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

祖先在子宫内接触致肥胖物质引起的跨代肥胖：种系基因组结构的变化、性腺体细胞的作用以及性二态性的代谢组学分析

• 批准号: 9753239
• 负责人: BRUCE BLUMBERG
• 金额: $ 59.64万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9753239
• 关键词: ATAC-seq; Address; Adipose tissue; Affect; Animal Model; Animals; Architecture; Chemical Exposure; Chemicals; Chromatin; Chromatin Structure; DNA; DNA Methylation; DNA Sequence; DNA Sequence Alteration; Diet; Dietary Fats; Dose; Embryo; Endocrine Disruptors; Environmental Exposure; Epididymis; Epigenetic Process; Event; Exposure to; Fasting; Fat-Restricted Diet; Fatty acid glycerol esters; Female; Gene Expression; Generations; Genes; Genomics; Germ Cells; Goals; Gonadal structure; Heritability; High Fat Diet; Hormones; Human; In Vitro; Individual; Investigation; Knowledge; Laboratories; Leptin; Link; Literature; Liver; Maps; Metabolic; Metabolic Pathway; Modeling; Molecular; Mus; Obesity; Obesity Epidemic; Onset of illness; Phenotype; Play; Pregnancy; Public Health; Publishing; Reproducibility; Research; Resistance; Risk Assessment; Role; Satiation; Series; Somatic Cell; Structure of primordial sex cell; Testing; Time; Tissue-Specific Gene Expression; Weight Gain; base; burden of illness; cost; design; differential expression; disease phenotype; drinking water; epigenomics; experimental study; gene environment interaction; genome-wide; improved; in utero; in vivo; innovation; insight; lipid biosynthesis; male; metabolome; metabolomics; multiple omics; nanomolar; non-genetic; novel; obesogen; offspring; pregnant; prenatal; prenatal exposure; prevent; sexual dimorphism; sperm cell; structural genomics; transcriptome; transgenerational epigenetic inheritance; tributyltin

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.

项目摘要 在动物模型中的研究已经将直接暴露于内分泌干扰化学品（EDCs）与 在接触者的后代中发病。许多团体已经证明， 化学品暴露的跨代影响，这被认为是表观遗传的例子。 虽然跨代效应在文献中得到了大量的支持，但 缺乏DNA序列的变化是有争议的，因为根本的机制还没有被发现。 满意的解释。如果我们不知道环境暴露的跨代遗传是如何进行的， 我们如何将这些化学品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 跨代效应？我们开发了一个跨代肥胖模型。妊娠F0时 雌性小鼠通过饮用水、增加的脂肪、 至少在接下来的四代后代（F1-F4代）中可以检测到积累， 即使是低脂饮食在整个妊娠期间接受三丁基锡化合物处理的妊娠F0代母鼠的雄性F4代后代 发展出一种跨代的“节俭表型”：他们在禁食期间抵抗脂肪减少， 当膳食脂肪适度增加时，尽管恢复到正常的低水平， 高脂肪饮食。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TBT暴露改变了染色质结构和可及性，导致区域性变化 甲基化DNA块和重要代谢基因的差异表达，包括饱腹感 荷尔蒙，瘦素。我们提出了一个全面的系列实验，旨在检验假设，技术性贸易壁垒 通过改变染色质结构诱导跨代肥胖，染色质结构通过生殖细胞传递， 后代。我们提出了以下具体目标来测试这一新的假设：目标1：识别 生殖细胞中的三丁基锡化合物暴露会引起哪些基因组结构变化，以及这些变化是如何传播的 下一代。目的2：性腺体细胞在跨代表型中的作用。目的 3：祖先的三丁基锡化合物暴露在代谢组中引起了什么变化，这些变化能否用于确定 为什么跨代肥胖表现型似乎是男性特有的？描绘这些分子 这些机制将大大提高我们对基因-环境相互作用的认识，为风险奠定基础。 评估，包括跨代效应的贡献，并将提供如何深入了解 肥胖症是可以预防的，肥胖症的流行也可以减少-这是一个重要和及时的公共卫生问题。