Transgenerational Influences Research Articles

Elevated paternal glucocorticoid exposure modifies memory retention in female offspring

Recent studies have demonstrated that behavioral traits are subject to transgenerational modification by paternal environmental factors. We previously reported on the transgenerational influences of increased paternal stress hormone levels on offspring anxiety and depression-related behaviors. Here, we investigated whether offspring sociability and cognition are also influenced by paternal stress. Adult C57BL/6J male mice were treated with corticosterone (CORT; 25mg/L) for four weeks prior to paired-matings to generate F1 offspring. Paternal CORT treatment was associated with decreased body weights of female offspring and a marked reduction of the male offspring. There were no differences in social behavior of adult F1 offspring in the three-chamber social interaction test. Despite male offspring of CORT-treated fathers displaying hyperactivity in the Y-maze, there was no observable difference in short-term spatial working memory. Spatial learning and memory testing in the Morris water maze revealed that female, but not male, F1 offspring of CORT-treated fathers had impaired memory retention. We used our recently developed methodology to analyze the spatial search strategy of the mice during the learning trials and determined that the impairment could not be attributed to underlying differences in search strategy. These results provide evidence for the impact of paternal corticosterone administration on offspring cognition and complement the cumulative knowledge of transgenerational epigenetic inheritance of acquired traits in rodents and humans.

Parental Exposure to Dim Light at Night Prior to Mating Alters Offspring Adaptive Immunity

Exposure to dim light at night (dLAN) disrupts natural light/dark cycles and impairs endogenous circadian rhythms necessary to maintain optimal biological function, including the endocrine and immune systems. We have previously demonstrated that white dLAN compromises innate and cell mediated immune responses in adult Siberian hamsters (Phodopus sungorus). We hypothesized that dLAN has transgenerational influences on immune function. Adult male and female Siberian hamsters were exposed to either dark nights (DARK) or dLAN (~5 lux) for 9 weeks, then paired in full factorial design, mated, and thereafter housed under dark nights. Offspring were gestated and reared in dark nights, then tested as adults for cell-mediated and humoral immunity. Maternal exposure to dLAN dampened delayed type hypersensitivity (DTH) responses in male offspring. Maternal and paternal exposure to dLAN reduced DTH responses in female offspring. IgG antibodies to a novel antigen were elevated in offspring of dams exposed to dLAN. Paternal exposure to dLAN decreased splenic endocrine receptor expression and global methylation in a parental sex-specific manner. Together, these data suggest that exposure to dLAN has transgenerational effects on endocrine-immune function that may be mediated by global alterations in the epigenetic landscape of immune tissues.

Paternal environmental enrichment transgenerationally alters affective behavioral and neuroendocrine phenotypes

Recent studies have demonstrated that paternal stress in rodents can result in modification of offspring behavior. Environmental enrichment, which enhances cognitive stimulation and physical activity, modifies various behaviors and reduces stress responses in adult rodents. We investigated the transgenerational influence of paternal environmental enrichment on offspring behavior and physiological stress response. Adult C57BL/6J male mice (F0) were exposed to either environmental enrichment or standard housing for four weeks and then pair-mated with naïve females. The F2 generation was generated using F1 male offspring. Male and female F1 and F2 offspring were tested for anxiety using the elevated-plus maze and large open field at 8 weeks of age. Depression-related behavior was assessed using the forced-swim test. Hypothalamic-pituitary-adrenal (HPA) axis function was determined by quantification of serum corticosterone and adrenocorticotropic hormone (ACTH) levels at baseline and after forced-swim stress. Paternal environmental enrichment was associated with increased body weights of male F1 and F2 offspring. There was no significant effect on F1 offspring anxiety and depression-related behaviors. There were no changes in anxiety-related behaviors in the F2 offspring, however these mice displayed a reduced latency to immobility in the forced-swim test. Furthermore, F2 females had significantly higher serum corticosterone levels post-stress, but not ACTH. These results show that paternal environmental enrichment exerts a sex-specific transgenerational impact on the behavioral and physiological response to stress. Our findings have implications for the modelling of psychiatric disorders in rodents.

