Minireview. Transgenerational Inheritance of the Stress Response. a New Frontier in Stress Research....

Minireview: Transgenerational Inheritance of theStress Response: A New Frontier in Stress Research

Stephen G. Matthews and David I. W. Phillips

Departments of Physiology, Medicine, and Obstetrics and Gynaecology (S.G.M.), Faculty of Medicine,University of Toronto, Medical Sciences Building, Toronto, Ontario M5S 1A8, Canada; and MedicalResearch Council Epidemiology Resource Centre (D.I.W.P.), Southampton General Hospital,Southampton SO16 6YD, United Kingdom

It is well established in animal models that the prenatal environment can have a major impact onstress axis function throughout life. These changes can predispose to various metabolic, cardio-vascular, and neurobiological pathophysiologies. Emerging evidence indicates that the same pro-grammingeffects occur inhumans. It is nowbecoming clear that thepathophysiological effects arenot confined to the first-generation offspring and that there is transgenerationalmemory of fetalexperience that can extend across multiple generations. The complex mechanisms by which trans-generational transmission of stress responsiveness occur are rapidly becoming a focus of investi-gation. Understanding these fundamental biological processes will allow for development ofintervention strategies that prevent or reverse adverse programming of the stress response.(Endocrinology 151: 713, 2010)

Although alterations in the hypothalamo-pituitary-ad-renal (HPA) axis and associated neuroendocrinechanges form a key component of the response of the or-ganism to stressful challenges, it is becoming increasinglyclear that these neuroendocrine responses to stress do notmerely affect a single generation but are transmitted to sub-sequent generations and that this occurs by means of non-genomic mechanisms. This has been demonstrated experi-mentally in studies in a variety of different animal species,andinamore limitedwayinhumanobservational studies,byshowing that stressful exposures duringpregnancy affect theset-point of HPA responses in the offspring and that theseeffects may be transmitted through the maternal line affect-ing subsequent generations. This new frontier in stress re-search is not only of biological interest but may also haveimportant clinical, economic, and societal consequences be-cause it has the potential to provide one explanation as tohow adverse environmental influences affecting one gener-ationcan influence thephysiology,behavior,anddisease riskin subsequent generations. We have confined this short re-view to the effects of a modified fetal environment on HPAfunction across multiple generations.

Maternal Programming of HPA Function inFirst-Generation Offspring

Animal studiesAvery large numberof animal studies have investigated

the effects of manipulating the fetal environment on stressreactivity and behaviors in later life in first-generation (F1)offspring.These studieshavebeenextensively reviewed (1,2). As a general consensus, maternal stress during preg-nancy leads to increased HPA activity in rat, guinea pig,and primate offspring. However, there has likely beensome bias as a result of its being more difficult to publishnegative findings or results that do not align with the con-sensus. One of the major challenges in this field has beenthe fact that outcomes of these animal studies have beenhighly variable. Within a given species, effects in the F1offspring are highly dependent on the nature of the ma-nipulation (i.e. maternal stress, glucocorticoid exposure,undernutrition, or overnutrition) as well as the timing,intensity, and duration of the manipulation in pregnancy.In this regard, we have shown in the guinea pig that al-though maternal stress in late gestation leads to elevated

ISSN Print 0013-7227 ISSN Online 1945-7170Printed in U.S.A.Copyright 2010 by The Endocrine Societydoi: 10.1210/en.2009-0916 Received August 3, 2009. Accepted September 23, 2009.First Published Online November 3, 2009

Abbreviations: HPA, Hypothalamo-pituitary-adrenal; 11-HSD, 11-hydroxysteroid dehy-drogenase; PS, prenatal stress; PTSD, posttraumatic stress disorder.

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HPA activity in male offspring, exposure to synthetic glu-cocorticoid, at very similar times in gestation, results inreduced HPA activity (3, 4). With respect to timing ofexposure, Kapoor et al. (3) demonstrated that brief expo-sure to maternal stress at 70% gestation resulted in adultmale guinea pig offspring that exhibited elevated basalcortisol levels but normal adrenocortical responses tostress. In contrast, exactly the same stress administered at90% gestation resulted in adult male offspring that ex-hibited normal basal cortisol concentrations but in-creased HPA responsiveness to challenge (3). Outcomesare also dependent on the sex of the offspring, the age atwhich the outcome is assessed, and in females, the stage inthe reproductive cycle when analysis of the given outcomeis undertaken. For example, normally cycling adult femaleguinea pigs, born to mothers exposed to stress in late ges-tation, exhibited a reduced salivary cortisol response tostress compared with control offspring, but only duringthe estrous phase of the cycle (5). In general, females areunderrepresented in the animal literature, because manyof the earlier (and some present) studies are confined tooutcome analysis in male offspring, perhaps due to theconsiderations above. There also appears to be strong in-teraction between the prenatal and postnatal environ-ments, such that manipulation of the postnatal environ-ment (such as cross-fostering) can reduce or reverse theeffects of the prenatal manipulation.

