Project 3: Developmental Exposures and Diet: Epigenetics of Metabolic Syndrome

流行病学和动物研究现在已经确定， 胚胎发育在晚年的疾病易感性中起关键作用。此外，这种暴露 在怀孕期间，通过表观遗传学与随后的疾病形成直接相关。 机制等然而，很少有研究考虑到围产期和青春期的综合影响， 暴露对生命过程代谢综合征风险和生殖发育的影响。利用现有的 围产期暴露的小鼠模型，重点是双酚A（BPA），邻苯二甲酸酯和铅（Pb）， 代表性毒物，我们专注于围产期和青春期暴露对后代的影响 代谢状态和表观遗传基因调控。具体来说，我们将调查围产期暴露是否 BPA/邻苯二甲酸盐/铅混合物导致表观遗传改变并破坏生命过程生理状态， 可通过饮食和持续的青春期暴露来改变的事件。首先，利用我们的 生理相关母体毒物水平的小鼠模型，我们将评估妊娠和 出生后高脂饮食改变了围产期BPA或Pb暴露对生命过程生理的影响 参数第二，我们将使用复杂的小鼠表型来检查围产期的关系， 和青春期前后暴露于化学混合物对代谢和生殖状况的影响，并确定 表观遗传不稳定基因对代谢平衡和激素调节很重要。最后，动物模型 很好地阐明了暴露、表观遗传组织特异性和时间依赖性之间的复杂关系。 表观遗传漂变因此，我们将进行公正的谱系特异性全甲基化组，转录组， 和多个时间点的组蛋白标记分析。这些全面研究的结果将阐明 组织特异性和随年龄漂移的问题，进行表观遗传流行病学研究的固有复杂性， 问题研究从这个项目的知识是至关重要的破译的作用，表观遗传编程的早期 疾病发病机制中的暴露，包括代谢综合征和生殖成功，以及 发展新的基于表观遗传学的人类疾病诊断和治疗策略。

Epidemiological and animal studies now firmly establish that environmental exposures during eariy embryonic development play a critical role in disease susceptibility in later-life. Moreover, such exposures during gestation have been directly linked with subsequent disease formation through epigenetic mechanisms. Little research, however, has considered the combined effects of perinatal and peripubertal , exposures on life course metabolic syndrome risk and reproductive development. Utilizing an established mouse model of perinatal exposures and focusing on bisphenol A (BPA), phthalates, and lead (Pb) as representative toxicants, we focus on the influence of perinatal and peripubertal exposures on offspring metabolic status and epigenetic gene regulation. Specifically, we will investigate whether perinatal exposure to BPA/phthalates/Pb mixture results in epigenetic alterations and disrupts life course physiologic status, events that are subject to modification by diet and continued peripubertal exposure. First, capitalizing on our mouse models of physiologically relevant maternal toxicant levels, we will assess whether pregnancy and postnatal high-fat diet modifies the effects of perinatal BPA or Pb exposure on life course physiological parameters. Second, we will use sophisticated mouse phenotyping to examine the relationship of perinatal and peripubertal exposure to chemical mixtures on metabolic and reproductive status and identify key epigenetic labile genes important for metabolic homeostasis and hormonal regulation. Finally, animal models are well-poised to elucidate complex relationships among exposures, epigenetic tissue specificity, and timedependent epigenetic drift. Thus, we will conduct unbiased lineage specific whole methylome, transcriptome, and histone mark analysis at multiple time points. Results of these comprehensive studies will elucidate issues of tissue specificity and drift with age, inherent complexities in conducting epigenetic epidemiological studies. Knowledge from this project is crucial for deciphering the role of epigenetic programming by early exposures in the pathogenesis of diseases, including metabolic syndrome and reproductive success, and for the development of novel epigenetic-based diagnostic and therapeutic strategies for human diseases.