PresentationEndocrinology

Prenatal Stress, Telomere Biology, and Fetal Programming of Health and Disease Risk

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Science Signaling  30 Oct 2012:
Vol. 5, Issue 248, pp. pt12
DOI: 10.1126/scisignal.2003580
A Presentation from the European Society for Paediatric Endocrinology (ESPE) New Inroads to Child Health (NICHe) Conference on Stress Response and Child Health in Heraklion, Crete, Greece, 18 to 20 May 2012.

Abstract

A substantial body of epidemiological, clinical, cellular, and molecular evidence converges to suggest that conditions during the intrauterine period of life play a critical role in developmental programming to influence subsequent health and susceptibility for common, complex disorders. Elucidation of the biological mechanisms underlying these effects is an area of considerable interest and investigation, and it is important to determine whether these mechanisms are distinct for different health outcomes or whether there are some common underlying pathways that may account for the effects of disparate prenatal and early postnatal conditions on various health and disease risk phenotypes. We propose that telomere biology may represent a common underlying mechanism connecting fetal programming and subsequent health outcomes. It appears that the initial establishment of telomere length and regulation of telomere homeostasis may be plastic and receptive to the influence of intrauterine and other early life conditions. Moreover, telomere homeostasis in various cell types may serve as a fundamental integrator and regulator of processes underlying cell genomic integrity and function, aging, and senescence over the life span. We advance the hypothesis that context- and time-inappropriate exposures to various forms of physiological stress (maternal-placental-fetal endocrine aberrations and immune, inflammatory, and oxidative stresses) during the intrauterine period of development may alter or program the telomere biology system in a manner that accelerates cellular dysfunction, aging, and disease susceptibility over the life span.

Presentation Notes

Slide 1: Science Signaling logo

The slideshow and notes for this Presentation are provided by Science Signaling (http://www.sciencesignaling.org).

Slide 2: Prenatal stress, telomere biology, and fetal programming of health and disease risk

This Presentation focuses on the putative influence of stress and stress biology within the larger issue of fetal programming of health and disease risk, specifically on the role of telomere biology as a mechanism for mediating the effects of stress.

Slide 3: The University of California Irvine Development, Health, and Disease Research Program

The transdisciplinary Development, Health, and Disease Research Program at the University of California, Irvine (UC Irvine) focuses on the interplay between biological, behavioral, and psychosocial processes during intrauterine life and their short- and long-term consequences for development, health, and disease risk.

Slide 4: Outline

There are three major components to this presentation. First, the concept of fetal or developmental origins of health and disease risk is discussed, with an emphasis on the role of prenatal stress and maternal-placental-fetal stress biology. Next, the possible role of telomere biology as a signaling mechanism mediating the effects of the intrauterine environment on subsequent health and disease risk outcomes is explicated. Last, a summary of ongoing studies and future directions is provided.

Slide 5: Burden of disease in developed nations and societies in rapid transition

Listed here are health outcomes that confer the major burden of disease in Western, developed countries. Each of these outcomes is termed as a “complex common” disease. These conditions also are referred to as noncommunicable diseases (NCDs) to separate them from conditions having an infectious etiology. Last year, for the first time in human history, these complex common disorders became the leading global cause of mortality, exceeding deaths related to infectious etiology. The 2011 World Health Organization (WHO) report of the most recent health statistics available from all member nations reveals some interesting and sobering facts. NCDs account for two-thirds of all global deaths, and this is not a phenomenon restricted to developed, Western nations or restricted to old age; 80% of these deaths occurred in low- or middle-income nations, and 25% of them occurred in individuals less than 60 years of age (1).

Slide 6: Determinants of health and disease risk

The likelihood of any given individual developing a complex common disorder can, at its most simple level, be expressed as a joint function of cumulative exposure to risk factors for that particular condition and her or his predisposition (or susceptibility or vulnerability). It is well established that there is considerable interindividual variation in the effects produced by a particular given “dose” of risk exposure. Traditionally, predisposition or susceptibility has been thought of as a function or direct consequence of genetic variation, but we now know this view to be incomplete. Predisposition or susceptibility arises from the integrity or robustness of both the structure and functional efficiency of various physiological systems. These are determined by developmental processes, which, in turn, are a function of not only genetic makeup but also, perhaps equally or even more importantly, of the early developmental environment. This understanding forms the basis of the fetal or developmental programming of health and disease risk concept.

Slide 7: Some considerations

It is important to note that the effects of any given set of environmental conditions on development and health would be expected to vary as a function of time or stage of development, context, interactions with other environmental conditions, and species-specific characteristics such as developmental pace or ontogeny, physiology, body size, and life span.

