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

• 批准号: 8649396
• 负责人: Rita K Loch-Caruso
• 金额: $ 25.01万
• 依托单位: NORTHEASTERN UNIVERSITY
• 依托单位国家: 美国
• 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/8649396
• 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

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 早产是昂贵的，危险的和普遍的。在波多黎各，早产率最高， 美国的任何司法管辖区，全球只有马拉维以下。流行病学研究与环境 早产的化学品暴露。虽然胎盘和胎盘外膜在胎盘发育中起着至关重要的作用， 怀孕，潜在的环境污染物，以促进早产，通过对这些行动 组织几乎没有被探索过。通过对胎盘和胎盘外组织毒性作用的研究， 我们将确定毒理学解释的流行病学之间的联系暴露选择 环境污染和早产。我们将继续与TMT团队密切合作， 研究两种环境污染物是共同的超级基金网站，二-2-乙基己基邻苯二甲酸酯 （DEHP）和三氯乙烯（TCE）。虽然目前流行的早产模型集中在激活 胎盘和胎盘外膜中的促炎途径导致产生洋地黄素 最终刺激分娩，最近的报告表明，由于增加的生成， 活性氧（ROS）起着重要的作用。该项目建立在我们令人兴奋且新颖的发现之上 DEHP和TCE的生物活性代谢物刺激氧化应激、炎症介质和细胞死亡 在人类胎盘细胞中-与人类和动物早产和低出生体重相关的作用 模型此外，通过研究产生细胞内ROS的模型促氧化剂，我们已经确定了一个关键点， 细胞信号通路在这些反应中很重要。在妊娠大鼠中，TCE的作用与 在体外观察到TCE代谢物的反应。 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的妊娠大鼠中的生物标志物，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 评估胎盘母体血液和羊水此外，我们将定义ROS敏感机制 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、原代人胎盘滋养层细胞、原代人胎盘滋养层细胞、 胎盘巨噬细胞和体外暴露于DEHP的人胎盘外膜的transwell培养物 和TCE代谢物。在一个新的目标，这个项目，我们将定义毒物微生物相互作用的感染， 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 该项目将与接触科学和流行病学研究双向互动。