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Fetal growth restriction (FGR) is a common outcome in human suboptimal gestation and is related to prenatal origins of cardiovascular dysfunction in offspring. Despite this, therapy of human translational potential has not been identified. Using human umbilical and placental vessels and the chicken embryo model, we combined cellular, molecular, and functional studies to determine whether N‐acetylcysteine (NAC) and hydrogen sulphide (H2S) protect cardiovascular function in growth‐restricted unborn offspring. In human umbilical and placental arteries from control or FGR pregnancy and in vessels from near‐term chicken embryos incubated under normoxic or hypoxic conditions, we determined the expression of the H2S gene CTH (i.e. cystathionine γ‐lyase) (via quantitative PCR), the production of H2S (enzymatic activity), the DNA methylation profile (pyrosequencing) and vasodilator reactivity (wire myography) in the presence and absence of NAC treatment. The data show that FGR and hypoxia increased CTH expression in the embryonic/fetal vasculature in both species. NAC treatment increased aortic CTH expression and H2S production and enhanced third‐order femoral artery dilator responses to the H2S donor sodium hydrosulphide in chicken embryos. NAC treatment also restored impaired endothelial relaxation in human third‐to‐fourth order chorionic arteries from FGR pregnancies and in third‐order femoral arteries from hypoxic chicken embryos. This NAC‐induced protection against endothelial dysfunction in hypoxic chicken embryos was mediated via nitric oxide independent mechanisms. Both developmental hypoxia and NAC promoted vascular changes in CTH DNA and NOS3 methylation patterns in chicken embryos. Combined, therefore, the data support that the effects of NAC and H2S offer a powerful mechanism of human translational potential against fetal cardiovascular dysfunction in complicated pregnancy. Key points: Gestation complicated by chronic fetal hypoxia and fetal growth restriction (FGR) increases a prenatal origin of cardiovascular disease in offspring, increasing interest in antenatal therapy to prevent against a fetal origin of cardiovascular dysfunction.We investigated the effects between N‐acetylcysteine (NAC) and hydrogen sulphide (H2S) in the vasculature in FGR human pregnancy and in chronically hypoxic chicken embryos.Combining cellular, molecular, epigenetic and functional studies, we show that the vascular expression and synthesis of H2S is enhanced in hypoxic and FGR unborn offspring in both species and this acts to protect their vasculature.Therefore, the NAC/H2S pathway offers a powerful therapeutic mechanism of human translational potential against fetal cardiovascular dysfunction in complicated pregnancy. [ABSTRACT FROM AUTHOR]

Background: Diabetes in pregnancy is associated with increased risk of long-term metabolic disease in the offspring, potentially mediated by in utero epigenetic variation. Previously, we identified multiple differentially methylated single CpG sites in offspring of women with gestational diabetes mellitus (GDM), but whether stretches of differentially methylated regions (DMRs) can also be identified in adolescent GDM offspring is unknown. Here, we investigate which DNA regions in adolescent offspring are differentially methylated in blood by exposure to diabetes in pregnancy. The secondary aim was to characterize the RNA expression of the identified DMR, which contained the nc886 non-coding RNA. Methods: To identify DMRs, we employed the bump hunter method in samples from young (9–16 yr, n = 92) offspring of women with GDM (O-GDM) and control offspring (n = 94). Validation by pyrosequencing was performed in an adult offspring cohort (age 28–33 years) consisting of O-GDM (n = 82), offspring exposed to maternal type 1 diabetes (O-T1D, n = 67) and control offspring (O-BP, n = 57). RNA-expression was measured using RT-qPCR in subcutaneous adipose tissue and skeletal muscle. Results: One significant DMR represented by 10 CpGs with a bimodal methylation pattern was identified, located in the nc886/VTRNA2-1 non-coding RNA gene. Low methylation status across all CpGs of the nc886 in the young offspring was associated with maternal GDM. While low methylation degree in adult offspring in blood, adipose tissue, and skeletal muscle was not associated with maternal GDM, adipose tissue nc886 expression was increased in O-GDM compared to O-BP, but not in O-T1D. In addition, adipose tissue nc886 expression levels were positively associated with maternal pre-pregnancy BMI (p = 0.006), but not with the offspring's own adiposity. Conclusions: Our results highlight that nc886 is a metastable epiallele, whose methylation in young offspring is negatively correlated with maternal obesity and GDM status. The physiological effect of nc886 may be more important in adipose tissue than in skeletal muscle. Further research should aim to investigate how nc886 regulation in adipose tissue by exposure to GDM may contribute to development of metabolic disease. [ABSTRACT FROM AUTHOR]

This review analyzes the published evidence regarding maternal factors that influence the developmental programming of long-term adiposity in humans and animals via the central nervous system (CNS). We describe the physiological outcomes of perinatal underfeeding and overfeeding and explore potential mechanisms that may mediate the impact of such exposures on the development of feeding circuits within the CNS—including the influences of metabolic hormones and epigenetic changes. The perinatal environment, reflective of maternal nutritional status, contributes to the programming of offspring adiposity. The in utero and early postnatal periods represent critically sensitive developmental windows during which the hormonal and metabolic milieu affects the maturation of the hypothalamus. Maternal hyperglycemia is associated with increased transfer of glucose to the fetus driving fetal hyperinsulinemia. Elevated fetal insulin causes increased adiposity and consequently higher fetal circulating leptin concentration. Mechanistic studies in animal models indicate important roles of leptin and insulin in central and peripheral programming of adiposity, and suggest that optimal concentrations of these hormones are critical during early life. Additionally, the environmental milieu during development may be conveyed to progeny through epigenetic marks and these can potentially be vertically transmitted to subsequent generations. Thus, nutritional and metabolic/endocrine signals during perinatal development can have lifelong (and possibly multigenerational) impacts on offspring body weight regulation. [ABSTRACT FROM AUTHOR]

