Perfluroalkylated Substances Exposures and Cytotrophoblast Differentiation

项目摘要/摘要。 该项目的目标是检验假设，全氟烷基化物质(PFAS)对 影响胎盘的形成，从而影响妊娠结局。这项工作获得了额外的意义 鉴于公众对这些持久性化合物的关注日益增加。建议数 实验还将填补我们对这些化学物质在人体内影响的理解上的空白。 胎盘发育，人们对此知之甚少。怀孕的母亲会接触到各种化学物质， 包括全氟辛烷磺酸。后者的暴露很普遍，高水平的暴露与对甲状腺的不良影响有关。 功能、胆固醇代谢和出生结局。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、营养和废物交换。的不足之处 胎盘发育和功能是许多妊娠并发症的基础，如先兆子痫和 胎儿宫内生长受限。尽管胎盘很重要，但关于它的许多方面仍不清楚，特别是它的 作为毒物学目标的角色。在这里，我建议研究PFAS对器官祖细胞数量的影响 细胞，称为细胞滋养层细胞(CTB)，它建立了母胎界面的结构 怀孕了。为了做到这一点，我将使用这一过程的体外模型。主要的四氯化碳将被隔离并暴露在 全氟辛酸、全氟辛酸或GenX。这些全氟辛烷磺酸的毒理学效应将通过两种方式加以阐明。首先，使用 CTB模型，将确定相关的全氟辛酸、全氟辛酸或GenX的有效浓度和质量 基于光谱的方法将被用来在蛋白质组(AIM)水平上确定它们的全局影响 1)。其次，在与公共卫生暴露相关的水平上，PFAS蛋白的功能相关性 可以在胎盘发育中扮演等级角色的目标将通过模仿 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 在关键的发育阶段提高我们对化合物对人类健康影响的知识 窗户。完成这项研究将推动申请者在重要的新方向上的培训 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学- 基于蛋白质组学的分析。陈浩博士将从他的导师团队那里获得宝贵的意见，该团队由以下成员组成 产前环境暴露、生物信息学和生殖生物学方面的专家。与HIS合作 导师们，陈博士将培养成功过渡到独立医生所需的关键技能 环境健康方面的学术生涯。这将通过一个有重点的发展计划来实现。 包括说教课程和与他的导师的密切合作。在这项提议结束时，Dr。 陈将领导对全氟辛烷磺酸对四氯化碳的影响及其作用的第一次调查，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.