Many of the species differences observed likely arisefrom differences in the profile of fetal body and braindevelopment that exist between species. In this regard,neuroendocrine development is linked to phases of rapidbrain growth (6). The latter occurs during fetal life in thesheep, guinea pig, and many primates. In humans, therapid phase of brain development is initiated in the lasttrimester andextends into thepostnatal period,whereas inmany rodent species (including rats and mice), maximalbrain growth is not initiated until postnatal life. As such,a period of maternal stress in the sheep at midgestationwould correspond to a very different phase of fetal brainand neuroendocrine development in the rat at the samestage of gestation.

Human studiesGivenwhat we now know from studies in animal mod-

els, in which thematernal environment can be tightly con-trolled, it is perhaps not surprising that human studiesshow similar effects although as with the animal models,the changes in the offspring are often variable and con-tradictory in nature. A number of studies have evaluatedthe effect of stress-provoking experiences during preg-nancy (i.e.daily hassles, life events, anddomestic violence)sometimes in combination with evaluation of the maternal

response to stress (perceived stress or anxiety) and assess-ment of maternal cortisol secretion on offspring neuroen-docrine responses. All these approaches have limitationsbecause there is substantial intra-individual variation inthe way different mothers respond to various stressors.Furthermore, measures of perceived stress tend to bepoorly associated with physiological measurements ofHPA or sympathoadrenal activation. Finally, becausemany studies have been relatively small and have multipleassessments of both maternal stress and outcomes, theyrisk generating false-positive findings. Nevertheless, thereis an emerging consensus that maternal stress is linkedwith a range of HPA or related neuroendocrine perturba-tions in the offspring and associated adverse developmen-tal outcomes (1).

In a longitudinal study of mothers and children, self-reported maternal anxiety during late pregnancy was as-sociated with an increased awakening salivary cortisol se-cretion in the offspring at 10 yr of age, after accounting forobstetric and sociodemographic factors. The effect onawakening cortisol remained significant after controllingfor multiple postnatal assessments of maternal anxietyand depression (7). A similar study of mother-child dyadsfrom The Netherlands reported that prenatal anxiety (in-cluding daily hassles, fear about pregnancy outcome, orgivingbirth) at 16wkgestationwas associatedwithhighercortisol responses in the offspring to vaccination at 5 yr ofage. High prenatal maternal cortisol levels also predictedcortisol responses in the offspring (8). In a retrospectivestudy of healthy young adults whosemothers experiencedsevere stress during pregnancy (i.e. death or severe illnessin a close relative), cortisol responses to a psychosocialstress test (The Trier Social Stress Test) were higher thanobserved in the control group. However, baseline pretestcortisol concentrations were lower as were cortisol re-sponses to an ACTH challenge, whereas the home diurnalcortisol concentrations were similar in both groups (9).

Another approach has been to evaluate the effect offamine or other intensely stressful, major disasters on thestress responses of the offspring born to exposed pregnantwomen, but again because of the diverse nature of theseevents, the results tend to be highly variable. Several stud-ies show that the offspring of women pregnant at the timeof the disaster tend to be smaller and more premature atbirth and have a wide range of subsequent behavioral andphysiological abnormalities (10). TheDutch faminewas a5-month period of severe food shortage during the lastwinter ofWorldWar II. Previous studies have shown thatexposure to famine in early gestation is associatedwith anincrease in coronary artery disease and atherogenic lipidprofile and altered clotting in the offspring. This group

8 Matthews and Phillips Minireview Endocrinology, January 2010, 151(1):713


hadenhancedbloodpressure responses to stress; however,they failed to show alterations in HPA function (11).