Early-life malnutrition plays a critical role in foetal development and predisposes to metabolic diseases later in life, according to the concept of 'developmental programming'. Different types of early nutritional imbalance, including undernutrition, overnutrition and micronutrient deficiency, have been related to long-term metabolic disorders. Accumulating evidence has demonstrated that disturbances in nutrition during the period of preconception, pregnancy and primary infancy can affect mitochondrial function and epigenetic mechanisms. Moreover, even though multiple mechanisms underlying non-alcoholic fatty liver disease (NAFLD) have been described, in the past years, special attention has been given to mitochondrial dysfunction and epigenetic alterations. Mitochondria play a key role in cellular metabolic functions. Dysfunctional mitochondria contribute to oxidative stress, insulin resistance and inflammation. Epigenetic mechanisms have been related to alterations in genes involved in lipid metabolism, fibrogenesis, inflammation and tumorigenesis. In accordance, studies have reported that mitochondrial dysfunction and epigenetics linked to early-life nutrition can be important contributing factors in the pathogenesis of NAFLD. In this review, we summarise the current understanding of the interplay between mitochondrial dysfunction, epigenetics and nutrition during early life, which is relevant to developmental programming of NAFLD. [ABSTRACT FROM AUTHOR]

Advanced age at conception usually refers to human mothers aged 35 years plus and fathers aged 40 years plus. Advanced parental age may be responsible for genetic and/or epigenetic alterations and may affect the health of offspring. Limited epidemiological and experimental studies have addressed the effect of advanced parental age on cardio‐metabolic functions in human and rodent offspring. This mini review aimed to present the knowledge by focusing on adverse and favourable outcomes related to sex‐specific risks and intergenerational inheritance. The outcomes identified by this review were mainly negative, but there were also some positive results. [ABSTRACT FROM AUTHOR]

Purpose of Review : Increasing bone mineral accrual during childhood might delay the onset of osteoporosis. We discuss the scientific evidence for early life approaches to optimising skeletal health. Recent Findings: There is an ever-growing body of evidence from observational studies suggesting associations between early life exposures, particularly during foetal development, and bone mineral density (BMD). The findings of such studies are often heterogeneous, and for some exposures, for example, maternal smoking and alcohol intake in pregnancy or age at conception, intervention studies are not feasible. The most frequently studied exposures in intervention studies are calcium or vitamin D supplementation in pregnancy, which overall suggest positive effects on offspring childhood BMD. Summary: Maternal calcium and/or vitamin D supplementation during pregnancy appear to have positive effects on offspring BMD during early childhood, but further long-term follow-up is required to demonstrate persistence of the effect into later life. [ABSTRACT FROM AUTHOR]

Gestational diabetes mellitus (GDM) is a maternal metabolic disorder that perturbs placental development and increases the risk of offspring short- and long-term metabolic disorders. The mechanisms by which GDM impairs placental development remain poorly understood. Here, we defined the DNA methylome of GDM placentas and determined whether GDM perturbs methylation at genes important for placental development. We conducted an epigenome-wide association study of 42 placentas from pregnancies in the South African Soweto First 1000 days cohort (S1000). Using genome-wide bisulfite sequencing, we compared non-GDM placentas to GDM placentas with similar proportions from obese and non-obese mothers. Compared to non-GDM, GDM placentas exhibited a distinct methylation profile consisting of 12,210 differentially methylated CpGs (DMCs) that mapped to 3,875 genes. Epigenetically altered genes were enriched in Wnt and cadherin signalling pathways, both critical in placentation and embryogenesis. We also defined regional DNA methylation perturbation in GDM placentas at 11 placental development genes. These findings reveal extensive changes to the placental epigenome of GDM pregnancies and highlight perturbation enriched at important placental development genes. These molecular changes represent potential mechanisms for GDM-induced placental effects that may serve as candidate biomarkers for placental, maternal, and foetal health. Using a study design that used similar proportions of obese and non-obese mothers in our case and control pregnancies, we minimized the detection of changes due to obesity alone. Further work will be necessary to investigate the extent of the influence of obesity on these GDM-related placental epigenetic changes.

Cadmium (Cd) exposure in adulthood is associated with nonalcoholic fatty liver disease (NAFLD), characterized by steatosis, inflammation, and fibrosis. The prevalence of NAFLD in children is increasing, suggesting a role for the developmental environment in programming susceptibility. However, the role of developmental Cd exposure in programming NAFLD and the underlying mechanisms remain unclear. We have proposed that imprinted genes are strong candidates for connecting the early life environment and later life disease. In support of this, we previously identified roles for the Imprinted Gene Network (IGN) and its regulator Zac1 in programming NAFLD in response to maternal metabolic dysfunction. Here, we test the hypothesis that developmental Cd exposure is sufficient to program NAFLD, and further, that this process is mediated by Zac1 and the IGN. Using mice, we show that developmental cadmium chloride (CdCl2) exposure leads to histological, biochemical, and molecular signatures of steatosis and fibrosis in juveniles. Transcriptomic analyses comparing livers of CdCl2-exposed and control mice show upregulation of Zac1 and the IGN coincident with disease presentation. Increased hepatic Zac1 expression is independent of promoter methylation and imprinting statuses. Finally, we show that over-expression of Zac1 in cultured hepatocytes is sufficient to induce lipid accumulation in a Ppar γ -dependent manner and demonstrate direct binding of Zac1 to the Pparγ promoter. Our findings demonstrate that developmental Cd exposure is sufficient to program NAFLD in later life, and with our previous work, establish Zac1 and the IGN as key regulators of prosteatotic and profibrotic pathways, two of the major pathological hallmarks of NAFLD. [ABSTRACT FROM AUTHOR]

The final weeks of gestation represent a critical period for dairy cows that can determine the success of the subsequent lactation. Many physiological changes take place and additional exogenous stressors can alter the success of the transition into lactation. Moreover, this phase is pivotal for the final stage of intrauterine development of the fetus, which can have negative long-lasting postnatal effects. Heat stress is widely recognised as a threat to dairy cattle welfare, health, and productivity. Specifically, late gestation heat stress impairs the dam's productivity by undermining mammary gland remodelling during the dry period and altering metabolic and immune responses in early lactation. Heat stress also affects placental development and function, with relevant consequences on fetal development and programming. In utero heat stressed newborns have reduced birth weight, growth, and compromised passive immune transfer. Moreover, the liver and mammary DNA of in utero heat stressed calves show a clear divergence in the pattern of methylation relative to that of in utero cooled calves. These alterations in gene regulation might result in depressed immune function, as well as altered thermoregulation, hepatic metabolism, and mammary development jeopardising their survival in the herd and productivity. Furthermore, late gestation heat stress appears to exert multigenerational effects, influencing milk yield and survival up to the third generation. As climate change continues at a rapid pace, more livestock will be subjected to heat stress for longer periods and absolute levels. In dairy cattle, heat stress profoundly impacts the subsequent productivity of late gestation cows and programs lower productivity and health in the offspring. This review considers the biological basis for the impact of heat stress on the dam and the daughter, and the epigenetic signals that result in the observed phenotypes. [ABSTRACT FROM AUTHOR]