Trans-generational influences of sulfamethoxazole on lifespan, reproduction and population growth of Caenorhabditis elegans

Trans-generational effects are increasingly used to indicate long-term influences of environmental pollutants. However, such studies can be complex and yield inconclusive results. In this study, the trans-generational effects of sulfamethoxazole (SMX) on Caenorhabditis elegans on lifespan, reproduction and population growth were tested for 7 consecutive generations, which included gestating generation (F0), embryo-exposed generation (F1), germline-exposed generation (F2), the first non-exposed generation (F3) and the three following generations (F4–F6). Results showed that lifespan was significantly affected by embryo exposure (F1) at 400µm SMX with a value as low as 47% of the control. The reproduction (a total brood size as 49% of the control) and population growth (81% of the control) were significantly affected in germline exposure (F2). Lifespan and reproduction were severely inhibited in non-exposed generations, confirming the real trans-generational effects. Notably, initial reproduction and reproduction duration showed opposite generation-related changes, indicating their interplay in the overall brood size. The population growth rate was well correlated with median lethal time, brood size and initial reproduction, which indicated that the population would increase when the nematodes lived longer and reproduced more offspring within shorter duration.

1123 Transgenerational paternal influence on temperament and growth performance of crossbred beef calves

1123 Transgenerational paternal influence on temperament and growth performance of crossbred beef calves

Nongenetic Inheritance of Induced Resistance in a Wild Annual Plant.

Nongenetic inheritance (e.g., transgenerational epigenetic effects) has received increasing interest in recent years, particularly in plants. However, most studies have involved a few model species and relatively little is known about wild species in these respects. We investigated transgenerational induced resistance to infection by the devastating oomycete Phytophthora infestans in Solanum physalifolium, a wild relative of cultivated potato. We treated plants with β-aminobutyric acid (BABA), a nontoxic compound acting as an inducing agent, or infected plants with P. infestans. BABA treatment reduced lesion size in detached-leaf assays inoculated by P. infestans in two of three tested genotypes, suggesting that resistance to oomycetes can be induced by BABA within a generation not only in crops or model species but also in wild species directly collected from nature. Both BABA treatment and infection in the parental generation reduced lesions in the subsequent generation in one of two genotypes, indicating a transgenerational influence on resistance that varies among genotypes. We did not detect treatment effects on seed traits, indicating the involvement of a mechanism unrelated to maternal effects. In conclusion, our study provides data on BABA induction and nongenetic inheritance of induced resistance in a wild relative of cultivated potato, implying that this factor might be important in the ecological and agricultural landscape.

Transgenerational influence of sensorimotor training on offspring behavior and its neural basis in Drosophila

Whether specific learning experiences by parents influence the behavior of subsequent generations remains unclear. This study examines whether and what aspects of parental sensorimotor training prior to conception affect the behavior of subsequent generations and identifies the neural circuitries in Drosophila responsible for mediating these effects. Using genetic and anatomic techniques, I find that both first- and second-generation offspring of parents who underwent prolonged olfactory training over many days displayed a weak but selective approach bias to the same trained odors. However, I also find that the offspring did not differentiate between orders based on whether parental training was aversive or appetitive. Disruption of both olfactory-receptor and dorsal-paired-medial neuron input into the mushroom bodies abolished this change in offspring response, but disrupting synaptic output from α/β neurons of the mushroom body themselves had little effect on behavior even though they remained necessary for enacting newly trained conditioned responses. This study provides a circuit-based understanding of how specific sensory experiences in Drosophila may bias the behavior of subsequent generations, and identifies a transgenerational dissociation between the effects of conditioned and unconditioned sensory stimuli.

Toward the Desegregation of Thought and Affect in Psychological Theorizing

AbstractThis article interrogates the historical segregation of thought and affect in psychological theorizing. I note how, across a range of theoretical approaches to the study of thinking, the relations between thought and affect have been either negated or ignored or underemphasized. In the context of the recent ‘turn to affect’ in the social sciences, which has been seen as offering a new paradigm for conceptualizing social and psychological phenomena, this elision is all the more striking, and a selective overview of current writings illustrative of this literature is presented. Yet, reciprocally, it is noteworthy that the ‘turn to affect’ literature has not addressed the relation between affect and thought, and hence that it contributes to the theoretical segregation that I argue is problematic. I then discuss some recent proposals within psychology that, in each of their specific ways, dissolve the theoretical dualism between thinking and affect, and offer an integrative reformulation that synthesizes the affective, intellectual, and psychosocial constituents of thought, as well as some works outside of psychology that can be viewed as illustrating the fusion of thought and affect. I argue for an approach that recognizes the biographical intertwining of the affective and intellectual life of the epistemic agent and the way in which both are shaped by processes of social constitution and by transgenerational influences.

