Effects of Phthalates on Trophoblast Differentiation: From Biology to Biomarkers

邻苯二甲酸盐对滋养层分化的影响：从生物学到生物标志物

• 批准号: 8799315
• 负责人: Jennifer Joan Adibi
• 金额: $ 18.18万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-16 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8799315
• 关键词: Effects; Phthalates; Trophoblast; Differentiation; Biology

Project Summary/Abstract I seek funding to extend my training in epidemiology in two new directions-namely, human placental biology and mass spectrometry. Learning these laboratory-based methods will move me closer to accomplishing my long-term goals of becoming an independent academic investigator and offering new insights and methods to research on low dose chronic exposures to endocrine disrupting compounds and their role in health disorders that originate in early pregnancy. During the K99 phase, under the primary mentorship of Dr. Susan Fisher, I will receive training in trophoblast (Tb) stem cell biology, state-of-the-art microarray-based methodologies that are used to analyze gene expression at a global level, including bioinformatics approaches for data analysis. Building on the results of my initial post-doctoral research, I theorize that Tbs, the specialized cells that carry out many of the placenta's most important functions, are exposed to phthalates early in pregnancy with adverse consequences on placental development and function. We will test hypotheses regarding clinical outcomes and biological parameters that include molecular, cellular, and morphologic measures of human placental development and function. Specifically, I will conduct experiments to test the hypothesis that cultured human Tb stem cells will show dose-dependent changes in patterns of gene expression when they are exposed to environmentally relevant doses of di-(2-ethylhexyl) phthalate and di-n-butyl phthalate (Aim 1). During the R00 phase, I will test the theory, in a longitudinal study of pregnant women, that placental genes that are differentially expressed as a consequence of phthalate exposure in vitro are similarly regulated, in a dose-dependant manner, in vivo (Aim 2). As part of this aim, I will evaluate the correlation between the conventional dosimeter of prenatal exposure, urinary phthalate metabolite concentrations, and the dose to the target placental tissue. My primary mentor and co-mentors in obstetrics/gynecology, mass spectrometry, biostatistics, and epidemiology will guide the process whereby I learn the methods that are required to accomplish the goals set forth in this proposal. At the conclusion of this training program I will have developed new methodologies and tools that I and other investigators can use to ask more directed questions about the consequences of phthalate exposures during pregnancy in terms of alterations in placental function and consequently, human development. This work is important because phthalates, which can disrupt cell and tissue differentiation, are well established as reproductive and developmental toxicants in rodents; yet the relevance of these finding to humans is not well understood. With biomarkers specific to phthalate-induced placental damage, it will become possible to identify high-risk pregnancies and provide opportunities for prevention, at the population level, and possibly intervention at the level of health care delivery systems to improve placental and fetal outcomes.

项目摘要/摘要 我寻求资金以将流行病学的培训扩展到两个新的方向，即人类胎盘生物学 和质谱。学习这些基于实验室的方法将使我更接近完成我的 成为独立学术研究者并提供新的见解和方法的长期目标 研究低剂量的慢性暴露于内分泌破坏化合物及其在健康障碍中的作用 这起源于怀孕早期。在K99阶段，在Susan Fisher博士的主要指导下 将接受滋养细胞（TB）干细胞生物学的培训，基于微阵列的最先进的方法论 用于在全球层面分析基因表达，包括用于数据分析的生物信息学方法。 基于我最初的博士后研究的结果，我认为TBS是携带的专门单元 出现许多胎盘最重要的功能，在怀孕初期暴露于邻苯二甲酸盐。 对胎盘发育和功能的不利后果。我们将检验有关临床的假设 结局和生物学参数包括人类的分子，细胞和形态学测量 胎盘发展和功能。具体而言，我将进行实验以检验培养的假设 人结核病干细胞在基因表达模式的剂量依赖性变化时会变化 暴露于环境相关剂量的苯甲酸二（2-乙基己基）和邻苯甲酸二苯二甲酸苯甲酸酯（AIM 1）。 在R00阶段，我将在对孕妇的纵向研究中测试该理论 在体外暴露于邻苯二甲酸酯的结果，在A 剂量依赖性方式，体内（AIM 2）。作为此目标的一部分，我将评估 产前暴露，尿邻苯二甲酸盐代谢物浓度和剂量的常规剂量计 靶胎盘组织。我的主要导师和妇产科领域的主要指导者，质谱法， 生物统计学和流行病学将指导我学习所需方法的过程 完成此提案中规定的目标。在此培训计划的结论结束时，我将开发 我和其他调查人员可以用来提出有关有关该方法的更多定向问题的新方法和工具 怀孕期间邻苯二甲酸盐暴露的后果是根据胎盘功能的改变和 因此，人类的发展。这项工作很重要，因为邻苯二甲酸盐会破坏细胞和 组织分化是啮齿动物中繁殖和发育有毒物质的充分确立的。但是 这些发现与人类的相关性并不理解。具有特定于邻苯二甲酸酯诱导的生物标志物 胎盘损害，将有可能识别高风险怀孕并为 预防，在人口层面，可能在医疗保健提供系统级别进行干预至 改善胎盘和胎儿结局。