Transgenerational effects of endocrine disruptors: epigenetics and physiology

描述（由申请人提供）：越来越多的证据表明，在子宫内和发育早期接触环境化学物质可能在以后的生活中肥胖和相关代谢疾病的发展中发挥作用。内分泌干扰物是在内分泌通路中模仿内源性激素的外源性物质。双酚a （BPA）是一种化学增塑剂和雌激素，用于生产聚碳酸酯塑料和环氧树脂。人类暴露在低水平的双酚a中是普遍存在的，主要是通过饮食。我们实验室和其他研究人员的研究表明，啮齿动物在怀孕期间暴露于BPA会导致成年后肥胖增加和葡萄糖耐受性受损。BPA对子宫和早期发育影响的重要机制被认为是改变基因表达的表观遗传调控。我们在小鼠身上的初步数据支持了这一假设，即在怀孕期间暴露于BPA会导致胚胎和胎盘中两个对发育和肥胖至关重要的基因Igf2和Snrpn的印迹丢失。这些发现使我们假设，在发育过程中暴露于双酚a会改变包括生殖细胞在内的关键细胞的表观遗传谱，从而导致基因的改变

DESCRIPTION (provided by applicant): There is growing evidence that in utero and early developmental exposures to environmental chemicals may play a role in the development of obesity and related metabolic diseases later in life. Endocrine disrupting compounds are exogenous substances that mimic endogenous hormones in the endocrine pathway. Bisphenol-A (BPA) is a chemical plasticizer and xenoestrogen used in the production of polycarbonate plastics and epoxy resins. Human exposure to BPA is ubiquitous at low levels and occurs primarily through the diet. Studies in our laboratory and other investigators have shown that exposure of rodents to BPA during pregnancy results in increased adiposity and impaired glucose tolerance in adulthood. An important mechanism for in utero and early developmental effects of BPA is thought to be altered epigenetic regulation of gene expression. In support of this hypothesis is our preliminary data in mouse that BPA exposure during pregnancy results in loss of imprinting at two genes critical for development and obesity, Igf2 and Snrpn, in the embryo and placenta. These findings lead us to hypothesize that BPA exposure during development alters the epigenetic profile in key cells including the germline, resulting in altered gene expression, an abnormal phenotype, and transgenerational transmission of the phenotype. Other than the placenta, we cannot obtain target tissues such as islets, liver, or fat from humans during development. Thus an animal model can provide insight into mechanisms that can be later explored in the human. We propose the following specific aims: Specific Aim 1 will assess the epigenome of F1 offspring exposed to BPA in utero as well as the F2-F3 generations. In addition to testing the expression and DNA methylation of imprinted genes, we will assay genome-wide DNA methylation changes and key histone modifications in F1-F3 offspring. The F1-F3 generations will also be metabolically phenotyped and germline of F2 and F3 epigenetically assayed. Specific Aim 2 will ascertain whether BPA exposure of males during puberty and early adulthood alters the germline and leads to transgenerational transmission of an altered epigenotype and abnormal phenotype. In Specific Aim 3 we will determine whether low dose BPA exposure in combination with DEHP, and vinclozolin alters the epigenome in the germline and leads to transgenerational transmission of an abnormal phenotype. Through the comprehensive analyses in the in vivo model, the results of the proposed project will build a solid standard for extrapolation of effects and mode of action to other classes of endocrine disrupting chemicals that are present in food and are identified as potential inducers of obesity and related metabolic diseases later in life. The proof of the principle of prenatal programming by environmental contaminants may change our awareness of critical assessment of the risk of such compounds.