Grandmother's smoking when pregnant with the mother and asthma in the grandchild: the Norwegian Mother and Child Cohort Study

BackgroundA trans-generational influence of prenatal tobacco smoke exposure on asthma development has been proposed but the evidence remains sparse.MethodsWe examined the grandmother's smoking when pregnant with the mother in relation...

New perspectives in behavioural development: adaptive shaping of behaviour over a lifetime?

The last years have seen an explosion of publications on consistent, i.e. repeatable, behavioural differences among individuals and their potential adaptive significance and evolutionary origin. Stable, repeatable traits imply reduced plasticity and this is particularly interesting in the case of behaviour, which is the most flexible trait of an animal in its interaction with the biotic and abiotic environment. While the importance of consistent individual differences has been widely acknowledged, the lifetime development of these differences and their potentially adaptive or maladaptive consequences for individuals only recently came into the focus of research [1,2]. As a result, widespread evidence for the existence of changes in behaviour and behavioural plasticity over the lifetime of individuals begins to accumulate [3]. This has raised novel questions concerning the overwhelming importance of ontogenetic and trans-generational influences on the development and fitness of behavioural phenotypes and the mechanisms influencing changes during an individual’s lifetime. Much theoretical work has been published on the importance of and limits to individual plasticity, mostly in the framework of the reaction norm. Less empirical work has actually studied, how the reaction norm comes about in an individual’s lifetime and how or whether it may change over the lifetime [4]. This raises important questions about the adaptivity of the phenotypic plasticity of behaviour and the question when within a lifetime such plasticity might be particularly relevant. Do particular windows of plasticity exist, and if so why are they where they are within the lifetime of an organism? The potential lifetime plasticity also raises the question about the evolution of the reaction norm and, more recently, about the evolution of its plasticity, questions that so far have received but little attention. In these fields of investigation theory has moved far ahead of empirical studies. Often, if not always, individuals face uncertain environmental conditions throughout their life, forcing them to adapt plastically in order to maximise fitness. Under such uncertain conditions we expect natural selection to favour plasticity. However, plastic responses to the environment can only be adaptive, if informative environmental cues exist that allow prediction of future conditions with reasonably high probability [5]. Depending on the cues available and the ontogenetic stage of an individual we expect differential effects of such predictive cues: Early in life highly informative cues, whether derived from maternal influences or perceived directly, may potentially act in an organisational manner, whereas less informative cues or cues perceived at a later age may lead to more immediate plasticity (see [4] for a definition of different types of plasticity). This may lead to developmental influences on plasticity, i.e. early environments may particularly influence the reaction norm. This idea of plasticity of the reaction norm as a trait that develops and thereby influences the reaction norm expressed during the lifetime of an individual is rather novel [6]. However, it follows directly from Gene x Environment interactions (GxE) influencing the reaction norm. Along the developmental axis Gene x Age (GxA) and Individual x Age (IxA) interactions will then determine the expression of the developing reaction norm in interaction with the environments encountered by an individual (see [7]). As pointed out earlier [2] genes themselves provide an environment for other genes so that even more complex interactions are to be expected. As these interactions may change with the state and the age of an individual it becomes clear why ontogenetic processes are of prime * Correspondence: fritz.trillmich@uni-bielefeld.de Animal Behaviour, Bielefeld University, Morgenbreede 45, 33615 Bielefeld, Germany Full list of author information is available at the end of the article Trillmich et al. Frontiers in Zoology 2015, 12(Suppl 1):S1 http://www.frontiersinzoology.com/content/12/S1/S1

Prenatal diethylstilbestrol induces malformation of the external genitalia of male and female mice and persistent second-generation developmental abnormalities of the external genitalia in two mouse strains

