Perfluroalkylated Substances Exposures and Cytotrophoblast Differentiation

项目概要/摘要。 本项目的目标是检验全氟烷基化物质（PFAS） 影响胎盘的形成，从而影响妊娠结局。这项工作增加了意义 鉴于公众对这些持久性化合物的关注日益增加。拟议 实验还将填补我们对这些化学物质在人类发育过程中的影响的认识空白。 胎盘发育，对此知之甚少。怀孕的母亲会接触到各种各样的化学物质， 包括PFAS。后一种接触很普遍，高水平与对甲状腺的不利影响有关 功能、胆固醇代谢和出生结果。胎盘，一种暂时的胚胎/胎儿器官， 在怀孕期间形成，促进气体，营养物质和废物与母亲交换。缺陷 胎盘发育和功能是许多妊娠并发症的基础，如先兆子痫和 宫内生长受限尽管胎盘很重要，但关于胎盘，特别是其 作为毒理学目标。在这里，我建议研究PFAS对器官祖细胞数量的影响， 细胞，称为细胞滋养层（CTB），在妊娠期间建立母胎界面的结构。 怀孕为此，我将使用这一过程的体外模型。原代CTB将被隔离并暴露于 PFOA、PFNA或GenX。这些PFAS的毒理学效应将通过两种方式阐明。首先利用 在CTB模型中，将确定PFOA、PFNA或GenX的相关有效浓度， 基于光谱的方法将用于确定它们在蛋白质组水平上的全局效应（Aim 1）。第二，研究与公共卫生暴露相关的水平，PFAS蛋白的功能相关性， 将通过模拟胎盘发育中可能起分级作用的靶点， 观察到的化学效应，例如，2.上下调节（目标2）。因此，这些实验的结果将 推进我们对人类健康的影响，在一个关键的发展过程中的化合物的知识 窗口完成这项研究将推进申请人在重要的新方向的培训， 由他的主要导师苏珊·费舍尔博士的专业知识：人类胎盘生物学和质谱- 基于蛋白质组学分析。陈昊博士将从他的导师团队获得宝贵的意见， 产前环境暴露、生物信息学和生殖生物学专家。与他的合作 作为导师，陈博士将培养成功过渡到独立工作所需的关键技能。 环境卫生学术生涯。这将通过一个重点突出的发展计划来实现 包括教学课程和与导师的密切合作。在本报告的结尾，博士。 Chen将领导PFAS对CTB及其功能的影响的首次研究， 这些化学品对发育和生殖健康的影响。

Project Summary/Abstract. The goal of this project is to test the hypothesis that perfluoroalkylated substances (PFAS) negatively impact formation of the placenta, and consequently, pregnancy outcomes. This work gains added significance in light of the increasing public health concerns towards these persistent compounds. The proposed experiments will also fill gaps in our understanding regarding the effects of these chemicals during human placental development, about which little is known. Pregnant mothers are exposed to a variety of chemicals, including PFAS. The latter exposures are widespread and high levels are linked with adverse effects on thyroid function, cholesterol metabolism, and birth outcomes. The placenta, a temporary embryonic/fetal organ that forms during pregnancy, facilitates gas, nutrients, and waste exchange with the mother. Deficiencies in placental development and function underlie numerous pregnancy complications, such as preeclampsia and intrauterine growth restriction. Despite its importance much remains unknown about the placenta, especially its role as a toxicological target. Here I propose studying PFAS effects on the organ's population of progenitor cells, termed cytotrophoblasts (CTBs), which establish the architecture of the maternal-fetal interface during pregnancy. To do so I will use an in vitro model of this process. Primary CTBs will be isolated and exposed to PFOA, PFNA, or GenX. The toxicological effects of these PFAS will be elucidated in two ways. First, using the CTB model, relevant effective concentrations of PFOA, PFNA, or GenX will be determined and a mass spectrometry-based approach will be used to determine their global effects at the level of the proteome (Aim 1). Second, honing in on levels relevant to public health exposures, the functional relevance of PFAS protein targets that could play hierarchical roles in placental development will be investigated by mimicking the observed chemical effects, e.g., up or down regulation (Aim 2). Thus, the results of these experiments will advance our knowledge about the human health effects of the compounds during a critical developmental window. Completing this study will advance the applicant's training in important new directions that are enabled by the expertise of his primary mentor, Dr. Susan Fisher: human placental biology and mass spectrometry- based proteomics analyses. Dr. Hao Chen will receive valuable input from his mentorship team, composed of experts in prenatal environmental exposures, bioinformatics, and reproductive biology. In collaboration with his mentors, Dr. Chen will develop critical skills that are required for a successful transition to an independent academic career in environmental health. This will be accomplished through a focused development plan consisting of didactic courses and close collaboration with his mentors. At the conclusion of this proposal, Dr. Chen will have led the first investigation of PFAS effects on CTBs and their function, providing insight into the impact of these chemicals towards developmental and reproductive health.