Gestational diabetes mellitus (GDM) is a maternal metabolic disorder that perturbs placental development and increases the risk of offspring short- and long-term metabolic disorders. The mechanisms by which GDM impairs placental development remain poorly understood. Here, we defined the DNA methylome of GDM placentas and determined whether GDM perturbs methylation at genes important for placental development. We conducted an epigenome-wide association study of 42 placentas from pregnancies in the South African Soweto First 1000 days cohort (S1000). Using genome-wide bisulfite sequencing, we compared non-GDM placentas to GDM placentas with similar proportions from obese and non-obese mothers. Compared to non-GDM, GDM placentas exhibited a distinct methylation profile consisting of 12,210 differentially methylated CpGs (DMCs) that mapped to 3,875 genes. Epigenetically altered genes were enriched in Wnt and cadherin signalling pathways, both critical in placentation and embryogenesis. We also defined regional DNA methylation perturbation in GDM placentas at 11 placental development genes. These findings reveal extensive changes to the placental epigenome of GDM pregnancies and highlight perturbation enriched at important placental development genes. These molecular changes represent potential mechanisms for GDM-induced placental effects that may serve as candidate biomarkers for placental, maternal, and foetal health. Using a study design that used similar proportions of obese and non-obese mothers in our case and control pregnancies, we minimized the detection of changes due to obesity alone. Further work will be necessary to investigate the extent of the influence of obesity on these GDM-related placental epigenetic changes. [ABSTRACT FROM AUTHOR]

Maternal gestational diabetes and obesity are associated with adverse outcomes in offspring, including increased risk of diabetes and cardiovascular diseases. Previously, we identified a lower DNA methylation degree at genomic sites near the genes ESM1, MS4A3, and TSPAN14 in the blood cells of adolescent offspring exposed to gestational diabetes and/or maternal obesity in utero. In the present study, we aimed to investigate if altered methylation and expression of these genes were detectable in blood, as well in the metabolically relevant subcutaneous adipose tissue, in a separate cohort of adult offspring exposed to gestational diabetes and obesity (O-GDM) or type 1 diabetes (O-T1D) in utero, compared with the offspring of women from the background population (O-BP). We did not replicate the findings of lower methylation of ESM1, MS4A3, and TSPAN14 in blood from adults, either in O-GDM or O-T1D. In contrast, in adipose tissue of O-T1D, we found higher MS4A3 DNA methylation, which will require further validation. The adipose tissue ESM1 expression was lower in O-GDM compared to O-BP, which in turn was not associated with maternal pre-pregnancy BMI nor the offspring's own adiposity. Adipose tissue TSPAN14 expression was slightly lower in O-GDM compared with O-BP, but also positively associated with maternal pre-pregnancy BMI, as well as offspring's own adiposity and HbA1c levels. In conclusion, the lower DNA methylation in blood from adolescent offspring exposed to GDM could not be confirmed in the present cohort of adult offspring, potentially due to methylation remodeling with increased aging. In offspring adipose tissue, ESM1 expression was associated with maternal GDM, and TSPAN14 expression was associated with both maternal GDM, as well as pre-pregnancy BMI. These altered expression patterns are potentially relevant to the concept of developmental programming of cardiometabolic diseases and require further studies. [ABSTRACT FROM AUTHOR]

Locomotion is a defining characteristic of animal life and plays a crucial role in most behaviors. Locomotion involves physical activity, which can have far-reaching effects on physiology and neurobiology, both acutely and chronically. In human populations and in laboratory rodents, higher levels of physical activity are generally associated with positive health outcomes, although excessive exercise can have adverse consequences. Whether and how such relationships occur in wild animals is unknown. Behavioral variation among individuals arises from genetic and environmental factors and their interactions as well as from developmental programming (persistent effects of early-life environment). Although tremendous progress has been made in identifying genetic and environmental influences on individual differences in behavior, early-life effects are not well understood. Early-life effects can in some cases persist across multiple generations following a single exposure and, in principle, may constrain or facilitate the rate of evolution at multiple levels of biological organization. Understanding the mechanisms of such transgenerational effects (e.g., exposure to stress hormones in utero, inherited epigenetic alterations) may prove crucial to explaining unexpected and/or sex-specific responses to selection as well as limits to adaptation. One area receiving increased attention is early-life effects on adult physical activity. Correlational data from epidemiological studies suggest that early-life nutritional stress can (adversely) affect adult human activity levels and associated physiological traits (e.g., body composition, metabolic health). The few existing studies of laboratory rodents demonstrate that both maternal and early-life exercise can affect adult levels of physical activity and related phenotypes. Going forward, rodents offer many opportunities for experimental studies of (multigenerational) early-life effects, including studies that use maternal exposures and cross-fostering designs.

Background: Estriol (E3) is a steroid hormone formed only during pregnancy in primates including humans. Although E3 is synthesized at large amounts through a complex pathway involving the fetus and placenta, it is not required for the maintenance of pregnancy and has classically been considered virtually inactive due to associated very weak canonical estrogen signaling. However, estrogen exposure during pregnancy may have an effect on organs both within and outside the reproductive system, and compounds with binding affinity for estrogen receptors weaker than E3 have been found to impact reproductive organs and the brain. Here, we explore potential effects of E3 on fetal development using mouse as a model system. Results: We administered E3 to pregnant mice, exposing the fetus to E3. Adult females exposed to E3 in utero (E3-mice) had increased fertility and superior pregnancy outcomes. Female and male E3-mice showed decreased anxiety and increased exploratory behavior. The expression levels and DNA methylation patterns of multiple genes in the uteri and brains of E3-mice were distinct from controls. E3 promoted complexing of estrogen receptors with several DNA/histone modifiers and their binding to target genes. E3 functions by driving epigenetic change, mediated through epigenetic modifier interactions with estrogen receptors rather than through canonical nuclear transcriptional activation. Conclusions: We identify an unexpected functional role for E3 in fetal reproductive system and brain. We further identify a novel mechanism of estrogen action, through recruitment of epigenetic modifiers to estrogen receptors and their target genes, which is not correlated with the traditional view of estrogen potency. [ABSTRACT FROM AUTHOR]

