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

发育性铅暴露对心脏分化的性别特异性代谢和表观遗传编程。

• 批准号: 10246462
• 负责人: Laurie Kathleen Svoboda
• 金额: $ 15.59万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-25 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10246462
• 关键词: 3-Dimensional; Action Potentials; Acute; Adult; Adult Children; Affect; Animal Model; Antioxidants; Area; Attention; Behavioral; Bioinformatics; Cardiac; Cardiac Myocytes; Cardiac development; Cardiac health; Cardiovascular Diseases; Cardiovascular system; Cell Differentiation process; Cells; Cessation of life; Clinical; Coupled; Cues; DNA Methylation; Data; Development; Dose; Environmental Exposure; Environmental Health; Environmental Pollution; Epigenetic Process; Equilibrium; Etiology; Exhibits; Female; Fluorescence; Functional disorder; Gene Expression; Glutathione; Goals; Heart; Heart Diseases; Heavy Metals; Heritability; Human; Incidence; Intervention; Lactation; Lead; Life; Link; Liquid Chromatography; Mass Spectrum Analysis; Measures; Mediator of activation protein; Mentored Research Scientist Development Award; Metabolic; Metabolic Pathway; Metabolism; Mitotic; Modeling; Modification; Molecular; Morbidity - disease rate; Mus; Nutritional; Optics; Outcome; Oxidation-Reduction; Pathogenesis; Patients; Perinatal; Pharmacology; Play; Predisposition; Pregnancy; Process; Prognosis; Protocols documentation; Public Health; Reactive Oxygen Species; Reduced Glutathione; Research; Research Personnel; Role; Sex Differences; Source; Testing; Toxicant exposure; Training; United States; base; building materials; cancer cell; cardiovascular disorder risk; cardiovascular effects; cardiovascular health; career; design; disability; drinking water; heart cell; heart function; human model; induced pluripotent stem cell; lead exposure; male; mortality; mouse model; novel; offspring; oxidation; programs; self assembly; sex; stem cell biology; stem cell differentiation; stem cell model; stem cells; toxicant; transcriptome sequencing; urban area; 3-Dimensional; Action Potentials; Acute; Adult; Adult Children; Affect; Animal Model; Antioxidants; Area; Attention; Behavioral; Bioinformatics; Cardiac; Cardiac Myocytes; Cardiac development; Cardiac health; Cardiovascular Diseases; Cardiovascular system; Cell Differentiation process; Cells; Cessation of life; Clinical; Coupled; Cues; DNA Methylation; Data; Development; Dose; Environmental Exposure; Environmental Health; Environmental Pollution; Epigenetic Process; Equilibrium; Etiology; Exhibits; Female; Fluorescence; Functional disorder; Gene Expression; Glutathione; Goals; Heart; Heart Diseases; Heavy Metals; Heritability; Human; Incidence; Intervention; Lactation; Lead; Life; Link; Liquid Chromatography; Mass Spectrum Analysis; Measures; Mediator of activation protein; Mentored Research Scientist Development Award; Metabolic; Metabolic Pathway; Metabolism; Mitotic; Modeling; Modification; Molecular; Morbidity - disease rate; Mus; Nutritional; Optics; Outcome; Oxidation-Reduction; Pathogenesis; Patients; Perinatal; Pharmacology; Play; Predisposition; Pregnancy; Process; Prognosis; Protocols documentation; Public Health; Reactive Oxygen Species; Reduced Glutathione; Research; Research Personnel; Role; Sex Differences; Source; Testing; Toxicant exposure; Training; United States; base; building materials; cancer cell; cardiovascular disorder risk; cardiovascular effects; cardiovascular health; career; design; disability; drinking water; heart cell; heart function; human model; induced pluripotent stem cell; lead exposure; male; mortality; mouse model; novel; offspring; oxidation; programs; self assembly; sex; stem cell biology; stem cell differentiation; stem cell model; stem cells; toxicant; transcriptome sequencing; urban area

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.

抽象的： 心血管疾病（CVD）是全球发病率和死亡率的主要原因，并且有 其发病率，病理生理学和预后的性别差异很大。积累的证据表明 早期毒性暴露在CVD的病因中的重要作用；但是，分子机制 这些关联的基础尚不清楚。特别是，性的作用是易感性的决定因素 有毒物质引起的心血管健康作用仍然鲜为人知。 PB暴露继续构成A 重要的公共卫生问题，尤其是在城市贫困地区。围产期和成人暴露于PB 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 早期的PB暴露可能会影响CVD的长期风险是通过破坏精确的 统治正常心脏发展的表观遗传学计划。癌症和干细胞生物学的最新研究 证明表观遗传变化和细胞分化紧密耦合到代谢状态 the cell, enabling cells to detect, and rapidly respond to, environmental cues.值得注意的是，来自雄性的干细胞 女性捐助者在分化程序中表现出内在差异，以及对 有毒的暴露。尽管PB暴露对心脏功能有已知的影响，但发育性PB的影响 心脏发展过程中表观遗传和代谢程序的暴露以及潜在的性别差异 在这些效果中，尚未研究。使用已建立的围产期环境的鼠标模型 暴露于暴露，我们最近发现发育性PB暴露会导致性别特定的变化 成年后代小鼠心脏中的DNA甲基化。我们进一步发现了PB暴露的心 小鼠表现出谷胱甘肽的氧化显着增加，谷胱甘肽是一种细胞抗氧化剂和代谢物的氧化 与表观遗传编程和干细胞分化紧密耦合。这些结果表明围产期 PB暴露可能会以性别特异性的方式破坏心脏中正常的代谢和表观遗传程序。 使用男性和女性捐助者的人类衍生的患者诱导的多能细胞（IPSC） 该建议是阐明PB引起的人类编程的确切分子机制 心脏分化和功能，并了解性别差异如何影响对此的敏感性 毒物。人IPSC衍生的心肌细胞的初步研究表明急性PB暴露 促进剂量依赖性的动作潜力持续时间增加，这表明PB可能具有 心律失常作用，并证明了该模型评估PB诱导心脏影响的实用性 功能。本K01提案中概述的培训和研究将为 开发成功的R01应用程序和作为独立研究者有影响力的职业 环境健康领域正在研究。