Slide 8: Key issues

We emphasize two issues related to the causation of complex common disorders. First, causation may emerge primarily through interactions between multiple risk factors, rather than as the major effect of any single specific factor. Second, in the context of fetal development, the fetus actively alters the biology of the maternal compartment that, in turn, influences the developmental course of the fetus. This has been referred to as “reciprocal determinism,” and an appreciation of the role of environmental conditions in embryonic and fetal life warrants the incorporation of principles from the areas of evolutionary biology, specifically life history theory, developmental plasticity, and maternal-fetal conflict theory (2, 3).

Slide 9: Parental effects in ecology and evolution

Another important issue of note is that the milieu of a pregnant woman may act directly on not just one but the next two generations of her descendants. The maternal milieu obviously affects the child she is carrying but also can affect the germ cells of all the children that will be born to that child. Direct parental or maternal effects can thus occur across three generations. For a comprehensive discussion, the reader is referred to (4).

Slide 10: Rationale for the study of the effects of prenatal stress

One of the key functions of the stress response is redistribution of energetic resources across different systems. It is this function that may be particularly relevant in the context of development, when, in accordance with the principles underlying life history theory, decisions about energy allocation are made in response to current or previous environmental conditions. Through an evolutionary lens, it appears that the most salient environmental variations underlying natural selection relate to energy allocation and nutrition, as well as to challenges that affect integrity and survival until reproductive age. It is for this reason that prenatal stress would be expected to influence many, if not all, developmental outcomes. Another reason for considering a role for prenatal stress in future health and disease outcomes has to do with the large disparities in sociodemographic or socioeconomic status that characterize the population distribution of complex common disorders. Stress has been hypothesized as a mediator of this association, and if this is the case, it stands to reason that exposure to excessive prenatal stress may contribute to the well-documented socioeconomic and sociodemographic disparities in developmental, birth, and child health outcomes.

Slide 11: Role of stress biology in developmental programming

Stress biology likely plays an important role in fetal or developmental programming. First, responses to endocrine, immune, and oxidative stress are among the most reliable, objective indicators of human fetal exposure to in utero stress. Several animal and human studies, including work from our research program, suggest that a broad array of intrauterine perturbations, including clinical, nutritional, behavioral, and psychosocial stressors, cause perturbations in maternal-placental-fetal (MPF) endocrine and immune processes. Second, there are no direct neural or vascular connections between the mother and her developing fetus. All communication between the maternal and fetal compartments is mediated by the placenta, an organ of fetal origin, and endocrine and immune stress responses serve as key communication signals between the maternal and the fetal compartments. Third, epidemiological, clinical, cellular, and molecular evidence converge to suggest that stress-related endocrine and immune processes, particularly proinflammatory cytokines and the corticotropin-releasing hormone (CRH)–glucocorticoid axis, may serve as key physiological pathways mediating the effects of intrauterine perturbations on the fetus, including the developing fetal brain. These processes play a major, obligatory role in the initiation, maintenance, and progression of normal gestation, fetal development, and birth, and perturbations of these systems are associated with adverse outcomes (5).

Slide 12: Specific questions

The overall goal of our research program is to elucidate and quantify the influence of maternal stress during pregnancy on fetal development and subsequent birth, infant, child, and adult health outcomes. Specific questions address which aspects of maternal stress may be particularly salient, which fetal and subsequent child and adult outcomes are influenced by maternal stress, and whether the stress is a direct effect of circumstances during pregnancy or whether the stress is secondary to other processes, such as obstetric complications. We are also interested in determining the magnitude and nature of any effects of maternal stress on child health and whether there are critical periods of susceptibility in gestation when the effects of stress are particularly pronounced. It is also important to identify the biological and behavioral mechanisms that mediate the effects of maternal stress, the biological systems that are implicated in this process, and how stress signals are transduced between the maternal and fetal compartments.

Slide 13: Recent research projects

In the recent past, researchers at the UC Irvine Development, Health, and Disease Research Program have conducted several NIH-funded projects that have addressed pregnancy and birth outcomes and examined the role of maternal stress and physiological stress reactivity, the interplay between stress and infection and between the endocrine and immune systems, and stress-related maternal-fetal gene-environment interactions. Some key findings include the following: After accounting for the effects of other established sociodemographic and obstetric risk factors, maternal stress exposure is significantly and independently associated with increased risk of adverse pregnancy and birth outcomes related to the length of gestation (preterm birth) and fetal growth (69). Our studies suggest that the effects of maternal psychosocial stress are mediated, in part, by stress-related alterations in MPF endocrine and immune processes (1013). Our studies also suggest that maternal psychosocial stress increases the risk of developing reproductive tract infection during pregnancy (14). Last, our studies have established that over the course of gestation, there is a progressive attenuation of not only maternal biologic but also psychological responses to stress (15) and that after accounting for the effects of other established risk factors, individual differences in the degree of this attenuation is a significant predictor of shortened length of gestation and risk of earlier delivery (16).

