Transgenerational inheritance of prenatal obesogen exposure

描述（由申请人提供）：这是为响应RFA-ES-12-006“环境暴露后哺乳动物的跨代遗传”而提交的R 01申请。产前和产后早期的事件，如产妇营养，药物和化学品接触，接收，记住，然后在以后的生活中表现出健康后果。在美国，肥胖流行病每年花费超过2080亿美元用于与肥胖相关疾病相关的额外医疗保健费用。新出现的证据支持环境因素在肥胖中的重要作用。其中之一是接触内分泌干扰化学品（EDCs）。我们已发表的工作确定三丁基锡（TBT）是一种环境“肥胖原”，易使暴露个体体重增加。在子宫内接触三丁基锡化合物会导致长期的代谢功能障碍、脂肪积累增加和肥胖风险增加。这些数据支持三丁基锡化合物通过不适当调节哺乳动物脂肪细胞分化的“主调节因子”--过氧化物酶体增殖物激活受体γ（过氧化物酶体增殖物激活受体？）信号通路我们发表的初步结果表明，产前TBT暴露改变了多能间充质干细胞（MSC）的命运，将它们转移到脂肪细胞谱系，以牺牲骨骼为代价，这种重编程是跨代的，在F0暴露后至少持续到F3代。三丁基锡化合物暴露的影响的跨代遗传表明，这些影响是表观遗传和永久性的，表观遗传修饰的启动子导致上调的一个关键的过氧化物酶体增殖物激活受体？靶基因我们推测，产前暴露于TBT是表观遗传刻在记忆中的MSC隔间，重编程MSC向成脂和远离成骨谱系。提出了三个具体的目标来检验这一假设：1）哪些基因被产前TBT暴露的表观遗传学修饰，以引起MSC中的表达改变，从而以牺牲成骨谱系为代价促进脂肪细胞谱系？2)TBT如何对MSC的谱系分配产生跨代影响？3)三丁基锡化合物暴露的产后效应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学分析来解决这些问题。拟议的工作将提供一个深入的了解TBT（和可能的其他肥胖）的行为如何transgeneratively重新编程MSC的命运，并将确定TBT暴露的关键发育窗口。

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 (PPAR?) 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 PPAR? 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.