A study of mothers exposed to theWorld Trade Centercollapse in September2001duringpregnancy showed thatamong thosewhodeveloped posttraumatic stress disorder(PTSD), both themothers and their 1-yr-old offspring hadlower awakening and evening cortisol concentrationsthan those who did not develop PTSD. Importantly, thiseffect was most apparent among babies born to motherswith PTSD who were exposed to the trauma in the thirdtrimester (12). A similar effect was reported among theoffspring of Jewish Holocaust survivors with PTSD, whohad lower mean 24-h cortisol secretion compared withoffspring without parental PTSD (13). A further observa-tional studyhasbeencarriedout comparing theadolescentoffspring of women who were pregnant during the Cher-nobyl disaster of 1986 with the offspring of women whowere pregnant after the incident. At the age of 14, theyfound that cortisol of both sexes and, intriguingly, thetestosterone levels in girls were higher after prenatal ex-posure to the event fromthe second trimester onward (14).

Maternal Programming of HPA Function inthe Second Generation and Beyond

Animal studiesThere are very few published reports on transgenera-

tional transmission of the effects of maternal manipula-tion during pregnancy on offspring phenotype in the F2generation and beyond (15). An early study identified thatstress duringpregnancy led to increased activity in anopenfield inF2-generationoffspring, althoughnoassessment ofHPA function was undertaken (16). Other early studiesshowed transgenerational influences ofmaternal diet dur-ing pregnancy on birth weight (for review see Ref. 15).However, to the best of our knowledge, no studies havedemonstrated transgenerational effects of maternal stressduringpregnancyonHPA function inoffspringpast the F1generation. Notwithstanding, in a recent study, we dem-onstrated thatmaternal undernutritionmodifies basal andactivated HPA function as well cardiovascular functionfor at least twogenerations in theguineapig (17). Pregnantguinea pigs were fed 70%of normal intake in the first half(d 135; early restriction) or second half (d 3670; laterestriction) of pregnancy. Female offspring (F1) weremated with control males and fed ad libitum to createF2-generation offspring. Birth weight and growth weremost affectedbynutrient restriction in late gestation; how-ever, these effects were much greater in the F2 than in theF1 offspring despite no manipulation of the F1 pregnancy.Maternal undernutrition increased basal cortisol and al-tered HPA responsiveness to challenge in both genera-

tions, although the endocrine effects were most pro-nounced in the F1 and F2 offspring of the late restrictedmothers (17).With respect to the cardiovascular effects, F1offspring born to mothers that had undergone early re-striction exhibited increased blood pressure, and in-creased left ventricularwall thickness. These effects on leftventricular structure were maintained into the F2 genera-tion. This study clearly illustrates transgenerational pro-grammingofHPAand cardiovascular function.However,it also shows, as one might predict, that susceptibility ofdifferent organ systems to maternal undernutrition variesas a function of gestational age.

Other studies have reported transgenerational influ-ences of maternal diet composition on aspects of plasmaglucose regulation (18). Interestingly, glucose responses tothe ip glucose tolerance test were not different betweencontrols and protein-restricted F1-generation offspring.However, insulin sensitivity was reduced in the femaleF2-generationoffspringwhose grandmothers hadbeen ex-posed to protein restriction during pregnancy. This effectwas not evident in males, indicating sex specificity of theeffect. Another single study has reported that exposure ofpregnant rats to synthetic glucocorticoid dexamethasoneover the last week of gestation results in glucose intoler-ance in male F2-generation offspring, and this was asso-ciated with increased hepatic phosphoenolpyruvate car-boxykinase activity (19). Importantly, this effect passeddown the male line, indicating paternal transmission. Wereported preliminary evidence of reduced HPA activity inF2-generationoffspringwhose grandmothers hadbeen ex-posed to synthetic glucocorticoid but whose mothers hadgone through an undisturbed pregnancy. This effect wasinvestigated only in the context of maternal transmission,however; again, the effects were stronger in the F2- thanthe F1-generation offspring (20).

Human studiesThere is still very limited evidence for transgenerational

inheritance in humans beyond the first generation, butavailable data do suggest that fetal nutritional and endo-crine insultsmaypersist into subsequent generations.Dur-ing the Dutch Winter Famine of 1944/1945, pregnantwomen exposed to famine in late pregnancy gave birth tosmaller babies. However, female offspring exposed inutero in the first trimester gave birth to children with re-duced birth size independently of the effect on maternalbirth weight (21). Exposure of pregnant women to dieth-ylstilbestrol, a synthetic estrogen previously used to pre-vent miscarriage, led to a marked increase in reproductiveabnormalities and cancers in their children. Evidence isnowemerging that third-generational effects (an increasedrisk of hypospadias) in boys are transmitted through the



maternal line without further exposure of the interveninggeneration (22). Suggestive evidence for transgenerationaleffects involving the HPA axis comes from a study of theoffspring of Holocaust survivors with PTSD, who showlower 24-h urinary cortisol excretion than offspring ofsurvivors without PTSD (23). However, there is clearly aneed for more information, and it is anticipated that sev-eral prospective studies of the long-term consequences ofmaternal stress, which are in progress, will provide moredata on the extent of transgenerational influences onHPAfunction in humans.

