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，在子宫和发育早期接触环境化学物质可能会在日后肥胖和相关代谢性疾病的发展中发挥作用。内分泌干扰物是在内分泌途径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异种雌激素，用于生产聚碳酸酯塑料和环氧树脂。人类在低水平下对双酚A的接触是无处不在的，主要通过饮食发生。我们实验室和其他研究人员的研究表明，在怀孕期间接触双酚A会导致成年后肥胖增加和糖耐量受损。双酚A在子宫内和早期发育作用的一个重要机制被认为是改变了基因表达的表观遗传调节。支持这一假设的是我们在小鼠身上的初步数据，即怀孕期间暴露于BPA会导致胚胎和胎盘中对发育和肥胖至关重要的两个基因--Igf2和Snrpn--印记的丢失。这些发现使我们假设，在发育过程中暴露于双酚A会改变包括生殖系在内的关键细胞的表观遗传学特征，从而导致改变 基因表达，一种异常的表型，以及表型的跨代传递。除了胎盘，我们不能在发育过程中从人类获得目标组织，如胰岛、肝脏或脂肪。因此，动物模型可以为后来在人类身上探索的机制提供洞察力。我们提出了以下具体目标：具体目标1将评估宫内暴露于双酚A的F1后代以及F2-F3代的表观基因组。除了测试印记基因的表达和DNA甲基化，我们还将分析F1-F3后代全基因组DNA甲基化变化和关键的组蛋白修饰。还将对F1-F3代进行代谢表型分析，并对F2和F3进行表观遗传学分析。具体目标2将确定男性在青春期和成年期早期接触双酚A是否会改变生殖系，并导致改变的表观类型和异常表型的跨代传播。在特定的目标3中，我们将确定低剂量BPA联合DEHP和长春花碱是否会改变生殖系中的表观基因组，并导致异常表型的跨代传递。通过体内模型的全面分析，拟议项目的结果将建立一个可靠的标准，用于推断对食物中存在的其他类别的内分泌干扰化学物质的影响和作用模式，这些化学物质被确定为肥胖和相关代谢疾病的潜在诱因。环境污染物对产前规划原则的证明可能会改变我们对这类化合物风险的关键评估的认识。

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.