive cooling at


times during heat stress, summer pregnancy


rates may be


improved during periods of heat stress through strategic cooling, in which cows are

placed in an environment that allows maximal cooling during times when embryos


are most sensitive to heat stress effects.


These times have been defined as the period


of final oocyte maturation and ovulation (Putney et at,


of pregnancy (present study).


1989a) and the first few days


Also, administration of agents that protect embryos


from adverse effects of heat stress may be a useful approach to improve pregnancy


rates during summer.


Taurine, alanine and vitamin E supplementation to medium


5il 4 5 5 4 *4 I. 5 II 5 4




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