Transgenerational inheritance of prenatal obesogen exposure

描述(申请人提供)：这是一份R01申请，是对RFA-ES-12-006“环境暴露后哺乳动物的跨代遗传”的回应。出生前和出生后早期的事件，如母亲的营养、药物和化学物质暴露，被接受、记住，然后在以后的生活中表现为健康后果。在美国，肥胖流行病每年造成与肥胖相关疾病相关的额外医疗费用超过2080亿美元。越来越多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物(EDCs)。我们发表的研究发现，三丁基锡(TBT)是一种环境“肥胖源”，容易使暴露于环境中的人体重增加。在子宫内接触TBT会导致长期代谢功能障碍，增加脂肪堆积，增加肥胖风险。这些数据支持TBT通过不适当地调节哺乳动物脂肪细胞分化的“主调节器”--过氧化体增殖物激活受体--γ(PPAR？)信号通路。我们已发表的和初步的结果显示，产前TBT暴露改变了多潜能间充质干细胞(MSCs)的命运，将它们转移到脂肪细胞系，以牺牲骨骼为代价，这种重新编程是跨代的，至少在F0暴露后持续到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的，启动子的表观遗传修饰导致关键的PPAR？靶基因。我们假设，出生前暴露于TBT是在表观遗传学上铭刻在MSC间隔室的记忆中，重新编程MSCs朝向成脂而远离成骨谱系。为了验证这一假说，人们提出了三个具体的目标：1)出生前TBT暴露引起哪些基因的表观遗传修饰，从而引起MSCs表达的改变，从而以成骨谱系为代价促进脂肪细胞的谱系；2)TBT如何对MSCs的谱系分配产生跨代影响？3)TBT暴露的出生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。这项拟议的工作将提供对TBT(以及可能的其他致肥源)如何跨代作用以重新规划MSC命运的深入理解，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.