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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.

总结