Accumulating evidence has suggested that a suboptimal early life environment produces multigenerational developmental defects. A proposed mechanism is stable inheritance of DNA methylation. Here we show that maternal bisphenol A (BPA) exposure in C57BL/6 mice produces multigenerational metabolic phenotypes in their offspring. Using various methods including dual-energy X-ray absorptiometry analyses, glucose tolerance tests, and perifusion islet studies, we showed that exposure to 10 μg/kg/d and 10 mg/kg/d BPA in pregnant F0 mice was associated with higher body fat and perturbed glucose homeostasis in F1 and F2 male offspring but not female offspring. To provide insight into the mechanism of the multigenerational metabolic abnormalities, we investigated the maternal metabolic milieu and inheritance of DNA methylation across generations. We showed that maternal glucose homeostasis during pregnancy was altered in the F0 but not F1 female mice. The results suggested that a compromised maternal metabolic milieu may play a role in the health of the F1 offspring but cannot account for all of the observed multigenerational phenotypes. We further demonstrated that the metabolic phenotypes in the F1 and F2 BPA male offspring were linked to fetal overexpression of the imprinted Igf2 gene and increased DNA methylation at the Igf2 differentially methylated region 1. Studies in H19(Δ3.8/+) mouse mutants supported the role of fetal Igf2 overexpression in altered adult glucose homeostasis. We conclude that early life BPA exposure at representative human exposure levels can perturb metabolic health across multiple generations in the mouse through stable inheritance of DNA methylation changes at the Igf2 locus.

Background:Exposure to the environmental endocrine disruptor bisphenol A (BPA) is ubiquitous and associated with the increased risk of diabetes and obesity. However, the underlying mechanisms remain unknown. We recently demonstrated that perinatal BPA exposure is associated with higher body fat, impaired glucose tolerance, and reduced insulin secretion in first- (F1) and second-generation (F2) C57BL/6J male mice offspring.Objective:We sought to determine the multigenerational effects of maternal bisphenol A exposure on mouse pancreatic islets.Methods:Cellular and molecular mechanisms underlying these persistent changes were determined in F1 and F2 adult offspring of F0 mothers exposed to two relevant human exposure levels of BPA (10μg/kg/d-LowerB and 10mg/kg/d-UpperB).Results:Both doses of BPA significantly impaired insulin secretion in male but not female F1 and F2 offspring. Surprisingly, LowerB and UpperB induced islet inflammation in male F1 offspring that persisted into the next generation. We also observed dose-specific effects of BPA on islets in males. UpperB exposure impaired mitochondrial function, whereas LowerB exposure significantly reduced β-cell mass and increased β-cell death that persisted in the F2 generation. Transcriptome analyses supported these physiologic findings and there were significant dose-specific changes in the expression of genes regulating inflammation and mitochondrial function. Previously we observed increased expression of the critically important β-cell gene, Igf2 in whole F1 embryos. Surprisingly, increased Igf2 expression persisted in the islets of male F1 and F2 offspring and was associated with altered DNA methylation.Conclusion:These findings demonstrate that maternal BPA exposure has dose- and sex-specific effects on pancreatic islets of adult F1 and F2 mice offspring. The transmission of these changes across multiple generations may involve either mitochondrial dysfunction and/or epigenetic modifications. https://doi.org/10.1289/EHP1674

Although the factors responsible for the recent increase in the prevalence of diabetes worldwide are not entirely known, the morbidity associated with this disease results in substantial health and economic burden on society. Epigenetic modifications, including DNA methylation have been identified as one mechanism by which the environment interacts with the genome and there is evidence that alterations in DNA methylation may contribute to the increased prevalence of both Type 1 and Type 2 diabetes. This review provides a summary of DNA methylation and its role in gene regulation, and includes descriptions of various techniques to measure site-specific and genome wide DNA methylation changes. In addition, we review current literature highlighting the complex relationship between DNA methylation, gene expression, and the development of diabetes and related complications. In studies where both DNA methylation and gene expression changes were reported, DNA methylation status had a strong inverse correlation with gene expression, suggesting that this interaction may be a potential future therapeutic target. We highlight the emerging use of genome wide DNA methylation profiles as a biomarker to predict patients at risk of developing diabetes or specific complications of diabetes. Developing a predictive model that incorporates both genetic information and DNA methylation changes may be an effective diagnostic approach for all types of diabetes and could lead to additional innovative therapies.

