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 动物模型的研究已将直接暴露与内分泌破坏化学物质（EDC）联系起来 暴露个人后代的疾病发作。许多小组已经证明了 化学暴露的跨代作用，被认为是表观遗传的例子。 尽管变革效应在文献中得到了大量支持，但继承的概念 缺乏DNA序列变化是有争议的，因为潜在机制尚未 令人满意地解释了。如果我们不知道环境暴露的变革性继承如何 传输，我们如何将这些化学物质对疾病燃烧的影响纳入风险评估 充分保护公共卫生的范例？我们如何确定哪些化学物质可能具有 跨代效应？我们已经开发了肥胖症的转型模型。怀孕时F0 雌性小鼠通过饮用水与环境相关（NM）剂量的TBT治疗，脂肪增加 至少可以在接下来的四代后代（F1-F4代）中检测到累积 即使是低脂饮食。在妊娠期间用TBT处理的孕妇F0大坝的雄性F4后代 开发了转世的“节俭表型”：它们在禁食期间对脂肪损失有抵抗力，迅速获得 当饮食脂肪适度增加并保留此脂肪目的地时，体重将恢复到正常，低 - 脂肪饮食。我们发表的初步结果使我们提出了一种新的变革性继承模型 - 产前TBT暴露改变了染色质结构和可及性，导致区域变化 重要代谢基因的甲基化DNA块和差异表达，包括饱腹感 激素，瘦素。我们提出了一系列全面的实验，旨在测试TBT的假设 通过改变染色质结构来诱导转世肥胖，该结构通过生殖细胞传播到 随后的几代。我们提出以下特定目的旨在检验这一新假设：目标1：确定 TBT暴露在生殖细胞中引起了基因组结构的变化，以及它们如何传播 下一代。目标2：性腺体细胞在转化表型中的作用是什么？目的 3：祖先TBT暴露会发生什么变化，可以用来确定这些变化 为什么转化的肥胖表型似乎是男性特异性的？描绘这些分子 机制将极大地了解我们对基因环境相互作用的了解，应为风险奠定基础 评估包括变革效应的贡献，并将提供有关如何 可以预防肥胖症，并限制肥胖症流行 - 这是一个重要且及时的公共卫生问题。