BackgroundThe rapidly growing research field of developmental programming of health and disease risk investigates the early life origins of individual vulnerability for common, complex disorders that confer a major burden of disease.ObjectivesThe present article introduces the concept of developmental programming of disease vulnerability and summarizes studies on the mental and physical health consequences of exposure to childhood trauma and prenatal stress. Biological mechanisms that mediate disease risk after early life stress are discussed. The possibility of transgenerational transmission of effects of childhood trauma in exposed women to their children and potential mechanisms of this transmission are also presented.ConclusionA substantial number of studies show associations between early life stress and risk for mental and somatic diseases in later life. The underlying mechanisms are currently being studied at the molecular and epigenetic level. Potentially, these findings will allow unprecedented opportunities to improve the precision of current clinical diagnostic tools and the success of interventions. However, there is currently a lack of translation of research findings related to developmental programming to clinical applications.

Altered maternal haemoglobin levels during pregnancy are associated with pre-clinical and clinical conditions affecting the fetus. Evidence from animal models suggests that these associations may be partially explained by differential DNA methylation in the newborn with possible long-term consequences. To test this in humans, we meta-analyzed the epigenome-wide associations of maternal haemoglobin levels during pregnancy with offspring DNA methylation in 3,967 newborn cord blood and 1,534 children and 1,962 adolescent whole-blood samples derived from 10 cohorts. DNA methylation was measured using Illumina Infinium Methylation 450K or MethylationEPIC arrays covering 450,000 and 850,000 methylation sites, respectively. There was no statistical support for the association of maternal haemoglobin levels with offspring DNA methylation either at individual methylation sites or clustered in regions. For most participants, maternal haemoglobin levels were within the normal range in the current study, whereas adverse perinatal outcomes often arise at the extremes. Thus, this study does not rule out the possibility that associations with offspring DNA methylation might be seen in studies with more extreme maternal haemoglobin levels. [ABSTRACT FROM AUTHOR]

Altered nutrition or intrauterine exposure to various adverse conditions during fetal development or earlier in a mother's life can lead to epigenetic changes in fetal tissues, predisposing those tissues to diseases that manifest when offspring become adults. An example is a maternal obesity associated with gestational diabetes (GDM), where fetal exposure to a hyperglycemic, hyperinsulinemic, and/or hyperlipidemic gestational environment can provoke epigenetic changes that predispose offspring to various diseased conditions later in life. While it is now well established that offspring exposed to GDM have an increased risk of developing obesity, metabolic disorders, and/or cardiovascular disease in adult life, there are limited studies assessing the reproductive health of these offspring. This mini-review discusses the long-term effect of in utero exposure to GDM-associated adverse prenatal environment on the reproductive health of the offspring. Moreover, using evidence from various animal models and human epidemiological studies, this review offers molecular insight and understanding of how epigenetic reprogramming of genes culminates in reproductive dysfunction and the development of subfertility or infertility later in adult life. [ABSTRACT FROM AUTHOR]

• Maternal care has a profound effect on later-life behavior in offspring. • Extra-maternal factors have also been shown to influence later-life behavior. • We discuss variations in ambient temperature exposure and gene x environment interactions. • Other examples include milk composition, sibling interactions, and paternal care. • Future work on extra-maternal influences is important to understand the development of behavior. The early-life maternal environment has a profound and persistent effect on offspring neuroendocrine function, neurotransmitter systems, and behavior. Studies using rodent models suggest that early-life maternal care can influence the 'developmental programming' of offspring in part through altered epigenetic regulation of specific genes. The exploration of epigenetic regulation of these genes as a biological mechanism has been important to our understanding of how animals adapt to their environments and how these developmental trajectories may be altered. However, other non-maternal factors have been shown to act directly, or to interact with maternal care, to influence later-life phenotype. Based on accumulating evidence, including our research, we discuss other important influences on the developmental programming of offspring. We highlight early-life variations in temperature exposure and offspring genotype x environment interactions as prominent examples. We conclude with recommendations for future investigations on how early-life maternal care and extra-maternal influences lead to persistent changes in the brain and behavior of the offspring throughout development. [ABSTRACT FROM AUTHOR]

In recent years, androgens have emerged as critical regulators of female reproduction and women's health in general. While high levels of androgens in women are associated with polycystic ovary syndrome (PCOS), recent evidence suggests that a certain amount of direct androgen action through androgen receptor is also essential for normal ovarian function. Moreover, prenatal androgen exposure has been reported to cause developmental reprogramming of the fetus that manifests into adult pathologies, supporting the Developmental Origins of Health and Disease (DOHaD) hypothesis. Therefore, it has become imperative to understand the underlying mechanism of androgen actions and its downstream effects under normal and pat hophysiological conditions. Over the years, there has been a lot of studies on androgen receptor function as a transcriptional regulator in the nucleus as well as androgen-induced rapid extranuclear signaling. Conversely, new evidence suggests that androgen actions may also be mediated through epigenetic modulation involving both the nuclear and extra-nuclear androgen signaling. This review focuses on androgen-induced epigenetic modifications in female reproduction, specifically in the ovary, and discusses emerging concepts, latest perceptions, and highlight the areas that need further investigation. [ABSTRACT FROM AUTHOR]

Recent human and animal studies have delineated hypertension can develop in the earliest stage of life. A lack or excess of particular nutrients in the maternal diet may impact the expression of genes associated with BP, leading to an increased risk of hypertension in adulthood. Modulations in gene expression could be caused by epigenetic mechanisms through aberrant DNA methylation, histone modification, and microRNAs (miRNAs). Several molecular mechanisms for the developmental programming of hypertension, including oxidative stress, dysregulated nutrient-sensing signal, aberrant renin-angiotensin system, and dysbiotic gut microbiota have been associated with epigenetic programming. Conversely, maternal nutritional interventions such as amino acids, melatonin, polyphenols, resveratrol or short chain fatty acids may work as epigenetic modifiers to trigger protective epigenetic modifications and prevent offspring hypertension. We present a current perspective of maternal malnutrition that can cause fetal programming and the potential of epigenetic mechanisms lead to offspring hypertension. We also discuss the opportunities of dietary nutrients or nutraceuticals as epigenetic modifiers to counteract those adverse programming actions for hypertension prevention. The extent to which aberrant epigenetic changes can be reprogrammed or reversed by maternal dietary interventions in order to prevent human hypertension remains to be established. Continued research is necessary to evaluate the interaction between maternal malnutrition and epigenetic programming, as well as a greater focus on nutritional interventions for hypertension prevention towards their use in clinical translation. [ABSTRACT FROM AUTHOR]

