Project 2: Pollutant Activation of Cell Pathways in Gestational Tissues

我们研究的长期目标是减少不良出生结果，如早产。 将早产率降至7.6%是《2010年健康人》的目标，但早产率继续上升， 占2005年活产婴儿的12.8%。不幸的是，早产的病因，宫内生长 限制，和其他不良的出生结果知之甚少，虽然感染的关键作用， 涉及炎症和氧化应激。有限的研究将不良出生结局与 暴露于超级基金相关的有毒物质本报告确定并解决了一个关键的知识差距， 建议是缺乏有关将环境污染物暴露与 早产和其他不良出生结果。我们假设与超级基金有关的污染物 激活妊娠组织中的活性氧敏感途径， 从而增加早产风险。这一假设的依据如下 信息：1）邻苯二甲酸酯，三氯乙烯和许多其他污染物刺激反应性 哺乳动物细胞中的氧; 2）活性氧可以通过DNA损伤启动细胞凋亡， 通过膜脂质氧化、细胞因子和前列腺素（PG）合成的非凋亡性细胞死亡 通过影响基因转录; 3）细胞死亡和炎症的胎盘和妊娠 胎膜早破与早产、宫内生长受限和其他不良出生有关 前列腺素PGE 2和PGF 2 α是分娩的关键介质。的 拟议的研究将提供第一个实验数据，以支持环境的机制， 污染物暴露增加了妇女早产和其他不良生育结果的风险。通过 这表明，一种常见的毒理学效应，氧化应激，激活相关的途径， 这些数据将为环境污染物的合理生物学解释提供证据 与早产的关系。

The long-term objective of our research is to reduce adverse birth outcomes such as preterm birth. Reducing preterm births to 7.6% is a Health People 2010 objective, yet preterm births continue to rise and accounted for 12.8% of live births in 2005. Unfortunately, the etiology of preterm birth, intrauterine growth restriction, and other adverse birth outcomes are poorly understood, though critical roles for infection, inflammation and oxidative stress are implicated. Limited studies relate adverse birth outcomes with exposure to Superfund-relevant toxicants. A critical knowledge gap that is identified and addressed in this proposal is the lack of information on biological explanations that link environmental pollutant exposures with preterm birth and other adverse birth outcomes. We hypothesize that Superfund-related contaminants activate reactive oxygen species-sensitive pathways in gestational tissues to promote onset of parturition and thereby increase risk for preterm birth. This hypothesis is based on the following information: 1) phthalates, trichloroethylene, and many other pollutants stimulate generation of reactive oxygen species in mammalian cells; 2) reactive oxygen species can initiate apoptosis through DNA damage, non-apoptotic cell death through membrane lipid oxidation, and cytokine and prostaglandin (PG) synthesis through effects on gene transcription; 3) cell death and inflammation of the placenta and gestational membranes are associated with preterm birth, intrauterine growth restriction and other adverse birth outcomes; and 4) the prostaglandins PGE2 and PGF2alpha are critical mediators of parturition. The proposed research will provide the first experimental data to support mechanisms by which environmental pollutant exposures increase women's risk for preterm birth and other adverse birth outcomes. By demonstrating that a common toxicological effect, oxidative stress, activates pathways associated with parturition, these data will provide evidence for a plausible biological explanation for environmental pollutant exposure associations with preterm birth.