Slide 14: Primate (human) maternal-placental-fetal endocrine unit

In terms of endocrine pathways, cortisol has been studied extensively as a mediator of the effects of maternal stress on the developing fetus. It is important to note the presence of another important pathway that seems to be specific to primates, which is placental CRH. Primates are unique among mammals in that they are the only species whose placentas produce CRH during pregnancy. Placental CRH exerts important effects in both the fetal and the maternal compartments to support various aspects of fetal growth, maturation, and timing the onset of parturition (17).

Slide 15: Maternal-fetal gene-environment interactions in human pregnancy

It is well established that many of the effects of genetic variation on complex common health and disease risk outcomes depend upon environmental factors, because gene expression and gene product function are context-dependent phenomena. Considering the contribution of genetic variation to developmental outcomes is further complicated by the fact that there are two genomes and at least two sets of environmental conditions to be considered in the context of fetal development: the genomes of both the fetus and the mother, conditions that affect the mother, conditions affecting the fetus, and the bidirectional interactions between the mother and fetus. Therefore, we take a candidate approach, focusing on both maternal and fetal genes known to play a role in regulation of the endocrine stress axis, and our approach involves examining the combined effects of several maternal and fetal genes in particular contexts (gene-environment interactions) with respect to the various outcomes of interest.

To date, we have characterized the distribution and frequency of single nucleotide polymorphisms (SNPs) in stress-related genes by maternal race or ethnicity. One of our studies reports on the racial and ethnic differences in the architecture of the gene that encodes CRH between African-American and Caucasian women. We noted that at the time of publication (2007), the degree of this difference, as expressed by the Wright’s FST index (a measure of population differentiation), was higher for this gene than had been reported for any other gene (18). In another report on the association between infant birth weight and the variation in the gene that encodes the maternal CRH binding protein, we found that a particular SNP in this gene was independently associated with lower birth weight and that the magnitude of this effect was comparable to that of maternal smoking (19). One of our projects also examines the effects of variation in the mitochondrial genome on pregnancy and developmental outcomes.

Slide 16: Longer-term effects of prenatal stress exposure in human gestation

This presentation now turns to a consideration of the longer-term effects of prenatal stress exposure in humans.

Slide 17: Human epidemiological findings

A large number of human epidemiological studies across populations in North America, Europe, Asia, and Australia have reported robust associations between the birth phenotype, particularly birth weight, and risk for many complex common diseases in later life, including hypertension, coronary artery disease, and diabetes.

Slide 18: Is the effect of prenatal stress on adult physiology independent of birth phenotype?

The majority of human epidemiological studies addressing the fetal programming hypothesis have operationalized unfavorable intrauterine environments using indicators of adverse birth outcomes such as low birth weight.

We and others have argued that the long-term effects on child or adult disease-related phenotypes of interest may not necessarily be mediated by adverse birth outcomes. For example, several experimental studies in animals suggest that maternal exposure to psychosocial stress during gestation can independently exert long-term effects on several central and peripheral systems in the offspring and that titration of the prenatal stress exposure dose can produce significant long-term effects without necessarily altering the birth phenotype (2024). However, only a very small number of studies have investigated this effect in humans.

Slide 19: Approach

As a first step to addressing the effect of maternal stress on fetal programming of subsequent health outcomes, we conducted a retrospective study in a sample of healthy young adults born to mothers with healthy pregnancies and normal birth outcomes. One-half of the study population of young adults was born to mothers who had experienced a major stressful life event during the pregnancy, whereas the other half was a sociodemographically matched population with no history of maternal exposure to prenatal stress. We selected a study population of younger as opposed to older adults in order to focus on predisease markers of physiological dysregulation of metabolic, endocrine, and immune systems as early predictors of disease susceptibility. The potential effects of other established obstetric, newborn, and childhood risk factors on adult health were controlled using a stringent set of exclusionary criteria. Because subtle physiological differences in disease susceptibility are often not detected in the basal state, we employed appropriate challenge tests to quantify the function of these systems under stimulated conditions.

Slide 20: Long-term effects of prenatal stress exposure

Study assessments were performed to quantify health and physiological markers of disease risk. First, we quantified body composition and glucose-insulin metabolism by measuring body mass index (BMI) and percent fat mass, basal plasma glucose and plasma glucose after an oral glucose tolerance test, the fasting lipid profile, and the abundance of insulin, leptin, and adiponectin. To assay endocrine function, we measured the abundance of pituitary-adrenal stress hormones both basally and after behavioral and pharmacological stresses, looked at chronobiological regulation of adrenal function, and assessed hypothalamic-pituitary-adrenal (HPA) axis feedback sensitivity. To examine immune function, we looked at immune cell trafficking and phytohemagglutinin (PHA)–stimulated production of both pro- and anti-inflammatory cytokines by T helper cells (TH1 and TH2 cytokines). Finally, we assessed cognitive function by testing working memory under basal and stress conditions.