The incidence of metabolic disorders like type 2 diabetes and obesity continues to increase. In addition to the well-known contributors to these disorders, such as food intake and sedentary lifestyle, recent research in the exposure science discipline provides evidence that exposure to endocrine-disrupting chemicals like bisphenol A and phthalates via multiple routes (e.g., food, drink, skin contact) also contribute to the increased risk of metabolic disorders. Endocrine-disrupting chemicals (EDCs) can disrupt any aspect of hormone action. It is becoming increasingly clear that EDCs not only affect endocrine function but also adversely affect immune system function. In this review, we focus on human, animal, and in vitro studies that demonstrate EDC exposure induces dysfunction of the immune system, which, in turn, has detrimental effects on metabolic health. These findings highlight how the immune system is emerging as a novel player by which EDCs may mediate their effects on metabolic health. We also discuss studies highlighting mechanisms by which EDCs affect the immune system. Finally, we consider that a better understanding of the immunomodulatory roles of EDCs will provide clues to enhance metabolic function and contribute toward the long-term goal of reducing the burden of environmentally induced diabetes and obesity.

The placenta is metabolically active and supports the growth of the fetus. We hypothesize that deficits in the capacity of the placenta to maintain bioenergetic and metabolic stability during pregnancy may result in spontaneous preterm birth (SPTB). To explore this hypothesis, we performed a nested cased control study of metabolomic signatures in placentas from women with SPTB (<36 weeks gestation) compared to normal pregnancies (≥38 weeks gestation). To control for the effects of gestational age on placenta metabolism, we also studied a subset of metabolites in non-laboring preterm and term Rhesus monkeys. Comprehensive quantification of metabolites demonstrated a significant elevation in the levels of amino acids, prostaglandins, sphingolipids, lysolipids, and acylcarnitines in SPTB placenta compared to term placenta. Additional quantification of placental acylcarnitines by tandem mass spectrometry confirmed the significant elevation in SPTB human, with no significant differences between midgestation and term placenta in Rhesus macaque. Fatty acid oxidation as measured by the flux of 3H-palmitate in SPTB placenta was lower than term. Collectively, significant and biologically relevant alterations in the placenta metabolome were identified in SPTB placenta. Altered acylcarnitine levels and fatty acid oxidation suggest that disruption in normal substrate metabolism is associated with SPTB.

The incidence of metabolic disorders like type 2 diabetes (T2D) and obesity continue to increase. Although it is evident that the increasing incidence of diabetes confers a global societal and economic burden, the mechanisms responsible for the increased incidence of T2D are not well understood. Extensive efforts to understand the association of early-life perturbations with later onset of metabolic diseases, the founding principle of developmental origins of health and disease, have been crucial in determining the mechanisms that may be driving the pathogenesis of T2D. As the programming of the epigenome occurs during critical periods of development, it has emerged as a potential molecular mechanism that could occur early in life and impact metabolic health decades later. In this review, we critically evaluate human and animal studies that illustrated an association of epigenetic processes with development of T2D as well as intervention strategies that have been employed to reverse the perturbed epigenetic modification or reprogram the naturally occurring epigenetic marks to favor improved metabolic outcome. We highlight that although our understanding of epigenetics and its contribution toward developmental origins of T2D continues to grow, whether epigenetics is a cause, consequence, or merely a correlation remains debatable due to the many limitations/challenges of the existing epigenetic studies. Finally, we discuss the potential of establishing collaborative research efforts between different disciplines, including physiology, epigenetics, and bioinformatics, to help advance the developmental origins field with great potential for understanding the pathogenesis of T2D and developing preventive strategies for T2D.

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Adults born preterm are at increased risk of impaired glucose tolerance and diabetes. Late gestation fetuses exposed to high blood glucose concentration also are at increased risk of impaired glucose tolerance as adults. Preterm babies commonly become hyperglycemic and are thus exposed to high blood glucose concentration at an equivalent stage of pancreatic maturation. It is not known whether preterm birth itself, or complications of prematurity, such as hyperglycemia, alter later pancreatic function. To distinguish these, we made singleton preterm lambs hyperglycemic (HYPER) for 12 days after birth with a dextrose infusion and compared them with vehicle-treated preterm and term controls and with HYPER lambs made normoglycemic with an insulin infusion. Preterm birth reduced β-cell mass, apparent by 4 weeks after term and persisting to adulthood (12 mo), and was associated with reduced insulin secretion at 4 months (juvenile) and reduced insulin mRNA expression in adulthood. Hyperglycemia in preterm lambs further down-regulated key pancreatic gene expression in adulthood. These findings indicate that reduced β-cell mass after preterm birth may be an important factor in increased risk of diabetes after preterm birth and may be exacerbated by postnatal hyperglycemia.