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

基本信息

批准号：
8007444
负责人：
Jennifer Joan Adibi
金额：
$ 9万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-01-01 至 2011-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8007444
关键词：
Allografting Angiogenic Factor Applications Grants Arteries Bioinformatics Biological Biological Assay Biological Markers Biology Biometry Blood Blood flow Cell Differentiation process Cell model Cells Chronic Clinical Complex Cosmetics Data Analyses Development Dibutyl Phthalate Discipline of obstetrics Disease Dose Embryo Embryonic and Fetal Development Endocrine Disruptors Environment Environmental Exposure Environmental Health Epidemiology Exposure to Fetal Tissues Fetus Funding Gene Expression Genes Germ Cells Goals Growth Factor Gynecology Health Health Status High-Risk Pregnancy Hormones Human Human Development Immune Tolerance In Vitro Infant Intervention Knowledge Laboratories Learning Longitudinal Studies Maps Mass Spectrum Analysis Measures Mediating Mentors Mentorship Metabolic Metabolic Diseases Methodology Methods Modeling Molecular Monitor Obesity Organ Outcome Pathway interactions Pattern Peroxisome Proliferator-Activated Receptors Phase Physiology Placenta Placentation Plastics Play Polyvinyl Chloride Population Positioning Attribute Postdoctoral Fellow Pregnancy Pregnancy Outcome Pregnant Women Prevention Process Production Rattus Regulation Renal function Reproduction Research Research Personnel Risk Rodent Role Source Stem cells Structure System Testing Testis Tissue Differentiation Tissues Training Training Programs Umbilical Cord Blood Waste Products Work adipocyte differentiation adverse outcome analytical tool base consumer product cytokine embryo/fetus exposed human population fetal health care delivery human embryonic stem cell human tissue improved in utero in vivo in vivo Model insight mRNA Expression male member mullerian-inhibiting hormone nutrient metabolism offspring phthalates prenatal prenatal exposure public health relevance reproductive research study response stem cell biology theories tool toxicant trophoblast urinary

项目摘要

DESCRIPTION (provided by applicant): The candidate seeks funding to extend her training in epidemiology in two new directions, namely, human placental biology and mass spectrometry. Learning these laboratory-based methods will move her closer to accomplishing her 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, the candidate 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 her initial postdoctoral research, the candidate 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. The investigators will test hypotheses regarding clinical outcomes and biological parameters that include molecular, cellular, and morphologic measures of human placental development and function. Specifically, they 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, the candidate 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-dependent manner, in vivo (Aim 2). As part of this aim, the candidate will evaluate the correlation between the conventional dosimeter of prenatal exposure, urinary phthalate metabolite concentrations, and the dose to the target placental tissue. The primary mentor and co-mentors in obstetrics/gynecology, mass spectrometry, biostatistics, and epidemiology will guide the process whereby the candidate learn the methods that are required to accomplish the goals set forth in this proposal. At the conclusion of this training program the candidate will have developed new methodologies and tools that she 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. Public Health Relevance: The goal of this project is to prepare Dr. Jennifer Adibi to transition to a position as an independent academic investigator in environmental health sciences focusing on the consequences of phthalate exposures during human pregnancy. She will conduct experiments using in vitro and in vivo models to test the hypothesis that this toxicant disrupts trophoblast differentiation, and therefore placental development and function, thereby compromising human development in-utero.

描述（由申请人提供）：候选人寻求资金将她在流行病学方面的培训扩展到两个新方向，即人类胎盘生物学和质谱法。学习这些基于实验室的方法将使她更接近实现自己成为独立学术研究者的长期目标，并提供新的见解和方法来研究低剂量的长期暴露，以使内分泌干扰及其在早期怀孕早期起源的健康疾病中的作用及其在健康疾病中的作用。在K99阶段，在苏珊·费舍尔（Susan Fisher）博士的主要指导下，候选人将接受滋养细胞（TB）干细胞生物学的培训，基于最先进的微阵列方法，这些方法用于在全球范围内分析基因表达，包括生物信息学方法进行数据分析。在她最初的博士后研究结果的基础上，候选人认为，TBS是执行许多胎盘最重要功能的专门细胞，在怀孕初期暴露于邻苯二甲酸酯，对胎盘发育和功能产生不利影响。研究人员将测试有关临床结果和生物学参数的假设，包括人类胎盘发育和功能的分子，细胞和形态学测量。具体而言，他们将进行实验，以测试培养的人类TB干细胞将显示基因表达模式的剂量依赖性变化的假说，当它们暴露于环境相关剂量的di-（2-乙基己基）邻苯二甲酸酯和Di-N-N-丁基酯（AIM 1）时（AIM 1）。在R00阶段，候选人将在对孕妇的纵向研究中检验该理论，即由于邻苯二甲酸酯暴露在体外而差异表达的胎盘基因以剂量依赖性的方式同样调节体内（AIM 2）。作为此目标的一部分，候选人将评估产前暴露的常规剂量表，尿邻苯二甲酸酯代谢产物浓度和剂量对目标胎盘组织的相关性。妇产科，质谱，生物统计学和流行病学的主要指导者和联合会员将指导候选人学习实现本提案中规定目标所需的方法的过程。在该培训计划的结论结束时，候选人将开发她和其他研究人员可以用这些方法和工具来提出有关怀孕期间邻苯二甲酸盐暴露的后果的更多问题，以改变胎盘功能的改变，以及人类的发展。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，在啮齿动物中被很好地确定为生殖和发育有毒物质。然而，这些发现与人类的相关性并不能很好地理解。鉴于邻苯二甲酸酯引起的胎盘损害的生物标志物，将有可能识别高风险妊娠，并为预防，人口水平以及在医疗保健提供系统水平上进行干预以改善胎盘和胎儿成果的机会。公共卫生相关性：该项目的目的是准备詹妮弗·阿迪比（Jennifer Adibi）博士过渡为环境健康科学领域的独立学术研究员，重点是人类怀孕期间邻苯二甲酸盐暴露的后果。她将使用体外和体内模型进行实验，以检验这种毒物破坏滋养细胞分化的假设，从而破坏胎盘发育和功能，从而损害了人类的发展。