Slide 21: Summary of findings

The results of this study, summarized in the table on this slide, indicated that the young adults exposed during intrauterine life to maternal psychosocial stress consistently exhibited significant dysregulation of all the key physiological parameters we measured, thereby placing them at increased risk for developing complex common disorders. Specifically, individuals in the prenatal stress (PS) group exhibited higher BMI and percent body fat, primary insulin resistance, and a lipid profile consistent with metabolic syndrome (25), as compared with the control group. The PS group also showed altered immune function, with a TH2 shift in the TH1/TH2 balance, consistent with increased risk of asthma and autoimmune disorders (26), and altered endocrine function, with increased adrenocorticotropic hormone (ACTH) and reduced cortisol concentrations during pharmacological and psychological stimulation paradigms, consistent with the high-risk endocrine profile exhibited by individuals exposed to early life abuse (27). Furthermore, members of the PS group also exhibited impaired prefrontal cortex (PFC)–related cognitive performance during stress, as indicated by impaired working memory performance after hydrocortisone administration (28).

Slide 22: Questions and hypothesis

A substantial body of epidemiological, clinical, physiological, cellular, and molecular evidence converges to suggest that conditions during intrauterine life play a major role in shaping not only all aspects of fetal development and birth outcomes but also subsequent newborn, child, and adult health outcomes and susceptibility for many of the complex, common disorders that confer the major burden of disease in society (5, 29). Elucidation of the biological mechanisms underlying these observed effects is an area of intense interest and investigation. It is possible that there are separate outcome-specific mechanisms, or there may be a common underlying mechanism mediating the effects of a diverse range of intrauterine perturbations on a range of health and disease risk outcomes. With respect to the latter possibility, we have advanced the hypothesis that telomere biology may represent an important mechanism underlying the observed effects of disparate conditions in fetal life on subsequent health and disease risk–related phenotypes (30, 31).

Slide 23: Telomere biology as a signaling mechanism

This second part of the Presentation contains a discussion of telomere biology as a signaling mechanism mediating the effects of the intrauterine environment on subsequent health and disease risk outcomes.

Following a brief overview of the telomere biology system in health and disease, a rationale is presented for a role for telomere biology in mediating the effects of suboptimal intrauterine conditions. Putative mechanisms are considered, including alterations in the initial setting of telomere length and the production of telomerase, along with a summary of the effects of various prenatal perturbations on telomere biology in both humans and animal models. This is followed by the results of one of our recent studies on the association of prenatal stress exposure with telomere length in leukocytes. We conclude by listing the main research questions emerging in this area.

Slide 24: Overview of the telomere biology system

Telomere biology refers to the structure and function of telomeres as well as the production and function of telomerase. Telomeres are noncoding double-stranded repeats of guanine-rich tandem DNA sequences [5′-(TTAGGG)n-3′] that cap the ends of linear chromosomes and are bound by the multiprotein complex shelterin (32, 33). Shelterin mediates the formation of nucleotide loops that protect the end of the chromosome from being recognized by the DNA damage repair system as DNA breaks. Telomerase is the reverse transcriptase enzyme that adds telomeric DNA to existing telomeres (34). Because DNA polymerase is unable to fully replicate the 3′ end of the DNA strand (the “end-replication problem”), telomeres lose approximately 30 to 150 base pairs (bp) with each cell division.

Slide 25: Telomeres and cellular senescence

As somatic cells divide, telomeres eventually reach a critical short length, resulting in a decreased ability to recruit shelterin proteins, thus leading to cellular senescence or apoptosis (35). Loss of telomere function causes chromosomal fusion, activation of DNA damage checkpoint responses, genome instability, and impaired stem cell function. After cells become senescent, they exhibit various genetic and morphological changes that result in loss of tissue function.

Telomerase activity in germ cells ensures the maintenance of the telomere length and transmission of full-length chromosomes to progeny (36–38). Soon after fertilization, in the blastocyst and during early embryonic stages, telomerase abundance is very high, but it decreases with increasing gestational age and cellular differentiation (39, 40). In children and adults, telomerase is inactive in most tissues except for rapidly proliferating tissues like certain types of stem cells and active lymphocytes (41). However, many stem or stemlike cells in adult humans exhibit some telomerase activity when stimulated to divide. This lower amount of activity is apparently sufficient to slow, but not prevent, telomere shortening (41). Consistent with high telomerase activity in germ cells, these cells also have longer telomeres than somatic cells (42), possibly because of telomere elongation during germ cell maturation (43). Furthermore, there is evidence from a study of two different species (mice and cattle) that telomeres elongate during embryonic development, and this process is telomerase-dependent (38). A study that examined tissue samples from aborted human fetuses and from normal newborns found that telomere length was comparable across most fetal tissues and did not decline during gestation (44). Thus, telomere length seems to be initially increased and then maintained across most tissues throughout gestation. In a newborn individual, telomere length is highly correlated across white blood cells, umbilical artery cells, and foreskin tissues, but there is high variability between individuals (45). Furthermore, among the different hematopoietic cells in cord blood (hematopoietic progenitor cells, T cells, and granulocytes), correlations in telomere length across the different cell types are very high (46).

