Perfluroalkylated Substances Exposures and Cytotrophoblast Differentiation

全氟烷基化物质暴露和细胞滋养层分化

• 批准号: 9892276
• 负责人: Hao Chen
• 金额: $ 9.19万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-15 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9892276
• 关键词: Adverse effects; Affect; Architecture; Arteries; Bioinformatics; Biological; Biological Markers; Birth; Blood Vessels; Cell model; Cells; Chemical Surfactants; Chemicals; Cholesterol Homeostasis; Collaborations; Development; Development Plans; Down-Regulation; Embryo; Endocrine Disruptors; Environment; Environmental Exposure; Environmental Health; Equilibrium; Exposure to; Extracellular Matrix; Fatty Acids; Fetal Development; Fetal Growth Retardation; Fetus; Flame Retardants; Gases; Genetic; Goals; Health; Human; Impairment; Industrialization; Invaded; Investigation; Knowledge; Light; Link; Mass Spectrum Analysis; Maternal Exposure; Maternal-Fetal Exchange; Mentors; Mentorship; Metabolic; Metabolism; Modeling; Molecular; Mononuclear; Mothers; Nutrient; Organ; Outcome; Oxygen; Pathologic; Pathway interactions; Pharmacology; Phenotype; Placenta; Placental Biology; Placentation; Play; Poly-fluoroalkyl substances; Population; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Pregnant Women; Process; Proteins; Proteome; Proteomics; Public Health; Reporting; Reproductive Biology; Reproductive Health; Research Project Grants; Risk; Risk Assessment; Role; Sampling; Screening procedure; Second Pregnancy Trimester; Steroids; Surface; Syncytiotrophoblast; Testing; Thyroid Function Tests; Thyroid Gland; Toxic effect; Toxicology; Training; Up-Regulation; Uterus; Weight; Work; adverse pregnancy outcome; base; career; cell motility; cytotrophoblast; design; differential expression; environmental chemical exposure; epidemiology study; experimental study; fetal; human model; in utero; in vitro Model; insight; maternal serum; novel; perfluorooctanoic acid; polybrominated diphenyl ether; postnatal; prenatal; prenatal environmental exposure; response; skills; stem cells; wasting

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.

项目摘要/摘要。 该项目的目的是检验以下假设，即持氟烷基化的物质（PFA）负面 影响胎盘的形成，从而影响妊娠结局。这项工作提高了意义 鉴于对这些持续化合物的公共卫生越来越关注。提议 实验还将填补我们对这些化学物质在人类中影响的理解的空白 胎盘发展，几乎没有知道。怀孕的母亲暴露于多种化学物质， 包括PFA。后一种暴露是广泛的，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，临时的胚胎/胎儿器官 怀孕期间的形式，促进天然气，养分和与母亲交换。缺陷 胎盘发育和功能是许多怀孕并发症的基础，例如先兆子痫和 宫内生长限制。尽管它的重要性仍然很重要，但对胎盘，尤其是 作为毒理学目标的作用。在这里，我建议研究PFA对器官祖先群体的影响 细胞，称为细胞增生细胞（CTB），它们在孕产妇界面的结构中建立 怀孕。为此，我将使用此过程的体外模型。主CTB将被隔离并暴露于 PFOA，PFNA或GENX。这些PFA的毒理学作用将通过两种方式阐明。首先，使用 将确定CTB模型，PFOA，PFNA或GENX的相关有效浓度，并质量 基于光谱法的方法将用于确定其在蛋白质组水平上的全球效应（AIM 1）。其次，磨练与公共卫生暴露有关的水平，PFAS蛋白的功能相关性 可以通过模仿该目标来研究可以在胎盘发展中扮演分层角色的目标 观察到的化学作用，例如向上或向下调节（AIM 2）。因此，这些实验的结果将 在关键发展期间，提高我们对化合物对人类健康影响的知识 窗户。完成这项研究将在启用的重要新方向上推进申请人的培训 根据他的主要导师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。 Hao Chen博士将从他的指导团队中获得宝贵的意见，由他的指导团队组成 产前环境暴露，生物信息学和生殖生物学专家。与他的合作 导师，陈博士将发展至关重要的技能，以成功地过渡到独立 环境健康的学术生涯。这将通过集中的发展计划来完成 由教学课程和与导师的密切合作组成。在该提案的结论结束时，博士 Chen将领导PFA对CTB及其功能的首次调查，从而洞悉 这些化学物质对发展和生殖健康的影响。