Potential trans-generational influence of diethylstilbestrol (DES) exposure emerged with reports of effects in grandchildren of DES-treated pregnant women and of reproductive tract tumors in offspring of mice exposed in utero to DES. Accordingly, we examined the trans-generational influence of DES on development of external genitalia (ExG) and compared effects of in utero DES exposure in CD-1 and C57BL/6 mice injected with oil or DES every other day from gestational days 12 to 18. Mice were examined at birth, and on 5–120 days postnatal to evaluate ExG malformations. Of 23 adult (>60 days) prenatally DES-exposed males, features indicative of urethral meatal hypospadias (see text for definitions) ranged from 18% to 100% in prenatally DES-exposed CD-1 males and 31% to 100% in prenatally DES-exposed C57BL/6 males. Thus, the strains differed only slightly in the incidence of male urethral hypospadias. Ninety-one percent of DES-exposed CD-1 females and 100% of DES-exposed C57BL/6 females had urethral–vaginal fistula. All DES-exposed CD-1 and C57BL/6 females lacked an os clitoris. None of the prenatally oil-treated CD-1 and C57BL/6 male and female mice had ExG malformations. For the second-generation study, 10 adult CD-1 males and females, from oil- and DES-exposed groups, respectively, were paired with untreated CD-1 mice for 30 days, and their offspring evaluated for ExG malformations. None of the F1 DES-treated females were fertile. Nine of 10 prenatally DES-exposed CD-1 males sired offspring with untreated females, producing 55 male and 42 female pups. Of the F2 DES-lineage adult males, 20% had exposed urethral flaps, a criterion of urethral meatal hypospadias. Five of 42 (11.9%) F2 DES lineage females had urethral–vaginal fistula. In contrast, all F2 oil-lineage males and all oil-lineage females were normal. Thus, prenatal DES exposure induces malformations of ExG in both sexes and strains of mice, and certain malformations are transmitted to the second-generation.

Pre-reproductive maternal enrichment influences offspring developmental trajectories: motor behavior and neurotrophin expression.

Environmental enrichment is usually applied immediately after weaning or in adulthood, with strong effects on CNS anatomy and behavior. To examine the hypothesis that a pre-reproductive environmental enrichment of females could affect the motor development of their offspring, female rats were reared in an enriched environment from weaning to sexual maturity, while other female rats used as controls were reared under standard conditions. Following mating with standard-reared males, all females were housed individually. To evaluate the eventual transgenerational influence of positive pre-reproductive maternal experiences, postural and motor development of male pups was analyzed from birth to weaning. Moreover, expression of Brain Derived Neurotrophic Factor and Nerve Growth Factor in different brain regions was evaluated at birth and weaning. Pre-reproductive environmental enrichment of females affected the offspring motor development, as indicated by the earlier acquisition of complex motor abilities displayed by the pups of enriched females. The earlier acquisition of motor abilities was associated with enhanced neurotrophin levels in striatum and cerebellum. In conclusion, maternal positive experiences were transgenerationally transmitted, and influenced offspring phenotype at both behavioral and biochemical levels.

Maternal preconception body mass index and offspring cord blood DNA methylation: Exploration of early life origins of disease

Maternal obesity is associated with a variety of common diseases in the offspring. One possible underlying mechanism could be maternal obesity induced alterations in DNA methylation. However, this hypothesis is yet to be tested. We performed epigenomic mapping of cord blood among 308 Black mother-infant pairs delivered at term at the Boston Medical Center using the Illumina HumanMethylation27 BeadChip. Linear regression and pathway analyses were conducted to evaluate the associations between DNA methylation levels and prepregnancy maternal BMI (<25, 25-30, ≥30 kg/m(2) ). The methylation levels of 20 CpG sites were associated with maternal BMI at a significance level of P-value <10(-4) in the overall sample, and boys and girls, separately. One CpG site remained statistically significant after correction for multiple comparisons (FDR corrected P-value = 0.04) and was annotated to a potential cancer gene, ZCCHC10. Some of the other CpG site annotated genes appear to be critical to the development of cancers and cardiovascular diseases (i.e., WNT16, C18orf8, ANGPTL2, SAPCD2, ADCY3, PRR16, ERBB2, DOK2, PLAC1). Significant findings from pathway analysis, such as infectious and inflammatory and lipid metabolism pathways, lends support for the potential impact of maternal BMI on the above stated disorders. This study demonstrates that prepregnancy maternal BMI might lead to alterations in offspring DNA methylation in genes relevant to the development of a range of complex chronic diseases, providing evidence of trans-generational influence on disease susceptibility via epigenetic mechanism.

