Transgenerational inheritance of prenatal obesogen exposure

产前肥胖原暴露的跨代遗传

基本信息

批准号：
9321823
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
项目类别：
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/9321823
关键词：
Address Adipocytes Adipose tissue Adolescence Adult Affect Animal Model Animals Biological Cell Compartmentation Cells Chemical Exposure Chromatin Structure DNA DNA Methylation Data Development Discipline of Nursing Drug Exposure Endocrine Disruptors 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 Histone H3 Individual Learning Life Mammals Measures Mediating Memory Mesenchymal Stem Cells Metabolic Modeling Modification Mus Mutation Nurses Obesity Obesity associated disease Osteocytes PPAR gamma Pathway interactions Phenotype Predisposition Process Public Health Publishing Reproducibility 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 public health relevance response sperm cell stem cell fate transcription factor transcriptomics transgenerational epigenetic inheritance tributyltin

项目摘要

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，涉及产前和产后早期事件，例如母体营养、药物和化学品暴露。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。有证据支持环境因素在肥胖中发挥重要作用，其中之一是接触内分泌干扰化学物质 (EDC)，我们发表的研究表明，三丁基锡 (TBT) 是一种环境“致肥胖因素”，易导致子宫内 TBT 接触导致体重增加。这些数据支持这样的模型：TBT 通过调节哺乳动物脂肪细胞分化的“主调节器”——过氧化物酶体而发挥不适当的作用。我们发表的初步结果表明，产前 TBT 暴露会通过以骨为代价将多能间充质干细胞 (MSC) 转移到脂肪细胞谱系来改变它们的命运，并且这种重编程是跨代的。 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 F0 暴露后至少持续到 F3 代。我们发现，产前暴露于 TBT 会在 MSC 区室的记忆中进行表观遗传，从而将 MSC 重新编程为成脂谱系，远离成骨谱系。我们提出了三个具体目标来检验这一假设： 1) 产前 TBT 暴露对哪些基因进行表观遗传修饰，从而引起 MSC 中的表达改变，从而以成骨细胞谱系为代价促进脂肪细胞谱系的形成 2) TBT 如何发挥作用？对 MSC 中的谱系分配产生跨代影响？，3）TBT 暴露的产后影响是由表观遗传改变介导的吗？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。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。