Abstract DNA methylation could shape phenotypic responses to environmental cues and underlie developmental plasticity. Environmentally induced changes in DNA methylation during development can give rise to stable phenotypic traits and thus affect fitness. In the laboratory, it has been shown that the vertebrate methylome undergoes dynamic reprogramming during development, creating a critical window for environmentally induced epigenetic modifications. Studies of DNA methylation in the wild are lacking, yet are essential for understanding how genes and the environment interact to affect phenotypic development and ultimately fitness. Furthermore, our knowledge of the establishment of methylation patterns during development in birds is limited. We quantified genome‐wide DNA methylation at various stages of embryonic and postnatal development in an altricial passerine bird, the great tit Parus major. While, there was no change in global DNA methylation in embryonic tissue during the second half of embryonic development, a twofold increase in DNA methylation in blood occurred between 6 and 15 days posthatch. Though not directly comparable, DNA methylation levels were higher in the blood of nestlings compared with embryonic tissue at any stage of prenatal development. This provides the first evidence that DNA methylation undergoes global change during development in a wild bird, supporting the hypothesis that methylation mediates phenotypic development. Furthermore, the plasticity of DNA methylation demonstrated during late postnatal development, in the present study, suggests a wide window during which DNA methylation could be sensitive to environmental influences. This is particularly important for our understanding of the mechanisms by which early‐life conditions influence later‐life performance. While, we found no evidence for differences in genome‐wide methylation in relation to habitat of origin, environmental variation is likely to be an important driver of variation in methylation at specific loci.

Metabolic syndrome (MS) is a cluster of cardiometabolic factors that are strongly associated with the risk of serious chronic diseases. The prevalence of MS continues to grow, including among children, adolescents and people of active reproductive age. For the sphere of reproductive medicine, the problem of MS is of particular importance not only because of its negative impact on fertility, the frequency of complications of pregnancy and childbirth, but also because of its transgenerative effect on the health of offspring: it is proved that each of the components of the metabolic syndrome is a powerful epigenetic factor. Recent studies have revealed many new facets of the pathogenesis of MS and expanded the range of its etiologic factors beyond the alimentary factors, which determines the possibility of finding new approaches to prevention and treatment of this pathology. The review presents: evolution of diagnostic criteria for MS and reflection of this process in epidemiology and clinical approaches to the disease; epidemiological data on the prevalence of MS in young adults. A brief overview of a large array of scientific research of the last decade on etiology and pathogenesis of MS, in particular the role of adipose tissue dysfunction of visceral, ileofemoral and ectopic depots, causes of the tendency to prevail in one or another adipose tissue depot, new obesity classification, as well as the role of perinatal and epigenetic, ecological (environmental obesogenes, artificial light contamination), composition of intestinal microbiota, state of the sympathetic nervous system, nutritional deficiencies in the development of obesity and MS is provided. The gender differences of pathogenesis and clinical features of MS, as well as the association of MS with dyshormonal and other pathologies (PCOS, hyperprolactinemia, uterine myoma, endometriosis) of female reproductive health are considered.

Adverse prenatal environments, such as maternal stress and infections, can influence the health and performance of offspring. Mastitis is the most common disease in dairy cattle, yet the intergenerational effects have not been specifically investigated. Therefore, we examined the associations between the dam's mammary gland health and daughter performance using somatic cell score (SCS) as a proxy for mammary health. Using data obtained from Dairy Records Management Systems (Raleigh, NC), we linked daughter records with their dam's records for the lactation in which the daughter was conceived. Linear and quadratic relationships of dam mean SCS with the daughter's age at first calving (AFC; n = 15,992 daughters, 4,366 herds), first- (n = 15,119 daughters, 4,213 herds) and second-lactation SCS (n = 3,570 daughters, 1,554 herds), first- and second-lactation mature-equivalent 305-d milk yield, and milk component yields were assessed using mixed linear regression models. We uncovered a phenomenon similar to those found in human and mouse models examining prenatal inflammation effects, whereby daughters born from dams with elevated SCS had poorer performance. Dam mean SCS was positively associated with daughter's AFC and first- and second-lactation mean SCS. Furthermore, for every 1-unit increase in dam mean SCS, daughter's first- and second-lactation mature-equivalent fat yield declined by 0.34% and 0.91% (−1.6 ± 0.49 kg, −4.0 ± 1.0 kg, respectively), although no effect was found on first- or second-lactation milk or milk protein yield. When accounting for genetics, daughter SCS, and AFC (first lactation only), dam mean SCS was associated with reduced second-lactation milk fat yield (−3.5 ± 1.8 kg/unit SCS), and a tendency was found for first-lactation milk fat yield (−1.9 ± 1.0 kg/unit SCS). Taken together, the association of greater dam mean SCS with lesser daughter milk fat yield is likely due to a few underlying mechanisms, in particular, a predisposition for mastitis and alterations in the epigenome controlling milk fat synthesis. As such, future studies should examine epigenetic mechanisms as a potential underpinning of this phenomenon. [ABSTRACT FROM AUTHOR]

The ways in which the environment of early life shapes the long-term state of an individual's health and predilection to disease are often described as fetal or developmental programming. For many, the term 'the critical 1000 days' captures vividly the importance of the period between conception and weaning for health interventions at population level. In the academic literature, interdisciplinary work around this question has become known as the 'developmental origins of health and disease' (DOHaD), a broad concept that describes the scope and ambition of the field (Gluckman et al., 2010). While DOHaD research originally focused on the fetus, it soon widened its scope, from periconception to weaning, and then into childhood and even adolescence. Environmental influences examined began with nutrition, but now include parental stress and mental health, environmental chemicals, air pollution and many others. Recent work engages deeply with socioeconomic drivers of the developmental environment. This multilayered approach is especially significant in the current COVID-19 pandemic where the Sars-CoV-2 virus itself is only one of the potentially significant factors that, by affecting organisms in sensitive periods, could leave lasting traces. [ABSTRACT FROM AUTHOR]