Mechanisms of Programming: F1Generation

Prenatal stress (PS) leads to numerous cardiovascular andendocrine changes in the mother, including increases inplasma ACTH, -endorphin, glucocorticoid, and cate-cholamine concentrations. The placenta forms a struc-tural and biochemical barrier to many of these maternalfactors, although a number will still enter the fetus. Theremay also be indirect effects on the fetus via modificationof placental function. For example, increased maternalcatecholamine concentrations will lead to constriction ofplacental blood vessels andmay lead to fetal hypoxia (24).There may also be activation of the fetal sympathetic ner-vous system, a system that has also been shown to beprogrammedby the early environment (for review seeRef.25). Programming of the sympathetic nervous system andneurotransmitter systems in the brain will ultimately leadto altered physiological responses to stress in offspring.

Although a number of factors are doubtless important,glucocorticoids have become a popular candidate for me-diating the effects of PS on programming HPA functionand behavior into the F1 generation. Maternal and fetalplasma glucocorticoid concentrations are significantly el-evated after maternal stress in rats and guinea pigs. Undernormal circumstances, access of maternal endogenousglucocorticoid to the fetus is low. This results from theplacental expression of 11-hydroxysteroid dehydroge-nase (11-HSD) type 2. The efficiency of placental 11-HSD2 varies among species, however it is generally ac-cepted that placental 11-HSD2 is of primary importancein excluding maternal endogenous glucocorticoid fromthe fetus. In this regard, a recent study has shown that PSleads to a reduction in placental 11-HSD2 expression inthe rat (26). A number of approaches have been used todetermine the role ofmaternal glucocorticoid in program-ming of HPA function during PS. In one elegant study,pregnant rats were adrenalectomized and basal levels ofcorticosterone replaced. In this group, PS had no effect onHPA function in the adult offspring (27), suggesting that

maternal glucocorticoid, or a factor stimulated by glu-cocorticoids, passes to the fetus to mediate PS-inducedchanges in HPA function.

Although increased exposure of the fetus to maternalglucocorticoid may represent a mediator of the effects ofPS, the question that remains is how these effects are per-manent as well as how they can be transmitted acrossgenerations. In this regard, it is becoming increasingly ev-ident that the early environment can permanently influ-ence the genome through epigenetic mechanisms and inthis way modify endocrine function, metabolism, and be-havior of offspring. Importantly, key genes that regulateHPA function (GR, CRH, POMC, and 11-HSD2) havebeen shown to be epigenetically regulated (2833).

Maternal stress/anxiety and dietary protein restrictionduring pregnancy (3234) and altered levels of maternalcare (for review see Ref. 35) can leave permanent epige-netic marks in the genome and result in stable lifelongchanges in gene expression in offspring. The elegant stud-ies of Meaney and Szyf have elucidated some of the po-tential mechanisms by which maternal care can influencethe epigenome (for review seeRef. 35). Very recent rat andhuman studies have shown that maternal stress/anxietyduring pregnancy leads to altered methylation of the hy-pothalamic CRH promoter (rat offspring) and GR pro-moter in umbilical cord blood mononuclear cells (humaninfants) (32, 33). The question that remains is what me-diates the demethylation? In this connection, glucocorti-coids, which are known to be elevated during maternalstress, have been shown to cause permanent demethyl-ation of specific fetal hepatic gene promoters in late ges-tation (36). This demethylation results in enhanced tran-scription factor binding, and this is maintained afterglucocorticoid withdrawal, indicating stability of the ef-fect. Therefore, there is strong evidence emerging indicat-ing that increased fetal glucocorticoid exposure has pro-found influences on the fetal epigenome. The route bywhich fetal exposure to glucocorticoids influences themethylation is not currently known, although it may in-volve reductions in folate availability. In this regard,patients with Cushings syndrome exhibit hyperhomocys-teinemia (37). Hyperhomocysteinemia inhibits the activ-ity of DNA methyltransferases and induces hypomethy-lation (38). Therefore, there is strong evidence forepigenetic processes being important for modified HPAfunction and behaviors in the F1 generation.

Mechanisms of Programming: MultipleGenerations

The question remains as to how these effects could betransmitted across generations. The mechanisms under-



lying transgenerational programming likely involve atleast two pathways: 1) altered maternal endocrine adap-tation to pregnancy and2) transgenerational transmissionof epigenetic modification (Fig. 1).

