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.

概括早产昂贵，危险且普遍。在波多黎各，早产是最高的美国的任何司法管辖区，仅在全球马拉维以下。流行病学研究助理环境早产的化学暴露。虽然胎盘和外膜在怀孕，环境污染物的潜力通过对这些行动的作用为早产做出了贡献组织几乎没有被探索。通过研究毒性作用对胎盘和颅外组织的研究我们将确定暴露于选择的流行病学关联的毒理学解释环境污染物和早产。与保护团队紧密合作，我们将继续对超级基金位点共有的两种环境污染物的研究，di-2-乙基己基邻苯二甲酸酯（DEHP）和三氯乙烯（TCE）。尽管当前早产的流行模型将重点放在激活胎盘和颅外膜的促炎途径，导致前列腺素的产生最终刺激了劳动，最近的报告表明，由于产生增加而引起的氧化应激活性氧（ROS）起着重要作用。这个项目以我们令人兴奋和新颖的发现为基础 DEHP和TCE的生物活性代谢产物刺激氧化应激，炎症介质和细胞死亡在人类胎盘细胞中 - 与早产相关的作用，人类和动物的出生体重低型号。此外，使用产生细胞内ROS的模型促氧化剂，我们已经确定了一个键细胞信号通路在这些响应中很重要。在怀孕的大鼠中，TCE发挥了与用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出生相关联使用组织学评估胎盘病理学的结果，并使用免疫测定，mRNA分析和IHC 评估胎盘，母血和羊水。此外，我们将定义对ROS敏感的机制将DEHP和TCE与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，主要人胎盘滋养细胞，主要体外暴露于DEHP 和TCE代谢产物。为了对该项目的新目标，我们将定义有毒物质 - 微生物相互作用以感染人体外膜外膜体外。该项目将提供有关机制的新颖数据环境有毒物质增加了妇女早产的风险。作为这个合作中心的一部分，我们的项目将与暴露科学和流行病学研究在双向相互作用。