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: 10398836
• 负责人: BRUCE BLUMBERG
• 金额: $ 58.46万
• 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 2023-07-04
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10398836
• 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; Structure of primordial sex cell; Testing; Time; Tissue-Specific Gene Expression; 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; obesity prevention; obesogen; offspring; pregnant; prenatal; prenatal exposure; prevent; rapid weight gain; sexual dimorphism; sperm cell; 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.

项目概要 动物模型研究表明，直接接触内分泌干扰物 (EDC) 与 许多群体已经证明了这种疾病在暴露者的后代中发病。 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充分的支持，但遗传的概念 DNA序列变化的缺失是有争议的，因为潜在的机制尚未被阐明。 如果我们不知道环境暴露是如何跨代遗传的。 传播，我们如何将这些化学物质对疾病负担的影响纳入风险评估 我们如何确定哪些化学品可能具有充分保护公众健康的范式？ 跨代效应？我们开发了怀孕 F0 时的肥胖跨代模型。 通过饮用水给予雌性小鼠环境相关 (nM) 剂量的 TBT，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， 即使采用低脂饮食，怀孕 F0 母鼠的雄性 F4 后代在整个妊娠期间都接受 TBT 治疗。 形成了跨代的“节俭表型”：他们在禁食期间抵抗脂肪减少，迅速增加脂肪 当膳食脂肪适度增加时，尽管恢复到正常的低体重水平，但仍保留这种脂肪 我们发表的初步结果使我们提出了一种新的跨代遗传模型。 - 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 区块和重要代谢基因的差异表达，包括饱腹感 我们提出了一系列全面的实验来检验 TBT 的假设。 通过改变通过生殖细胞传递的染色质结构来诱导跨代肥胖 我们提出以下具体目标来检验这一新假设： 目标 1：确定 生殖细胞中接触 TBT 会引起基因组结构发生哪些变化以及这些变化是如何传播的 目标 2：性腺体细胞在跨代表型中的作用是什么。 3：祖先的 TBT 暴露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异性的？ 机制将极大地提高我们对基因与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，并将提供关于如何 肥胖是可以预防的，肥胖的流行趋势可以得到遏制——这是一个重要而及时的公共卫生问题。