Bisphenol A (BPA), an endocrine disrupting chemical (EDC), is a ubiquitous pollutant. As part of the Consortium Linking Academic and Regulatory Insights on BPA Toxicity (CLARITY-BPA), we sought to determine whether exposure of Sprague-Dawley rats to 2,500 μg/kg/day BPA (BPA) or 0.5 μg/kg/day ethinyl estradiol (EE) from gestational day 6 through postnatal day 21 induces behavior-relevant gene expression and DNA methylation changes in hippocampus and hypothalamus at adulthood. RNA and DNA were isolated from both regions. Expression of ten genes (Dnmt1, Dnmt3a, Dnmt3b, Esr1, Esr2, Avp, Ar, Oxt, Otr, and Bdnf) presumably altered by early-life BPA/EE exposure was examined. Three genes (Bdnf, Dnmt3b, and Esr1) were studied for DNA methylation changes in their putative 5ʹ promoter regions. Molecular changes in hippocampus were correlated to prior Barnes maze performance, including sniffing correct holes, distance traveled, and velocity. Exposure to BPA and/or EE disrupted patterns of sexually dimorphic gene expression/promoter DNA methylation observed in hippocampus and hypothalamus of controls. In the hippocampus of female offspring, BPA exposure resulted in hypermethylation of the putative 5ʹ promoter region of Bdnf, while EE exposure induced hypomethylation. Bdnf methylation was weakly associated with Bdnf expression in hippocampi of female rats. Hippocampal Bdnf expression in females showed a weak negative association with sniffing correct hole in Barnes maze. Hippocampal expression of Avp, Esr2, Oxt, and Otr was strongly associated with velocity of control rats in Barnes maze. Findings suggest BPA exposure induced non-EE-like gene expression and epigenetic changes in adult rat hippocampi, a region involved in spatial navigation.

Objective: There is growing evidence that exposure to trauma prior to conception can affect offspring. The authors have reported that adult offspring of Holocaust survivors showed lower methylation of FK506 binding protein 5 (FKBP5) intron 7, site 6 compared with Jewish comparison volunteers. The present study sought to replicate this finding in a larger sample and to examine parental and offspring correlates of observed effects.Methods: Cytosine methylation was measured in blood using pyrosequencing. The independent replication sample consisted of 125 Holocaust offspring and 31 control subjects. Additional analyses, performed in a larger sample of 147 offspring and 40 control subjects that included the 31 previously studied participants, examined associations of parental trauma-related variables (i.e., sex of the exposed parent, parental posttraumatic stress disorder, age at Holocaust exposure) and offspring characteristics (i.e., childhood trauma exposure, lifetime psychiatric diagnoses, psychotropic medication use, FKBP5 rs1360780 genotype, FKBP5 gene expression, and neuroendocrine measures) with offspring FKBP5 methylation.Results: FKBP5 site 6 methylation was significantly lower in Holocaust offspring than in control subjects, an effect associated with maternal Holocaust exposure in childhood and with lower offspring self-reported anxiety symptoms. FKBP5 gene expression was elevated in Holocaust offspring. FKBP5 methylation was associated with indices of glucocorticoid sensitivity but not with basal FKBP5 gene expression.Conclusions: This study replicates and extends the previously observed decrement in FKBP5 intron 7, site 6 methylation in Holocaust offspring. The predominance of this effect in offspring of mothers exposed during childhood implicates maternal developmental programming as a putative mechanism. [ABSTRACT FROM AUTHOR]

Gestational exposure to lead (Pb) adversely impacts offspring health through multiple mechanisms, one of which is the alteration of the epigenome including DNA methylation. This study aims to identify differentially methylated CpG sites associated with trimester-specific maternal Pb exposure in umbilical cord blood (UCB) leukocytes. Eighty-nine mother-child dyads from the Early Life Exposure in Mexico to Environmental Toxicants (ELEMENT) longitudinal birth cohorts with available UCB samples were selected for DNA methylation analysis via the Infinium Methylation EPIC BeadChip, which quantifies methylation at >850 000 CpG sites. Maternal blood lead levels (BLLs) during each trimester (T1: 6.56 ± 5.35 µg/dL; T2: 5.93 ± 5.00 µg/dL; T3: 6.09 ± 4.51 µg/dL), bone Pb (patella: 11.8 ± 9.25 µg/g; tibia: 11.8 ± 6.73 µg/g), a measure of cumulative Pb exposure, and UCB Pb (4.86 ± 3.74 µg/dL) were measured. After quality control screening, data from 786 024 CpG sites were used to identify differentially methylated positions (DMPs) and differentially methylated regions (DMRs) by Pb biomarkers using separate linear regression models, controlling for sex and estimated UCB cell-type proportions. We identified 3 DMPs associated with maternal T1 BLL, 2 with T3 BLL, and 2 with tibia bone Pb. We identified one DMR within PDGFRL associated with T1 BLL, one located at chr6:30095136-30095295 with T3 BLL, and one within TRHR with tibia bone Pb (adjusted P -value <.05). Pathway analysis identified 15 overrepresented gene pathways for differential methylation that overlapped among all 3 trimesters with the largest overlap between T1 and T2 (adjusted P -value <.05). Pathways of interest include nodal signaling pathway and neurological system processes. These data provide evidence for differential methylation by prenatal Pb exposure that may be trimester-specific. [ABSTRACT FROM AUTHOR]