In pregnancy, there are major adaptations in the regu-lation of the maternal HPA axis. Maternal HPA activityincreases in late gestation (24), but there is a reduction instress responsiveness (39). If maternal stress during preg-nancy (F0 mothers) results in female offspring (F1) thatexhibit altered pituitary-adrenocortical adaptations topregnancy, this would modify fetal exposure to mater-nal endogenous glucocorticoid and result in program-ming of HPA function in her F2 offspring with no ma-nipulation of the F1 pregnancy. Indeed, pharmacologicalinhibition of placental 11-HSD2, which represents theprimary barrier protecting the fetus from high maternalglucocorticoid concentrations, leads to endocrine and be-havioral outcomes in offspring that are analogous to thoseof excess fetal glucocorticoid exposure.

The potential for transgenerational epigenetic memoryremains a little more controversial. Although themajorityof DNA methylation in the germline is erased in earlyembryogenesis, some epigenetic signals (not just thoseconfined to imprinted genes) exhibit meiotic stability andcan be transmitted from one generation to the next (40).Transient exposure of pregnant rats to endocrine disrup-tor vinclozolin or methoxychlor caused decreased sper-matogenic capacity in the F1 generation. These effectswere transferred through the male germline to nearly allmales up to the F4 generation. The same group has iden-tified transgenerational transmission of altered methyl-

ation patterns through the germline to F3 (for review seeRef. 41). Although other studies indicating paternal trans-mission of DNA methylation are emerging, the mecha-nisms remain to be resolved. It is likely that there will beconsiderable interaction between glucocorticoid levels(maternal and fetal) and the fetal epigenomeduring F1 andF2 pregnancies. For example, a decrease in maternal en-dogenous glucocorticoid levels through pregnancy wouldlead to decreased fetal exposure to glucocorticoid. Alter-natively, a reduction in placental 11-HSD2 gene expres-sion,which is itself heavily epigenetically regulated,wouldalso lead to increased fetal glucocorticoid exposure. Bothscenarios could lead to reprogramming of the fetalepigenome.

Conclusions

There is accumulating evidence in a variety of animal spe-cies that manipulation of the fetal environment alters thebiobehavioral response to stress in the offspring and thatthese altered responsespersist acrossmultiple generations.These observations are generally paralleled in humanstudies (with as yet few data on F2 effects), although therearemajor and largely unexplaineddifferences in outcomesbetween studies. Despite gaps in our knowledge, these arepotentially important findings because they may explainboth laboratory and human observations that environ-mental influences affecting one generation influence thedisease risk in subsequent generations. This is because ofincreasing evidence that subtle changes in the activity of

FIG. 1. Schematic illustrating the potential routes by which the fetal environment may lead to transgenerational programming of HPA function.Modified fetal environment will directly affect development of brain and neuroendocrine structures, and this likely involves epigenetic processes.Altered endocrine and cardiovascular function in the first-generation (F1) offspring will lead to a modification of the normal adaptations that takeplace during pregnancy, and this may directly program endocrine function of the F2 offspring. Again, epigenetic mechanisms are likely involved.This process may be repeated for several generations. See text for further details.



the HPA axis and related neuroendocrine systems arelinked with disease. Hypercortisolemia increases suscep-tibility to several diseases, including depression, hyperten-sion, and diabetes, with similar associations being identi-fied in animal models (42). In contrast, hypocortisolemiahas been linked to chronic fatigue syndrome, chronic pel-vic pain, fibromyalgia, PTSD, burnout, and atypical de-pression (43). In evolutionary terms, these HPA alter-ationsmay be part of a strategy bywhich parents transmitinformation about their current environment to theirprogeny, allowing the generation of phenotypes adaptedto the environment predicted by the cues available duringfetal life, but with associated costs. So, for example, ex-posure to an adverse environment during pregnancy maylead to increased offspringHPAactivity and behavioral orphysiological changes that enhance early survival andtherefore reproductive potential but at the cost of greatersusceptibility to subsequent vascular or metabolic diseasewith advancing age.

Acknowledgments

Address all correspondence and requests for reprints to: Profes-sor S. G.Matthews, Department of Physiology, Faculty ofMed-icine, University of Toronto,Medical Sciences Building, 1KingsCollege Circle, Toronto, Ontario, Canada M5S 1A8. E-mail:[email protected].

Disclosure Summary: The authors have nothing to declare.

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