Slide 26: Telomeres, disease risk, and life span

Consistent with these observations, shortened telomeres or reduced telomerase production, or both, have been linked to several diseases, including, but not limited to, cardiovascular disease, hypertension, atherosclerosis, heart failure, type 2 diabetes (47-56), and shortened life span and early mortality (57-61).

Slide 27: Telomere biology system: The traditional view

Until recently, the telomere biology system was viewed as an interesting and important biomarker primarily of processes related to cellular aging.

Slide 28: Telomere biology: Recent findings I

In recent years, telomere biology has emerged as a topic of exceptional interest, moving well beyond its previously recognized role as a biomarker of cellular aging and senescence to one that appears to play a far more pervasive and potentially causal role in cellular integrity, physiology, regeneration, aging, and disease risk (6264). Recent discoveries suggest that the integrity of telomeres not only affects the replicative capacity of the cell but also underlies other changes that enforce a self-perpetuating pathway of global epigenetic changes to affect the integrity of overall chromatin structure, cellular senescence, and aging (6568). Thus, telomere length relates not only to longevity but also to the occurrence and progression of common chronic diseases.

Slide 29: Telomere biology: Recent findings II

In addition to maintenance of telomere length, recent discoveries suggest that telomerase plays a central and perhaps causal role in preserving healthy cell function by promoting the proliferation of resting stem cells, modulating signaling pathways during embryogenesis and adult tissue homeostasis (69), and protecting cellular proliferation capacity and survival under conditions of cellular stress. In addition to its role in modulating telomeres in nuclear DNA, telomerase also localizes to mitochondria, where it protects mitochondrial DNA, increases mitochondrial membrane potential, and decreases mitochondrial superoxide production, thus decreasing oxidative stress and improving mitochondrial efficiency and cellular function (63, 64).

Slide 30: Telomere biology: Recent findings III (references)

This slide provides some of the key references for the recent discoveries discussed in the previous slide (6264, 69, 70).

Slide 31: Fetal programming of telomere biology

It appears that the initial setting and regulation of telomere homeostasis, including chromosomal telomere length and both the telomeric and extratelomeric activities of telomerase, may be plastic and receptive to the influence of intrauterine or other early postnatal life conditions. Also, telomere homeostasis in various cell types, including the germ line, stem cells, and proliferating as well as post-mitotic tissue, may serve as a fundamental integrator and regulator of processes underlying cell genomic integrity, function, aging, and senescence over the life span. This may have major implications for health and disease susceptibility for complex common disorders. We advance the hypothesis that context- and time-inappropriate exposures to physiological stresses during the embryonic, fetal, and early postnatal periods of development may alter or program the telomere biology system in a manner that accelerates cellular dysfunction, aging, and disease susceptibility over the life span.

Slide 32: Determinants of telomere length

The initial (newborn) setting of telomere length represents a critically important aspect of an individual’s telomere homeostasis system. Telomere length (TL) is a joint function of (a) the initial (newborn) setting of TL; (b) TL attrition over time (which, in turn, is determined by cell replicative rate and cumulative exposure to DNA-damaging agents such as oxidative, inflammatory, or endocrine stress); and (c) the opposing, or counteracting, effects of telomerase (71, 72). Thus, a reduction in the initial (newborn) setting of TL likely confers greater susceptibility in later life for pathophysiological outcomes through the processes discussed above.

Slide 33: Programming of telomere biology

The determinants of newborn TL are poorly understood. Despite the relatively high heritability of telomere length, known genetic variants account for only a small portion of the variance in leukocyte TL (LTL) (73–75), highlighting the importance of a better understanding of environmental factors that may contribute to telomere length. LTL is the most commonly used measure of TL in human epidemiological studies, and it has been postulated that LTL dynamics reflect telomere dynamics in the wider hematopoietic stem cell (HSC) population (46). A recent report found strong correlations between TL in hematopoietic progenitor cells, T cells, and granulocytes from cord blood. HSCs ensure the lifelong production of blood cells through self-renewal and differentiation into all blood lineages, including peripheral leukocytes (76). In terms of potential programming effects of intrauterine factors on blood cell TL, it is important to note that the original pool of hematopoietic stem cells is formed and matures during early gestation, by day 40 of human pregnancy (76).