Exposure to a sub-optimal environment in the womb can result in poor fetal growth and impair the normal development of organs. The kidney, specifically the process of nephrogenesis, has been shown to be impacted by many common pregnancy exposures including an inadequate diet, poor placental function, maternal stress as well as maternal smoking and alcohol consumption. This can result in offspring being born with a reduced nephron endowment, which places these individuals at increased risk of hypertension and chronic kidney disease (CKD). Of recent interest is whether this disease risk can be passed on to subsequent generations and, if so, what are the mechanisms and pathways involved. In this review, we highlight the growing body of evidence that a low birth weight and hypertension, which are both major risk factors for cardiovascular and CKD, can be transmitted across generations. However, as yet there is little data as to whether a low nephron endowment contributes to this disease transmission. The emerging data suggests transmission can occur both through both the maternal and paternal lines, which likely involves epigenetic mechanisms such chromatin remodelling (DNA methylation and histone modification) and non-coding RNA modifications. In addition, females who were born small and/or have a low nephron endowment are at an increased risk for pregnancy complications, which can influence the growth and development of the next generation. Future animal studies in this area should include examining nephron endowment across multiple generations and determining adult renal function. Clinically, long term follow-up studies of large birth cohorts need to be undertaken to more clearly determine the impact a sub-optimal environment in one generation has on the health outcomes in the second, and subsequent, generation. [ABSTRACT FROM AUTHOR]

Accumulating evidence suggests that dysregulation of placental DNA methylation (DNAm) is a mechanism linking maternal weight during pregnancy to metabolic programming outcomes. The common marmoset, Callithrix jaccus, is a platyrrhine primate species that has provided much insight into studies of the primate placenta, maternal condition, and metabolic programming, yet the relationships between maternal weight and placental DNAm are unknown. Here, we report genome‐wide DNAm from term marmoset placentas using reduced representation bisulfite sequencing. We identified 74 genes whose DNAm pattern is associated with maternal weight during gestation. These genes are predominantly involved in energy metabolism and homeostasis, including the regulation of glycolytic and lipid metabolic processes pathways. Research Highlights: The placental DNA methylation (DNAm) landscape of the marmoset placenta presents unique differences and similarities with human placental methylation patterns.Maternal weight is associated with placental DNAm in genes that are predominantly involved in energy metabolism and homeostasis.The impact of altered placental DNAm on placental function and development may also contribute to the potential role of placental DNAm in developmental programming in the marmoset monkey. [ABSTRACT FROM AUTHOR]

The preconception environment is a significant modifier of dysgenesis and the development of environmentally-induced disease. To date, fetal alcohol spectrum disorders (FASDs) have been exclusively associated with maternal exposures, yet emerging evidence suggests male-inherited alterations in the developmental program of sperm may be relevant to the growth-restriction phenotypes of this condition. Using a mouse model of voluntary consumption, we find chronic preconception male ethanol exposure associates with fetal growth restriction, decreased placental efficiency, abnormalities in cholesterol trafficking, sex-specific alterations in the genetic pathways regulating hepatic fibrosis, and disruptions in the regulation of imprinted genes. Alterations in the DNA methylation profiles of imprinted loci have been identified in clinical studies of alcoholic sperm, suggesting the legacy of paternal drinking may transmit via heritable disruptions in the regulation of imprinted genes. However, the capacity of sperm-inherited changes in DNA methylation to broadly transmit environmentally-induced phenotypes remains unconfirmed. Using bisulphite mutagenesis and second-generation deep sequencing, we find no evidence to suggest that these phenotypes or any of the associated transcriptional changes are linked to alterations in the sperm-inherited DNA methylation profile. These observations are consistent with recent studies examining the male transmission of diet-induced phenotypes and emphasize the importance of epigenetic mechanisms of paternal inheritance beyond DNA methylation. This study challenges the singular importance of maternal alcohol exposures and suggests paternal alcohol abuse is a significant, yet overlooked epidemiological factor complicit in the genesis of alcohol-induced growth defects, and may provide mechanistic insight into the failure of FASD children to thrive postnatally.

DNA methylation could shape phenotypic responses to environmental cues and underlie developmental plasticity. Environmentally induced changes in DNA methylation during development can give rise to stable phenotypic traits and thus affect fitness. In the laboratory, it has been shown that the vertebrate methylome undergoes dynamic reprogramming during development, creating a critical window for environmentally induced epigenetic modifications. Studies of DNA methylation in the wild are lacking, yet are essential for understanding how genes and the environment interact to affect phenotypic development and ultimately fitness. Furthermore, our knowledge of the establishment of methylation patterns during development in birds is limited. We quantified genome‐wide DNA methylation at various stages of embryonic and postnatal development in an altricial passerine bird, the great tit Parus major. While, there was no change in global DNA methylation in embryonic tissue during the second half of embryonic development, a twofold increase in DNA methylation in blood occurred between 6 and 15 days posthatch. Though not directly comparable, DNA methylation levels were higher in the blood of nestlings compared with embryonic tissue at any stage of prenatal development. This provides the first evidence that DNA methylation undergoes global change during development in a wild bird, supporting the hypothesis that methylation mediates phenotypic development. Furthermore, the plasticity of DNA methylation demonstrated during late postnatal development, in the present study, suggests a wide window during which DNA methylation could be sensitive to environmental influences. This is particularly important for our understanding of the mechanisms by which early‐life conditions influence later‐life performance. While, we found no evidence for differences in genome‐wide methylation in relation to habitat of origin, environmental variation is likely to be an important driver of variation in methylation at specific loci. [ABSTRACT FROM AUTHOR]

Despite their unique histories, environments, and lifestyles, historically subjugated populations consistently show poorer health outcomes compared to the general population. The theory of historical trauma, which argues that a collective trauma experienced by one generation can negatively impact the wellbeing of future generations, is a potential framework to understand the adverse health outcomes seen among populations with histories of subjugation. However, the biological pathways through which historical trauma actually impacts health have been unclear. In this paper, we present a cumulative, two pathway model that describes how historical trauma can impact health in contemporary generations. The first pathway suggests that personal exposure to trauma or stressors, which are more common among populations that have experienced historical trauma, can induce epigenetic modifications that can contribute to the development of poor health. The second pathway posits that poor health can occur through intergenerational epigenetic modifications in response to parental and grandparental trauma or stressor exposures. Taken together, these pathways can provide insight into the higher rates of adverse health outcomes among individuals from populations that have historically endured collective trauma. Importantly, the potential reversible nature of epigenetic modifications suggests that these trauma-induced epigenetic effects are not necessarily permanent and that improvements in environmental conditions could reduce the high prevalence of poor health among historically disadvantaged communities. • Presents a conceptual model for understanding health impacts of historical trauma. • Describes how epigenetic modifications can facilitate these effects. • Discusses life course and intergenerational impacts of trauma and stressor exposure. • Recognizes that epigenetic-mediated historical trauma health effects could be ameliorated. [ABSTRACT FROM AUTHOR]

