Project 2: Toxicant Activation of Pathways of Preterm Birth in Gestational Tissue

项目 2：妊娠组织中早产途径的毒物激活

基本信息

批准号：
8831683
负责人：
Rita K Loch-Caruso
金额：
$ 22.57万
依托单位：
NORTHEASTERN UNIVERSITY
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：
2010-04-12 至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8831683
关键词：
Address Amniotic Fluid Animal Model Antioxidants Apoptosis Biological Biological Markers Birth Birth Rate Blood Cell Communication Cell Death Cell Line Cells Child Coculture Techniques Collaborations Communities Cysteine Data Development Dose Environmental Pollution Epidemiologic Studies Epidemiology Event Exposure to Family Funding Generations Hazardous Waste Sites Health Histology Home environment Human Immune Immunoassay In Vitro Individual Infant Infection Inflammation Inflammation Mediators Inflammatory Inflammatory Response Knowledge Life Link Low Birth Weight Infant Malawi Matrix Metalloproteinases Measures Mediating Mediator of activation protein Medical Membrane Messenger RNA Modeling Mono-S Occupational Exposure Outcome Outcome Measure Oxidative Stress Pathology Pathway interactions Placenta Play Pregnancy Pregnancy Outcome Premature Birth Prostaglandin Production Prostaglandins Public Health Puerto Rico Quality of life Rattus Reactive Oxygen Species Reporting Risk Role Science Signal Pathway Signal Transduction Signal Transduction Pathway Societies Streptococcus Group B Testing Therapeutic Tissues Toxic Environmental Substances Trichloroethylene Weight Woman Work biological adaptation to stress chemical reaction cytokine drinking water effective intervention environmental chemical exposure epidemiology study human MAPK14 protein improved in vitro Model in vivo infant death inhibitor/antagonist insight macrophage microbial microorganism interaction novel phthalates pregnant pup research study response superfund site tert-Butylhydroperoxide tissue culture toxicant trophoblast

项目摘要

SUMMARY Preterm birth is expensive, dangerous and prevalent. In Puerto Rico, the preterm birth rate is the highest of any jurisdiction in the U.S. and below only Malawi globally. Epidemiologic studies associate environmental chemical exposures with preterm birth. Although the placenta and extraplacental membranes play vital roles in pregnancy, the potential for environmental contaminants to contribute to preterm birth through actions on these tissues has hardly been explored. Through studies of toxicant actions on placental and extraplacental tissues, we will identify toxicologic explanations for epidemiologic associations between exposure to select environmental contaminants and preterm birth. Working closely with the PROTECT team, we will continue study of two environmental contaminants that are common to Superfund sites, di-2-ethylhexyl phthalate (DEHP) and trichloroethylene (TCE). Although current popular models of preterm birth focus on activation of pro-inflammatory pathways in placenta and extraplacental membranes leading to production of prostaglandins that ultimately stimulate labor, recent reports suggest that oxidative stress due to increased generation of reactive oxygen species (ROS) plays an important role. This project builds on our exciting and novel findings that bioactive metabolites of DEHP and TCE stimulate oxidative stress, inflammatory mediators, and cell death in human placental cells - actions associated with preterm birth and low birth weight in humans and in animal models. Moreover, working with a model pro-oxidant that generates intracellular ROS, we have identified a key cell signaling pathway important in these responses. In pregnant rats, TCE exerted effects consistent with the responses observed in vitro with a TCE metabolite. An important objective of our proposed experiments is to measure oxidative stress and inflammatory response biomarkers in pregnant rats exposed to DEHP and TCE, and associate these biomarkers with adverse birth outcomes using histology to assess placental pathology, and using immunoassay, mRNA analysis, and IHC to assess placenta, maternal blood, and amniotic fluid. In addition, we will define the ROS-sensitive mechanisms that link DEHP and TCE to downstream events associated with preterm birth in experiments conducted with various in vitro models, including a human placental cell line, primary human placental trophoblasts, primary placental macrophages, and transwell cultures of human extraplacental membranes exposed in vitro to DEHP and TCE metabolites. In an aim new to this project, we will define toxicant-microbial interactions for infection of human extraplacental membranes in vitro. This project will provide novel data on mechanisms by which environmental toxicants increase women's risk for preterm birth. As part of this collaborative Center, our project will interact bidirectionally with exposure science and epidemiology studies.

概括早产是昂贵、危险且普遍的。在波多黎各，早产率是最高的全球范围内美国及以下仅限马拉维的任何司法管辖区。流行病学研究与环境相关化学暴露导致早产。尽管胎盘和胎盘外膜在怀孕期间，环境污染物通过采取这些措施可能导致早产组织几乎没有被探索过。通过对胎盘和胎盘外组织的毒性作用的研究，我们将为暴露于特定环境之间的流行病学关联确定毒理学解释环境污染物和早产。我们将与 PROTECT 团队密切合作，继续对超级基金站点常见的两种环境污染物——邻苯二甲酸二-2-乙基己酯的研究（DEHP）和三氯乙烯（TCE）。尽管当前流行的早产模型侧重于激活胎盘和胎盘外膜中的促炎途径导致前列腺素的产生最终刺激分娩，最近的报告表明，由于氧化应激的产生增加活性氧（ROS）发挥着重要作用。该项目建立在我们令人兴奋的新颖发现的基础上 DEHP 和 TCE 的生物活性代谢物会刺激氧化应激、炎症介质和细胞死亡在人类胎盘细胞中 - 与人类和动物早产和低出生体重相关的作用模型。此外，通过使用产生细胞内 ROS 的促氧化剂模型，我们已经确定了一个关键细胞信号传导通路在这些反应中很重要。在怀孕大鼠中，TCE 发挥的作用与使用 TCE 代谢物在体外观察到的反应。我们提出的实验的一个重要目标是测量氧化应激和炎症反应暴露于 DEHP 和 TCE 的怀孕大鼠的生物标志物，并将这些生物标志物与不良分娩相关联使用组织学评估胎盘病理学，并使用免疫测定、mRNA 分析和 IHC 来评估结果评估胎盘、母血和羊水。此外，我们将定义ROS敏感机制在实验中将 DEHP 和 TCE 与早产相关的下游事件联系起来各种体外模型，包括人胎盘细胞系、原代人胎盘滋养层、原代胎盘巨噬细胞和体外暴露于 DEHP 的人胎盘外膜 Transwell 培养物和 TCE 代谢物。在该项目的一个新目标中，我们将定义感染的毒物-微生物相互作用体外人胎盘外膜。该项目将提供有关机制的新数据环境毒物会增加妇女早产的风险。作为该协作中心的一部分，我们项目将与暴露科学和流行病学研究双向互动。