Slide 34: Developmental time line for establishment of HSC pools

This figure depicts the developmental timeline for establishment of HSC pools. In humans, the original pool of HSCs is formed and matures by day 40 of pregnancy (76). The HSC population then undergoes expansion during the remainder of fetal development.

Slide 35: Programming of newborn telomere biology

A reduction in the initial setting of TL in the HSC pool likely confers greater susceptibility in later life for pathophysiological outcomes. Factors that contribute to the initial setting of TL, therefore, likely play an important role in programming of health and disease later in life.

Slide 36: Synchrony of telomere length among hematopoietic cells

The use of cord blood LTL as an index of the newborn setting of TL is justified by the findings of strong correlations of TL in cord blood between different types of hematopoietic progenitor cells, T lymphocytes, and granulocytes, and between TL in granulocytes and in all leukocytes (46).

Slide 37: Telomere length in the newborn

The use of cord blood LTL as an index of the newborn setting of TL is further justified by the finding that TL is highly correlated between different newborn tissues (cord blood, umbilical artery, foreskin) (45).

Slide 38: Prenatal adverse exposures and subsequent TL in offspring (animal studies)

Recent studies in animals and humans suggest that adverse or suboptimal conditions in intrauterine life are associated with shorter offspring TL (31, 7781), thereby supporting the notion that TL may, in part, be programmed in utero. There is relatively little empirical literature to date that has addressed the link between exposure to prenatal stress and telomere biology. Our review of this literature in animals and humans, summarized here and also presented in tabular form, provides support for our hypothesis that (a) early-life stress and stress biology may be associated with TL, rate of TL attrition, and telomerase activity, and (b) the magnitude of this association has potential clinical relevance for health and disease risk. Our review of the literature identified four experimental studies in animals, all of which provide evidence of a causal link between exposure to adverse intrauterine conditions and shortened offspring telomeres in cells across different tissues (7780). For instance, a very recent study by Hausmann and colleagues in chickens reported that prenatal administration of cortisol in the yolk resulted in a higher proportion of blood cells with short telomeres and increased abundance of reactive oxygen metabolites as well as increased duration of the acute stress response compared with untreated controls (80).

Slide 39: Prenatal adverse exposures and subsequent TL in offspring (human studies)

Our review identified 13 human studies that examined the associations between adverse prenatal conditions and various aspects of offspring telomere biology. Ten of these 13 studies assessed TL or telomerase activity in placental tissue or cord blood at birth, but only three addressed the longer-term effects on telomere length in children or young adults. The adverse conditions assessed during pregnancy in relation to offspring TL and telomerase activity included fetal growth restriction, obstetric risk conditions such as diabetes and preeclampsia, and exposure to excess prenatal psychosocial stress (31, 45, 8189).

Slide 40: Stress, behavioral processes, and telomere biology

The link between exposure to excess stress and adverse health outcomes is well established (90, 91). In recent years, accumulating evidence supports a role for telomere biology as a potential mechanism linking stress exposure and disease risk. Epel, Blackburn, and colleagues were the first to propose this hypothesis and to publish a study demonstrating a link between chronic psychosocial stress and telomere biology (92). This relationship between telomere biology and stress or socioeconomic disadvantage, or both, has since been replicated (9395). Exposure to severe psychological trauma or other psychopathological conditions such as posttraumatic stress disorder (PTSD) or depression has also been linked to reduced TL (9699). In addition to stress, other behavioral processes have also been associated with TL, such as obesity, smoking, diet, sleep quality, and physical activity (100). Finally, some studies suggest that lifestyle interventions may increase telomerase activity and thereby slow down cellular aging (101, 102).

Slide 41: Prenatal stress exposure is associated with the rate of biological aging in adult life

Little, however, is known about the effects of prenatal stress exposure on telomere biology. With our collaborators, we recently published the first human study of the effects of maternal psychosocial stress exposure during pregnancy on offspring TL. We found a significant association between exposure to maternal prenatal psychosocial stress and reduced LTL in young adult offspring (31). The effect was more pronounced in female offspring and was unchanged after adjusting for potential confounding factors (subject characteristics, birth weight percentile, and early life and concurrent stress).

Slide 42: Differences in biological aging rate based on leukocyte telomere length

The LTL of individuals in the prenatally stressed group was, on average, 178 bp shorter than that of individuals in the comparison group and 295 bp shorter in female subjects. The most recent and comprehensive review of studies of age-related attrition in TL suggests that in adults TL attrition averages ~60 bp/year at 20 years of age, and the attrition rate appears to decrease to ~20 bp/year by age 80 (72). Given that the participants in our study were ~25 years old, translating telomere shortening of this observed difference of 178 bp (295 bp for the women-only group) to years of aging indicates that the lymphocytes of individuals in the prenatally stressed group had aged the equivalent of ~3.5 additional years (5 additional years in the women-only group) relative to those in the comparison group.