Circadian rhythm disturbance (CRD) increases the risk of disease, e.g. metabolic syndrome, cardiovascular disease, and cancer. In the present study, we investigated later life adverse health effects triggered by repeated jet lag during gestation. Pregnant mice were subjected to a regular light-dark cycle (CTRL) or to a repeated delay (DEL) or advance (ADV) jet lag protocol. Both DEL and ADV offspring showed reduced weight gain. ADV offspring had an increased circadian period, and an altered response to a jet lag was observed in both DEL and ADV offspring. Analysis of the bones of adult male ADV offspring revealed reduced cortical bone mass and strength. Strikingly, analysis of the heart identified structural abnormalities and impaired heart function. Finally, DNA methylation analysis revealed hypermethylation of miR17-92 cluster and differential methylation within circadian clock genes, which correlated with altered gene expression. We show that developmental CRD affects the circadian system and predisposes to non-communicable disease in adult life. [ABSTRACT FROM AUTHOR]

Development of the pulmonary circulation is a critical component of fetal lung development, and continues throughout infancy and childhood, marking an extended window of susceptibility to vascular maldevelopment and maladaptation. Perinatal vascular insults may result in abnormal vascular structure or function, including decreased angiogenic signaling and vascular endowment, impaired vasoreactivity through increased pulmonary artery endothelial dysfunction and remodeling, or enhanced genetic susceptibility to pulmonary vascular disease through epigenetic modifications or germline mutations. Although some infants develop early onset pulmonary hypertension, due to the unique adaptive capabilities of the immature host many do not have clinically evident early pulmonary vascular dysfunction. These individuals remain at increased risk for development of late‐onset pulmonary hypertension, and may be particularly susceptible to secondary insults. This review will address the role of perinatal vascular insults in the development of late pulmonary vascular dysfunction with an effort to highlight areas of critical research need. Long‐term pulmonary vascular consequences of perinatal insults. A number of insults may contribute to increased risk and development of overt pulmonary vascular disease. Additionally, severity, synergy and timing of insults may impact susceptibility to pulmonary vascular disease. Note preterm birth represents a unique overlap of primary and secondary insults. [ABSTRACT FROM AUTHOR]

Aging research explores the basic biological mechanisms of aging and age-related disease. As the 'aging society' is framed as one of today's grand challenges, particularly in the global North, the field is gaining momentum. Epigenetic approaches have become important for aging research. This article explores which kinds of epistemic and biopolitical formations arise with the integration of epigenetics into aging research. Drawing on literature analysis, participant observation at international conferences in Europe, and interviews with selected speakers, we identify two distinctly different ways in which epigenetics and aging have become linked. On the one hand, epigenetics has become important for research focusing on the continuous biological malleability of aging processes in adults. On the other hand, it is integral to research investigating how early life development programs aging trajectories. These perspectives do not only differ epistemically, but also entail distinctly different visions of possible clinical, social, and political responses to the challenges of the aging society. Particularly, questions of social inequality and the growing health and morbidity gap in late-capitalist Western societies figure differently in each perspective. This shows that epigenetics, rather than moving biological research in one specific direction, can participate in heterogeneous epistemic formations with diverging biopolitical momenta. [ABSTRACT FROM AUTHOR]

The concept of developmental origins of diseases has gained a huge interest in recent years and is a constantly emerging scientific field. First observations hereof originated from epidemiological studies, linking impaired birth outcomes to adult chronic, noncommunicable disease. By now there is a considerable amount of both epidemiological and experimental evidence highlighting the impact of early life events on later life disease susceptibility. Albeit far from being completely understood, more recent studies managed to elucidate underlying mechanisms, with epigenetics having become almost synonymous with developmental programming. The aim of this review was to give a comprehensive overview of various aspects and mechanisms of developmental origins of diseases. Starting from initial research foci mainly centered on a nutritionally impaired intrauterine environment, more recent findings such as postnatal nutrition, preterm birth, paternal programming and putative interventional approaches are summarized. The review outlines general underlying mechanisms and particularly discusses mechanistic explanations for sexual dimorphism in developmental programming. Furthermore, novel hypotheses are presented emphasizing a non-mendelian impact of parental genes on the offspring's phenotype.

Highlights • Aging trajectory may vary depending on developmental settings. • Persistent change in epigenetic regulation is an important contributing mechanism. • Birth weight is a potential proxy to predict aging phenotype. Abstract There is accumulating evidence that aging phenotype and longevity may be developmentally programmed. Main mechanisms linking developmental conditions to later-life health outcomes include persistent changes in epigenetic regulation, (re)programming of major endocrine axes such as growth hormone/insulin-like growth factor axis and hypothalamic-pituitary-adrenal axis and also early-life immune maturation. Recently, evidence has also been generated on the role of telomere biology in developmental programming of aging trajectory. In addition, persisting changes of intestinal microbiota appears to be crucially involved in these processes. In this review, experimental and epidemiological evidence on the role of early-life conditions in programming of aging phenotypes are presented and mechanisms potentially underlying these associations are discussed. [ABSTRACT FROM AUTHOR]

Epidemiological and experimental studies have shown that the peri-conception period, pregnancy, and infancy are windows of particular sensibility to environmental clues which influence lifelong trajectories across health and disease. Nutrition, stress, and toxins induce epigenetic marks that control long-term gene expression patterns and can be transmitted transgenerationally. Chronic diseases of adulthood such as hypertension, diabetes, and obesity thus have early, developmental origins in the perinatal period. The early epigenome, in interaction with other actors such as the microbiome, add powerful layers of diversity to the biological predisposition generated by the genome. Such "programming" is a normal, adaptive component of development, including in normal pregnancies and births. However, perinatal disease, either maternal (such as pre-eclampsia, ges-tational diabetes, or inflammatory disease) or fetal, and neonatal diseases (such as intrauterine growth restriction and preterm birth) are major conditions of altered programming, translated into an increased risk for chronic disease in these patients when they reach adulthood. Early prevention, optimal perinatal nutrition, and specific follow-up measures are key factors in the early preservation of long-term health. [ABSTRACT FROM AUTHOR]