Project 2 - Toxicant-Stimulated Disruption of Gestational Tissues with Implications for Adverse Pregnancy Outcomes

总结 成立于2010年，TFTSuperfund研究中心集研究，培训和利益相关者 参与提供解决方案，减少污染物对波多黎各和全国怀孕的风险。这 该项目通过胎盘破坏的毒理学研究， 胎盘外膜作为早产的潜在机制。实验将使用外植体培养物， 来自健康足月分娩的初级人类胎盘绒毛膜和胎盘外膜（胎盘膜） 相关的人体组织模型，允许进行毒性评估的实验操作， 物种间差异的复杂性。该提案继续研究超级基金化学品， 波多黎各-邻苯二甲酸二（2-乙基己基）酯（DEHP）和三氯乙烯（TCE）-添加二（2-乙基己基）酯 乙基己基）对苯二甲酸酯（DEHTP），这是一种替代邻苯二甲酸酯的日益增加的商业用途， 与DEHP结构相关。因为邻苯二甲酸盐和三氯乙烯的大多数不良健康影响都归因于 代谢物，将使用全身分布的DEHP代谢物（单-[2- 邻苯二甲酸单[2-乙基-羧丙基]酯）、DEHTP（对苯二甲酸单[2-乙基己基]酯 和对苯二甲酸单-[2-乙基-5-羧基戊基]酯）和TCE（三氯乙酸酯和S-（1，2-二氯乙烯基）-L- 半胱氨酸）。此外，我们将评估上述邻苯二甲酸酯代谢物的组合暴露， 一种基于波多黎各妇女尿液中相对浓度的重组混合物。因为 胎盘是高度灌注的，这些血液传播的代谢物在暴露的环境中被有效地递送到胎盘。 妇女本提案基于当前的知识以及该项目和中心过去的成功经验， 提出了一个总体假设，即邻苯二甲酸酯和TCE代谢物激活了 破坏胎盘和胎盘功能的细胞因子反应，从而导致早产风险 出生在目的1和2中，我们将使用人胎盘绒毛外植体来建立浓度依赖性和 邻苯二甲酸酯和TCE代谢物的时间依赖关系（目标1），并测试氧化应激是否 通过这些毒物引发组织功能破坏（目的2）。因为胎盘和胎盘的感染是 导致早产的可识别原因，在目标3中，我们将探讨氧化应激作为一种机制， 毒物改变了链球菌对B族链球菌（GBS）感染的易感性。拟议的研究将 扩大邻苯二甲酸酯和TCE对胎盘和胎盘毒性的知识，为刺激提供新的见解 氧化应激和抑制妊娠组织抵抗细菌感染的生物学机制 环境污染物暴露会增加早产风险。通过与初级人类合作， 与晚期早产相关的组织培养模型-这是早产增加的主要原因 在美国，这些发现有可能转化为医学和公共卫生 对减少早产产生重大影响的干预措施。

SUMMARY Established in 2010, the PROTECT Superfund Research Center integrates research, training and stakeholder engagement to provide solutions for reducing pollutant risks to pregnancy in Puerto Rico and nationwide. This project contributes to the mission of PROTECT with toxicological studies of disruption of the placenta and extraplacental membranes as potential mechanisms of preterm birth. Experiments will use explant cultures of primary human placental villous and extraplacental membranes (EPM) from healthy term deliveries as highly relevant human tissue models that allow experimental manipulation for toxicity assessment and avoid complications of inter-species differences. This proposal continues study of Superfund chemicals relevant to Puerto Rico – di-(2-ethylhexyl) phthalate (DEHP) and trichloroethylene (TCE) – with addition of di-(2- ethylhexyl) terephthalate (DEHTP) which is an alternative phthalate of increasing commercial use that is structurally related to DEHP. Because most adverse health effects of phthalates and TCE are attributed to metabolites, experiments will be conducted with systemically distributed metabolites of DEHP (mono-[2- ethylhexyl] phthalate and mono-[2-ethyl-carboxypropyl] phthalate), DEHTP (mono-[2-ethylhexyl] terephthalate and mono-[2-ethyl-5-carboxypentyl] terephthalate), and TCE (trichloroacetate and S-(1, 2-dichlorovinyl)-L- cysteine). Furthermore, we will assess the combined exposure of the aforementioned phthalate metabolites in a reconstituted mixture based on their relative urinary concentrations in Puerto Rican women. Because the placenta is highly perfused, these blood-borne metabolites are efficiently delivered to the placenta in exposed women. This proposal builds on current knowledge – and past successes of this project and center – to propose the overarching hypothesis that phthalate and TCE metabolites activate oxidative stress upstream of cytokine responses that disrupt the function of the placenta and EPM, thereby contributing to risk for preterm birth. In Aims 1 and 2, we will use human placental villous explants to establish concentration-dependent and time-dependent relationships for the phthalate and TCE metabolites (Aim 1), and test whether oxidative stress initiates tissue function disruption by these toxicants (Aim 2). Because infection of the placenta and EPM is the leading identifiable cause of preterm birth, in Aim 3 we will probe oxidative stress as a mechanism by which toxicants modify susceptibility of EPM to Group B Streptococcus (GBS) infection. The proposed studies will expand knowledge of phthalate and TCE toxicity to placenta and EPM, providing new insights into stimulation of oxidative stress and inhibition of gestational tissue resistance to bacterial infection as biological mechanisms by which environmental contaminant exposures increase risk for preterm birth. By working with primary human tissue culture models relevant to late preterm birth – which accounts for most of the increase in preterm births in the United States – these findings have the potential for translation to medical and public health interventions with a significant impact on reducing preterm births.