Transgenerational obesity caused by ancestral exposure to obesogens in utero: changes in germline genomic architecture, roles of gonadal somatic cells, and metabolomic analysis of sexual dimorphism

项目总结 在动物模型中的研究已经将直接暴露于内分泌干扰物(EDCs)与 在受影响个人的后代中发病。许多团体已经证明了这一点 化学暴露的跨代效应，被认为是表观遗传的例子。 尽管跨代效应在文献中得到了实质性的支持，但在 没有DNA序列改变是有争议的，因为潜在的机制还没有 令人满意的解释。如果我们不知道环境暴露的跨代遗传是如何 如何将这些化学物质对疾病负担的影响纳入风险评估？ 充分保护公众健康的范例？我们如何确定哪些化学物质可能含有 代际效应？我们开发了一个肥胖的跨代模型。怀孕时F0 雌性小鼠通过饮用水接受与环境相关的(NM)剂量的TBT治疗，增加脂肪 至少在接下来的四代后代(F1-F4代)中可以检测到积累， 即使在低脂肪饮食中也是如此。妊娠F0代母猪的雄性F4后代在整个妊娠期间接受TBT治疗 形成了一种跨世代的“节俭表型”：他们对禁食期间的脂肪流失具有抵抗力，体重迅速增加 当饮食脂肪适度增加并保留这些脂肪时的体重，尽管恢复到正常的低水平- 肥胖饮食。我们发表的和初步的结果使我们提出了一个新的跨代遗传模型 -产前接触TBT改变了染色质结构和可及性，导致 DNA甲基化区块和重要代谢基因的差异表达，包括饱腹感 荷尔蒙，瘦素。我们提出了一系列全面的实验，旨在验证技术性贸易壁垒 通过改变通过生殖细胞传递的染色质结构来诱导代际肥胖 后代人。我们提出了以下具体目标来检验这一新假设：目标1：确定 TBT暴露在生殖细胞中会引起基因组结构的哪些变化以及这些变化是如何传播的 代代相传。目的2：性腺体细胞在跨代表型中的作用。目标 3：祖先接触TBT会在代谢组中引起什么变化？这些变化可以用来确定 为什么跨代肥胖表型似乎是男性特有的？描绘这些分子 机制将极大地提高我们对基因-环境相互作用的认识，应该为风险奠定基础 包括跨代影响的贡献的评估，并将提供关于如何 肥胖是可以预防和遏制的--这是一个重要和及时的公共卫生问题。

PROJECT SUMMARY Studies in animal models have linked direct exposures to endocrine disrupting chemicals (EDCs) with the onset of disease in descendants of the exposed individuals. Many groups have demonstrated such transgenerational effects of chemical exposures, which are proposed to be examples of epigenetic inheritance. Although transgenerational effects have substantial support in the literature, the concept of inheritance in the absence of DNA sequence changes is controversial because the underlying mechanisms have not been satisfactorily explained. If we do not know how transgenerational inheritance of environmental exposures is transmitted, how can we incorporate the effects of these chemicals on disease burden into risk assessment paradigms that adequately protect public health? How can we determine which chemicals may have transgenerational effects? We have developed a transgenerational model for obesity. When pregnant F0 female mice are treated with environmentally-relevant (nM) doses of TBT via their drinking water, increased fat accumulation can be detected in at least the next four generations of descendents (the F1-F4 generations), even on a low-fat diet. Male F4 descendents of pregnant F0 dams treated with TBT throughout gestation developed a transgenerational “thrifty phenotype”: they were resistant to fat loss during fasting, rapidly gained weight when dietary fat was increased modestly and retained this fat despite being returned to a normal, low- fat diet. Our published and preliminary results led us to propose a new model for transgenerational inheritance - that prenatal TBT exposure altered chromatin structure and accessibility, leading to regional changes in blocks of methylated DNA and differential expression of important metabolic genes, including the satiety hormone, leptin. We propose a comprehensive series of experiments designed to test the hypothesis that TBT induces transgenerational obesity by changing chromatin structure which is transmitted via the germ cells to subsequent generations. We propose the following Specific Aims to test this novel hypothesis: Aim 1: Identify what changes in genomic structure are elicited by TBT exposure in germ cells and how these are transmitted down the generations. Aim 2: What is the role of gonadal somatic cells in the transgenerational phenotype. Aim 3: What changes does ancestral TBT exposure elicit in the metabolome and can these be used to determine why the transgenerational obesity phenotype appears to be male-specific? Delineating these molecular mechanisms will greatly our knowledge of gene-environment interactions, should lay the groundwork for risk assessment that includes the contributions of transgenerational effects and will provide insights into how obesity can be prevented and the obesity epidemic curtailed - an important and timely public health issue.