Slide 43: Research questions

Our hypothesis that telomere biology may represent a signaling mechanism linking the effects of adverse intrauterine conditions with subsequent health and disease risk outcomes suggests the following research questions: First, what are the effects of exposure to elevated intrauterine stress on newborn and infant LTL? Second, what are the effects of exposure to elevated intrauterine stress on newborn leukocyte telomerase activity? Third, what are the effects of exposure to elevated intrauterine stress on placental telomerase biology?

Slide 44: Ongoing studies and future directions

The third part of this Presentation will summarize some of our ongoing studies and future directions.

Slide 45: Characterization of maternal stress and stress biology in human pregnancy: Major limitations

The first of our ongoing studies addresses limitations in the field related to the characterization of maternal stress and stress biology in human pregnancy. It is well established that the likelihood of occurrence of a stress-related adverse health outcome is a function of not only the amount of actual or perceived stress exposure over time but also that individual’s biologic propensity to respond to stress. With the exception of studies on exposure to natural disasters, wars, or acts of terrorism, human studies in the stress and pregnancy outcomes area have relied almost exclusively on self-reported retrospective recall measures of stress. Respondents are typically asked to rate, on average, how stressed, depressed, or anxious they have felt over the past week or month or since the beginning of the pregnancy. These traditional self-report recall measures are prone to numerous systematic biases that undermine their validity. Most studies of prenatal stress and birth outcomes have considered only the experience of prenatal stress and neglected the issue of individual differences in biologic stress reactivity during pregnancy.

Studies of the effects of maternal stress and related psychosocial processes on different outcomes of interest often treat other risk factors (for example, sociodemographic, historical, biophysical, obstetric, behavioral, psychosocial, genetic, and other environmental factors) as potential confounding variables and attempt to adjust for their putative effects through either study design (subject selection criteria) or statistical adjustment. However, emerging concepts of causation for complex common disorders suggest that it is not only possible but, in fact, probable that causation does not reside in any single factor or in the additive effects of numerous factors but rather lies in the interaction between multiple risk factors.

Slide 46: Ecological momentary assessment

Recent technological and methodological advances now allow us to apply the ecological momentary assessment (EMA) approach to the study of maternal stress and stress biology in human pregnancy to address many of these limitations. EMA methods emphasize the longitudinal, repeated collection of information about respondents’ momentary or current state, affect, experience, behavior, and biology in real time. These methods serve to minimize biases inherent in retrospective recall.

Slide 47: EMA of biobehavioral processes in human pregnancy

This slide depicts the protocol of our NIH-funded study using EMA to analyze biobehavioral processes in human pregnancy. In this representative, population-based cohort study, we collect data during three visits with volunteers during early, mid, and late gestation. Complete prospective data are collected in pregnant women over three 4-day assessments in early, mid, and late gestation. Electronic diaries are used to collect 15 measures per day of subjects’ psychological state and other contextual information. Continuous ambulatory measures of maternal heart rate and physical activity, as well as seven saliva samples over the course of each day, are collected for indicators of autonomic and endocrine activity. At the end of each ambulatory session, a maternal blood sample is collected for measures of MPF endocrine mediators. Furthermore, maternal anthropometric measurements and fetal ultrasound measures are assessed.

Slide 48: Newborn and infant follow-up studies

This EMA study longitudinally and serially characterizes stress, stress biology, and other related processes, such as nutrition, in a population-based cohort of pregnant women and their fetuses from early gestation through birth. Newborns from this cohort are recruited and longitudinally followed up over the course of infancy for studies of brain development, body composition, and metabolic function.

Slide 49: Prenatal stress biology and fetal programming of human brain development

Alterations in brain anatomy and structural and functional connectivity have been associated with several neurodevelopmental and neuropsychiatric disorders (103, 104). Many of these alterations are believed to precede disease onset and be causally related to disease symptoms and severity (105). This raises the question of what may cause these early alterations in the brain. Based on measures of putative genetic influence, such as heritability and recurrence risk ratios, the current and dominant research paradigm in the field postulates a major genetic contribution for common neuropsychiatric disorders. However, efforts to identify risk-conferring alleles have largely been unfulfilled (106). It seems unlikely that variation in the genetic makeup alone can meaningfully explain differences in the detailed neural architecture of the brain. That traditional view is rapidly being replaced by a model that considers the interplay between genes and the early environment in directing brain development. Whereas brain development may start from a genetic blueprint, it is the overlay of experience onto this blueprint that shapes development and leads to normal structure and function or altered susceptibility for psychopathology. Therefore, conditions during early development are likely to play an important role in this process (107), such that brain development is a product of the dynamic, bidirectional interplay between the individual’s genotype, acquired at conception, and the nature of the early environment, extending from embryonic and fetal life through birth, infancy, and into childhood and beyond.

