Transgenerational inheritance of prenatal obesogen exposure

描述（由申请人提供）：这是根据RFA-ES-12-006“环境暴露后哺乳动物的跨代遗传”提交的R01申请。产前和产后早期的事件，如产妇营养、药物和化学品暴露，被接受、记住，然后在以后的生活中表现为健康后果。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费用。新出现的证据支持环境因素在肥胖中扮演重要角色。其中之一就是接触内分泌干扰物（EDCs）。我们发表的研究表明，三丁基锡（TBT）是一种环境“致肥源”，使暴露在环境中的个体容易体重增加。在子宫内暴露于TBT会导致长期代谢功能障碍、脂肪积累增强和肥胖风险增加。这些数据支持了TBT通过不适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)信号通路起作用的模型。我们发表的和初步的研究结果表明，产前TBT暴露会改变多能间充质干细胞（MSCs）的命运，通过将它们转移到脂肪细胞谱系而牺牲骨骼，并且这种重编程是跨代的，在F0暴露后至少持续到F3代。TBT暴露影响的跨代遗传表明，这些影响是表观遗传的和永久性的，启动子的表观遗传修饰导致一个关键的PPARγ靶基因的上调。我们假设，产前暴露于TBT在表观遗传上铭刻在间充质干细胞室的记忆中，使间充质干细胞重编程，使其远离成骨谱系，向成脂性方向发展。为了验证这一假设，提出了三个具体目标：1)哪些基因通过产前TBT暴露被表观遗传修饰，从而引起MSCs中表达的改变，从而促进脂肪细胞谱系，而牺牲成骨细胞谱系？2) TBT如何对间充质干细胞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学、表观基因组学和转录组学分析来解决这些问题。这项工作将深入了解TBT（以及其他可能的肥胖源）如何跨代作用于MSC命运重编程，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 (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.