Transgenerational inheritance of prenatal obesogen exposure

产前肥胖原暴露的跨代遗传

• 批准号: 9116209
• 负责人: BRUCE BLUMBERG
• 金额: $ 67.03万
• 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 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9116209
• 关键词: Address; Adipocytes; Adipose tissue; Adolescence; Adult; Affect; Animal Model; Animals; Biological; Cells; Chemical Exposure; Chromatin Structure; DNA; DNA Methylation; Data; Development; Discipline of Nursing; Endocrine Disruptors; Engravings; Environmental Exposure; Environmental Risk Factor; Epidemic; Epigenetic Process; Event; Exposure to; Fatty acid glycerol esters; Fetus; Functional disorder; Future; Gene Expression; Gene Targeting; Generations; Genes; Genetic; Genome; Genomic DNA; Genomics; Goals; Health; Health Care Costs; Healthcare Systems; Individual; Learning; Life; Mammals; Measures; Mediating; Memory; Mesenchymal Stem Cells; Metabolic; Modeling; Modification; Mus; Mutation; Obesity; Obesity associated disease; Osteocytes; PPAR gamma; Pathway interactions; Pharmaceutical Preparations; Predisposition; Process; Public Health; Publishing; Research; Role; Signal Pathway; Specimen; Stem cells; Technology; Testing; Time; Transcriptional Regulation; Up-Regulation; Weight Gain; Work; adipocyte differentiation; base; bone; cost; deep sequencing; differential expression; early life exposure; environmental chemical; epigenetic regulation; epigenomics; genome analysis; histone modification; in utero; innovation; lipid biosynthesis; male; mother nutrition; novel; obesity risk; obesogen; obesogenic; offspring; osteogenic; postnatal; pregnant; prenatal; prenatal exposure; prevent; programs; promoter; response; sperm cell; stem cell fate; transcription factor; transcriptomics; transgenerational epigenetic inheritance; tributyltin

DESCRIPTION (provided by applicant): This is an R01 application submitted in response to RFA-ES-12-006, "Transgenerational Inheritance in Mammals after Environmental Exposure". Prenatal and early postnatal events such as maternal nutrition, drug, and chemical exposure are received, remembered, and then manifested in health consequences later in life. The obesity epidemic costs more than $208 billion annually in the US in additional health care costs associated with obesity-related diseases. Emerging evidence supports an important role for environmental factors in obesity. Among these is exposure to endocrine disrupting chemicals (EDCs). Our published work identified tributyltin (TBT) as an environmental "obesogen" that predisposes exposed individuals to weight gain. In utero TBT exposure leads to long-term metabolic dysfunctions, enhanced fat accumulation, and increased risk of obesity. These data support the model that TBT acts via inappropriate modulation of the "master regulator" of mammalian adipocyte differentiation - the peroxisome proliferator activated receptor gamma (PPARγ) signaling pathway. Our published and preliminary results reveal that prenatal TBT exposure alters the fate of multipotent mesenchymal stem cells (MSCs) by diverting them to an adipocyte lineage at the expense of bone and that this reprogramming is transgenerational, persisting through at least the F3 generation after F0 exposure. The transgenerational inheritance of the effects of TBT exposure suggests that these effects are epigenetic and permanent and that epigenetic modification of the promoter leads to up-regulation of a key PPARγ target gene. We hypothesize that prenatal exposure to TBT is epigenetically engraved in the memory of the MSC compartment, reprogramming MSCs toward the adipogenic and away from the osteogenic lineage. Three specific aims are proposed to test this hypothesis: 1) which genes are epigenetically modified by prenatal TBT exposure to elicit altered expression in MSCs that promotes the adipocyte lineage at the expense of the osteogenic lineage? 2) How does TBT exert transgenerational effects on lineage allocation in MSCs?, 3) Are postnatal effects of TBT exposure mediated by epigenetic alterations? We will use state-of-the-art genomic, epigenomic and transcriptomic analyses to address these questions. The proposed work will provide a deep understanding of how TBT (and likely other obesogens) act transgenerationally to reprogram MSC fate and will identify critical developmental windows for TBT exposure.

描述（由申请人提供）：这是针对 RFA-ES-12-006“环境暴露后哺乳动物的跨代遗传”提交的 R01 申请。产前和产后早期事件，例如孕产妇营养、药物和化学品暴露，会被接受、记住，然后在以后的生活中表现出健康后果。在美国，肥胖流行病每年造成与肥胖相关疾病相关的额外医疗费用超过 2080 亿美元。新的证据支持环境因素在肥胖中发挥重要作用。其中包括接触内分泌干扰化学物质（EDC）。我们发表的研究成果将三丁基锡 (TBT) 确定为一种环境“致肥胖物质”，使接触过的人容易体重增加。子宫内接触 TBT 会导致长期代谢功能障碍、增加脂肪积累并增加肥胖风险。这些数据支持这样的模型：TBT 通过不当调节哺乳动物脂肪细胞分化的“主调节器”——过氧化物酶体增殖物激活受体 γ (PPARγ) 信号通路来发挥作用。我们发表的初步结果表明，产前 TBT 暴露会改变多能间充质干细胞 (MSC) 的命运，通过以牺牲骨骼为代价将它们转移到脂肪细胞谱系，并且这种重编程是跨代的，至少持续到 F0 暴露后的 F3 代。 TBT 暴露影响的跨代遗传表明，这些影响是表观遗传的、永久性的，并且启动子的表观遗传修饰会导致关键 PPARγ 靶基因的上调。我们假设，产前接触 TBT 会通过表观遗传学的方式刻在 MSC 区室的记忆中，从而将 MSC 重新编程为成脂谱系，远离成骨谱系。提出了三个具体目标来检验这一假设：1）哪些基因通过产前 TBT 暴露进行表观遗传修饰，从而引起 MSC 中表达的改变，从而以成骨谱系为代价促进脂肪细胞谱系？ 2) TBT 如何对 MSC 中的谱系分配产生跨代影响？ 3) TBT 暴露的产后影响是否由表观遗传改变介导？我们将使用最先进的基因组、表观基因组和转录组分析来解决这些问题。拟议的工作将深入了解 TBT（以及可能的其他致肥胖因素）如何通过跨代行为重新编程 MSC 命运，并将确定 TBT 暴露的关键发育窗口。