Perfluroalkylated Substances Exposures and Cytotrophoblast Differentiation

项目摘要/摘要。 该项目的目标是检验全氟烷基化物质 (PFAS) 负面影响的假设 影响胎盘的形成，从而影响妊娠结局。这项工作变得更加重要 鉴于公众对这些持久性化合物日益关注。拟议的 实验还将填补我们对这些化学物质对人类的影响的理解空白。 胎盘发育，对此知之甚少。怀孕的妈妈会接触多种化学物质， 包括 PFAS。后者的暴露范围很广，高水平与甲状腺的不利影响有关 功能、胆固醇代谢和出生结果。胎盘，一种临时的胚胎/胎儿器官 在怀孕期间形成，促进与母亲的气体、营养物质和废物交换。不足之处 胎盘发育和功能是许多妊娠并发症的基础，例如先兆子痫和 宫内生长受限。尽管胎盘很重要，但仍有很多未知之处，尤其是它的作用 作为毒理学目标的作用。在这里我建议研究 PFAS 对器官祖细胞群的影响 细胞，称为细胞滋养层（CTB），在孕期建立母胎界面的结构 怀孕。为此，我将使用此过程的体外模型。主要 CTB 将被隔离并暴露于 PFOA、PFNA 或 GenX。这些 PFAS 的毒理学作用可以通过两种方式来阐明。首先，使用 CTB 模型，将确定 PFOA、PFNA 或 GenX 的相关有效浓度，并确定质量 基于光谱测定的方法将用于确定其在蛋白质组水平上的整体影响（目标 1）。其次，关注与公共卫生暴露相关的水平，即 PFAS 蛋白的功能相关性 将通过模仿在胎盘发育中发挥分层作用的目标进行研究 观察到的化学效应，例如上调或下调（目标 2）。因此，这些实验的结果将 增进我们对化合物在关键发育过程中对人类健康影响的了解 窗口。完成这项研究将促进申请人在重要的新方向上的培训 凭借他的主要导师 Susan Fisher 博士的专业知识：人类胎盘生物学和质谱法- 基于蛋白质组学分析。陈浩博士将从他的导师团队中获得宝贵的意见，该团队由以下人员组成： 产前环境暴露、生物信息学和生殖生物学方面的专家。与他的合作 在导师的指导下，陈博士将培养成功转型为独立人士所需的关键技能 环境健康方面的学术生涯。这将通过重点发展计划来实现 包括教学课程和与导师的密切合作。在该提案的结论中，博士。 Chen 将领导第一项关于 PFAS 对 CTB 及其功能的影响的调查，提供对 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.