Cohort Profile: Andhra Pradesh Children and Parents Study (APCAPS)

The Andhra Pradesh Children and Parents Study (APCAPS) was originally established to study the long-term effects of early-life undernutrition on risk of cardiovascular disease. Its aims were subsequently expanded to include trans-generational influences of other environmental and genetic factors on chronic diseases in rural India. It builds on the Hyderabad Nutrition Trial (HNT) conducted in 1987–90 to compare the effects on birthweight of a protein-calorie supplement for pregnant women and children. The index children of HNT and their mothers were retraced and examined in 2003–05, and the children re-examined as young adults aged 18–21 years in 2009–10. The cohort was expanded to include both parents and siblings of the index children in a recently completed follow-up conducted in 2010–12 (N = ∼6225 out of 10 213 participants). Recruitment of the remaining residents of these 29 villages (N = ∼55 000) in Ranga Reddy district of Andhra Pradesh is now under way. Extensive data on socio-demographic, lifestyle, medical, anthropometric, physiological, vascular and body composition measures, DNA, stored plasma, and assays of lipids and inflammatory markers on APCAPS participants are available. Details of how to access these data are available from the corresponding author.

Transgenerational effects and the cost of ant tending in aphids.

In mutualistic interactions, partners obtain a net benefit, but there may also be costs associated with the provision of benefits for a partner. The question of whether aphids suffer such costs when attended by ants has been raised in previous work. Transgenerational effects, where offspring phenotypes are adjusted based on maternal influences, could be important in the mutualistic interaction between aphids and ants, in particular because aphids have telescoping generations where two offspring generations can be present in a mature aphid. We investigated the immediate and transgenerational influence of ant tending on aphid life history and reproduction by observing the interaction between the facultative myrmecophile Aphis fabae and the ant Lasius niger over 13 aphid generations in the laboratory. We found that the effect of ant tending changes dynamically over successive aphid generations after the start of tending. Initially, total aphid colony weight, aphid adult weight and aphid embryo size decreased compared with untended aphids, consistent with a cost of ant association, but these differences disappeared within four generations of interaction. We conclude that transgenerational effects are important in the aphid–ant interactions and that the costs for aphids of being tended by ants can vary over generations.Electronic supplementary materialThe online version of this article (doi:10.1007/s00442-013-2659-y) contains supplementary material, which is available to authorized users.

Preadult Parental Diet Affects Offspring Development and Metabolism in Drosophila melanogaster

When Drosophila melanogaster larvae are reared on isocaloric diets differing in their amounts of protein relative to sugar, emerging adults exhibit significantly different development times and metabolic pools of protein, glycogen and trigylcerides. In the current study, we show that the influence of larval diet experienced during just one generation extends into the next generation, even when that subsequent generation had been shifted to a standard diet during development. Offspring of flies that were reared on high protein relative to sugar underwent metamorphosis significantly faster, had higher reproductive outputs, and different metabolic pool contents compared to the offspring of adults from low protein relative to sugar diets. In addition, isofemale lines differed in the degree to which parental effects were observed, suggesting a genetic component to the observed transgenerational influences.

A Couple Who Lost Joy

This paper was born out of a conversation between the co-authors as they made a rich-text study of the presentation and progress in treatment of a couple whose complaint was that they had lost joy. Pierre Cachia was the therapist and Jill Scharff, his writing partner. Writing about the consultation and early phases of analytic couple therapy, the therapist introduces the couple's presentation, current difficulties, and history. He then recounts a session in detail from the sixteenth month of treatment. As the session unfolds, the co-authors interrupt the clinical narrative to join in a free-form, open discussion of the emerging material. They share an attitude of curiosity about unconscious dynamics, transgenerational influences, and countertransference. Their respective voices merge as they develop an understanding of the underlying dynamics and the power of therapeutic action. Without reference to standard texts, they simply focus on the clinical narrative and their discussion of it to provide an experience-near illustration of analytic sensibility in couple therapy.