Slide 50: Study protocol

We are currently conducting a prospective, longitudinal, follow-up study in a population-based cohort of children born to mothers who have been extensively characterized during pregnancy with measures of the MPF endocrine and inflammatory milieu, obstetric complications, clinical and diagnostic tests, maternal sociodemographic, behavioral, and psychosocial characteristics, birth phenotype, banked samples of maternal biologic tissue, and extracted maternal and child DNA samples. A sample of 120 to 140 children from this cohort will be recruited at birth and followed until 12 months of age. We are conducting two major study assessments at 2 to 4 weeks (time point 1, T1) and at 12 months (time point 2, T2) of age, during which brain morphology, white matter integrity, and functional connectivity is measured. For assessing brain morphology, the sizes of the hippocampus, amygdala, and prefrontal cortex are determined from serial structural magnetic resonance imaging (MRI) scans. White-matter integrity, an indicator of myelination and how densely fibers are bundled in specific tracks, is derived from serial diffusion tensor imaging (DTI) scans, and functional connectivity of fronto-limbic brain circuits is derived from resting state functional MRI (fMRI) scans. Infants’ mental and motor development also is assessed at T1 and T2 with the Test of Infant Motor Performance (TIMP) and Bayley Scales of Infant Development. Furthermore, the quality of the postnatal environment is assessed with serial measures of parental stress, maternal sensitivity, maternal-child attachment, home environment, and child nutrition, which will allow us to test pre- and postnatal influences on brain development. By providing neuroimaging data in human newborns and young infants and linking these outcomes to well-characterized measures of the intrauterine and early postnatal environment, we suggest that the study will set the stage for translational research with implications for early identification of risk and vulnerable populations and will thereby inform the subsequent development of primary and secondary intervention strategies.

Slide 51: Prenatal stress biology and fetal programming of human obesity and metabolic function I

At the individual level, obesity results when energy intake exceeds energy expenditure. However, the relationship between excess energy intake and adiposity is not linear; there is great variation in the propensity to gain weight and accrue fat mass among children and adults with identical amounts of excess energy intake. This variation between individuals defines susceptibility for developing obesity. Once an individual becomes obese, it is difficult to lose weight and even more difficult to sustain weight loss because of the remarkable efficiency of energy balance homeostasis mechanisms (108110). For these reasons, it is important to gain a better understanding of the origins of individual differences in the propensity for weight and fat mass gain in order to predict obesity risk and develop strategies for primary prevention (109).

Slide 52: Prenatal stress biology and fetal programming of human obesity and metabolic function II

Physiological and psychological stressors during pregnancy have the potential to increase maternal and fetal cortisol, placental CRH, and inflammatory mediators. These increases in stress hormones and proinflammatory cytokines in the fetal compartment during sensitive or critical developmental windows could impact the structure and function of the brain and peripheral targets that are related to body composition, energy balance homeostasis, and metabolic function, such as adipose tissue, pancreas, and liver.

Slide 53: Fetal programming of newborn and infant obesity (adiposity) and metabolic dysfunction

We are currently conducting another NIH-funded study on the relationship between prenatal stress biology, infant body composition, and obesity risk in the same population of newborns described in slide 50. In this prospective, longitudinal follow-up study, measures are obtained in newborns and infants of body composition (with dual-energy x-ray absorptiometry, DXA) and energy expenditure (using doubly labeled water method, DLW), respectively. Blood samples from a heel stick are collected to quantify markers of glycemic control.

Slide 54: Future directions

Our future plans involve a multilevel approach that expands or extends current questions and incorporates additional approaches and/or exposures. These plans include (a) additional imaging studies of brain circuits and of white versus brown adipose tissue to address the role of prenatal stress and nutrition; (b) additional assessments of the interactions between fetal and maternal genotype and prenatal stress exposure for common variants in genes related to stress and to obesity or neurodevelopmental outcomes in order to obtain a more comprehensive characterization of the underlying developmental processes; (c) studies of newborn and infant telomere length and telomerase activity to determine the prenatal predictors and subsequent consequences of the initial, newborn setting of this key signaling system in health and disease risk; (d) studies of the role of biological stress mediators on the differentiation of human mesenchymal and neural stem cell tissue culture systems, in order to simulate the effects of this process of interest in an ex vivo model system that has direct relevance to embryonic and fetal development; and (e) studies of the maternal and child gut microbiomes to characterize interactions with prenatal stress mediators in order to better understand this interplay in the context of phenotypes and outcomes related to child adiposity and to brain development.

Slide 55: Collaborators

We gratefully acknowledge the contributions of our collaborators to this program of research and the funding provided by several grants from the National Institutes of Health.

Editor’s Note: This contribution is not intended to be equivalent to an original research paper. Note, in particular, that the text and associated slides have not been peer-reviewed.

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