Project 2: Pollutant Activation of Cell Pathways in Gestational Tissues

我们研究的长期目标是减少早产等不良分娩后果。 将早产儿减少到7.6%是《健康人物》2010年的目标，但早产儿继续上升， 占2005年活产婴儿的12.8%。不幸的是，早产、胎儿宫内发育的病因 限制和其他不利的出生结局知之甚少，尽管对感染起着关键作用， 炎症和氧化应激也有牵连。有限的研究将不良的出生结局与 接触与超级基金有关的毒物。在本报告中发现并解决的关键知识差距 建议是缺乏将环境污染物暴露与生物解释联系起来的信息 早产和其他不良分娩后果。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通路促进高血压的发生 分娩，从而增加早产的风险。这一假设基于以下几点 信息：1)邻苯二甲酸盐、三氯乙烯和许多其他污染物会刺激活性物质的生成 哺乳动物细胞中的氧物种；2)活性氧物种可以通过DNA损伤启动细胞凋亡， 膜脂氧化与细胞因子和前列腺素(PG)合成的非凋亡性细胞死亡 通过对基因转录的影响；3)胎盘和妊娠的细胞死亡和炎症 胎膜与早产、胎儿宫内发育受限和其他不良分娩有关。 结果；4)前列腺素PGE2和PGF2a是分娩的关键中介。这个 拟议的研究将提供第一批实验数据，以支持环境保护机制 接触污染物会增加妇女早产和其他不良生育后果的风险。通过 证明了一种常见的毒理学效应，即氧化应激，激活了与 这些数据将为环境污染物的合理生物学解释提供证据。 暴露与早产有关。

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.