Sex-Specific Metabolic and Epigenetic Programming of Cardiac Differentiation by Developmental Lead Exposure.

摘要： 心血管疾病（CVD）是世界范围内发病率和死亡率的主要原因， 其发病率、病理生理学和预后存在显著的性别差异。越来越多的证据表明 早期生命毒物暴露在CVD病因中的重要作用;然而， 这些关联的基础尚不清楚。特别是，性别作为易感性的决定因素， 对毒物引起的心血管健康影响仍然知之甚少。铅暴露继续构成 严重公共卫生问题，特别是在贫穷的城市地区。围产期和成人铅暴露是 与人类和动物模型中的不良心血管效应相关。一个重要的机制， 早期铅暴露可能影响心血管疾病的长期风险是通过破坏精确的 控制正常心脏发育的表观遗传程序。癌症和干细胞生物学的最新研究 表明表观遗传变化和细胞分化与代谢状态密切相关， 细胞，使细胞能够检测，并迅速作出反应，环境线索。值得注意的是，男性干细胞 和女性捐赠者表现出内在的差异，在分化程序，以及不同的敏感性， 毒物暴露尽管已知铅暴露对心脏功能的影响，但发育期铅的影响 暴露于心脏发育过程中的表观遗传和代谢编程，以及潜在的性别差异 在这些影响中，还没有被调查。利用已建立的围产期环境污染小鼠模型， 暴露，我们最近发现，发育铅暴露导致性别特异性的变化， 成年小鼠心脏中的DNA甲基化。我们进一步发现， 小鼠表现出谷胱甘肽氧化的显著增加，谷胱甘肽是一种细胞抗氧化剂和代谢物， 与表观遗传编程和干细胞分化密切相关。这些结果表明，围产期 铅暴露可能以性别特异性方式破坏心脏中的正常代谢和表观遗传编程。 使用来自男性和女性供体的人类患者来源的诱导多能干细胞（iPSC）， 这一建议旨在阐明铅诱导的人类编程的精确分子机制。 心脏的分化和功能，并了解性别差异如何影响这种易感性， 有毒物质在人iPSC衍生的心肌细胞中的初步研究表明，急性铅暴露 促进动作电位时程的剂量依赖性增加，表明铅可能具有 结果表明，该模型可用于评估铅对心脏的影响， 功能本K01提案中概述的培训和研究将为以下方面提供一个出色的框架： 开发成功的R01应用程序和作为独立调查员的有影响力的职业生涯， 环境健康的未充分研究领域。

Abstract: Cardiovascular diseases (CVDs) are a major cause of morbidity and mortality world-wide, and there are significant sex differences in their incidence, pathophysiology, and prognosis. Accumulating evidence suggests an important role for early-life toxicant exposures in the etiology of CVDs; however, the molecular mechanisms underlying these associations are unclear. In particular, the role for sex as a determinant of susceptibility to toxicant-induced cardiovascular health effects remains poorly understood. Pb exposure continues to pose a significant public health concern, particularly in poor urban areas. Perinatal and adult exposure to Pb are associated with adverse cardiovascular effects in human and animal models. One important mechanism by which early Pb exposure may influence the long-term risk of CVDs is through disruption of the precise epigenetic programs governing normal cardiac development. Recent studies in cancer and stem cell biology demonstrate that epigenetic changes and cellular differentiation are closely coupled to the metabolic state of the cell, enabling cells to detect, and rapidly respond to, environmental cues. Notably, stem cells from male and female donors exhibit intrinsic differences in differentiation programs, as well as differential sensitivity to toxicant exposures. Despite known impacts of Pb exposure on heart function, the effects of developmental Pb exposure on epigenetic and metabolic programming during cardiac development, and potential sex differences in these effects, have not been investigated. Using an established mouse model of perinatal environmental exposures, we have recently discovered that developmental Pb exposure leads to sex-specific changes in DNA methylation in the hearts of adult offspring mice. We have further discovered that hearts of Pb-exposed mice exhibit a significant increase in the oxidation of glutathione, a cellular antioxidant and metabolite that is closely coupled to epigenetic programming and stem cell differentiation. These results suggest that perinatal Pb exposure may disrupt normal metabolic and epigenetic programming in the heart in a sex-specific manner. Using human patient-derived induced pluriopotent stem cells (iPSCs) from male and female donors, the goal of this proposal is to elucidate the precise molecular mechanisms underlying Pb-induced programming on human cardiac differentiation and function, and to understand how sex differences may influence susceptibility to this toxicant. Preliminary studies in human iPSC-derived cardiomyocytes demonstrate that acute Pb exposure promotes a dose-dependent increase in action potential duration, suggesting that Pb may have arrhythmogenic effects, and demonstrating the utility of this model to assess Pb-induced effects on cardiac function. The training and research outlined in this K01 proposal will provide an outstanding framework for the development of a successful R01 application and an impactful career as an independent investigator in this understudied area of environmental health.