Parental height in relation to offspring coronary heart disease: examining transgenerational influences on health using the west of Scotland Midspan Family Study

Background Adult height is known to be inversely related to coronary heart disease (CHD) risk. We sought to investigate transgenerational influence of parental height on offspring’s CHD risk.Methods Parents took part in a cardiorespiratory disease survey in two Scottish towns during the 1970s, in which their physical stature was measured. In 1996, their offspring were invited to participate in a similar survey, which included an electrocardiogram recording and risk factor assessment.Results A total of 2306 natural offspring aged 30–59 years from 1456 couples were subsequently flagged for notification of mortality and followed for CHD-related hospitalizations. Taller paternal and/or maternal height was associated with socio-economic advantage, heavier birthweight and increased high-density lipoprotein cholesterol in offspring. Increased height in fathers, but more strongly in mothers (risk ratio for 1 SD change in maternal height = 0.85; 95% confidence interval: 0.76 to 0.95), was associated with a lower risk of offspring CHD, adjusting for age, sex, other parental height and CHD risk factors.Conclusion There is evidence of an association between taller parental, particularly maternal, height and lower offspring CHD risk. This may reflect an influence of early maternal growth on the intrauterine environment provided for her offspring.

The effect of food limitation on immunity factors and disease resistance in the western tent caterpillar

Epizootics of nucleopolyhedrovirus characterize declines of cyclic populations of western tent caterpillars, Malacosoma pluviale californicum. In field populations, infection can be apparently lacking in one generation and high in the next. This may suggest an increase in the susceptibility to infection of larvae at peak density or the triggering of a vertically transmitted virus. Here, we test the hypothesis that reduced food availability, as may occur during population outbreaks of tent caterpillars, influences the immunocompetence of larvae and increases their susceptibility to viral infection. We compared immunity factors, hemolymph phenoloxidase and hemocyte numbers, and the susceptibility to nucleopolyhedroviral infection of fifth instar larvae that were fully or partially fed as fourth instars. To determine if maternal or transgenerational influences occurred, we also determined the susceptibility of the offspring of the treated parents to viral infection. Food limitation significantly reduced larval survival, development rate, larval and pupal mass, moth fecundity and levels of hemolymph phenoloxidase, but not the numbers of hemocytes. Neither the food-reduced larvae nor their offspring were more susceptible to viral infection and were possibly even less susceptible at intermediate viral doses. Food reduction did not activate latent or covert viral infection of larvae as might be expected as a response to stress. We conclude that reducing the food intake of fourth instar larvae to an extent that had measurable and realistic impacts on their life history characteristics was not translated into increased susceptibility to viral infection.

The Impact of Maternal MTHFR677 Genotype and Lead Exposure on Infant Genomic DNA Methylation

ISEE-0828 Background and Objective: Previous studies have indicated that genetic variations in methylenetetrahydrofolate reductase (MTHFR), a key regulatory enzyme of the one-carbon metabolic pathway, influence genomic DNA methylation levels. However, little is know about the transgenerational influence of the major variant of MTHFR, C677T, on genomic DNA methylation levels. Our objective was to evaluate the impact of maternal MTHFR C677T genotype on cord blood genomic DNA methylation levels and to determine if this association was influenced by maternal lead exposures. Methods: Our subject population consisted of 97 maternal-infant pairs for which DNA methylation and MTHFR genotype data were available from the Early Life Exposures in Mexico to Environmental Toxicants (ELEMENT) study. Genomic DNA methylation, prenatal lead exposure and MTHFR genotyping were assessed by LINE-1 Pyrosequencing, maternal patella bone lead levels using a spot source 109Cd K-XRF instrument and TaqMan technology, respectively. Results: Maternal MTHFR C677T genotype influenced infant LINE-1 DNA methylation levels (CC = 79.86% ± 0.5; CT = 79.83% ± 0.3; and TT = 78.90% ± 0.36; P for trend = 0.07). Furthermore, once stratified by median maternal patella lead exposure, the association between maternal MTHFR C677T genotype and infant LINE-1 DNA methylation was only apparent among mothers with high lead exposure (CC = 80.0% ± 0.93; CT = 79.32% ± 0.48; and TT = 78.35% ± 0.54; P for trend = 0.09); vs. mothers with low lead exposure (CC = 79.79 ± 0.60; CT = 80.39 ± 0.4; and TT = 79.45 ± 0.47; P for trend = 0.51). No significant associations were found among infants MTHFR C677T genotype and DNA methylation. Conclusion: Data from this study suggest that genetic variants of MTHFR C677T among pregnant women are associated with a decrease in genomic DNA methylation in their offspring. Maternal genotype along with environmental exposures may play a large role in epigenetic programming.