Biomarkers and Genes Associated with Placental Development and Function in Response to Environmental Pollution

项目总结/摘要 许多流行病学调查表明，暴露于机动车排放的交通源性空气污染 车辆、工业空气毒素和其他环境毒素，以及不良出生结果指标 包括先兆子痫（PE）、早产（PTB）和宫内生长受限（IUGR）。这些 共同构成缺血性胎盘病的条件与婴儿发病率密切相关， 一系列成人疾病，从冠状动脉疾病到癌症。尽管人们普遍认为， 导致缺血性胎盘病和胎盘炎并发症的病理生理机制 功能不全有类似的生物学起源，早在有缺陷的胎盘植入时就开始了， 没有前瞻性检查胎盘功能的预测性研究。因此，非侵入性评估和 缺乏对胎盘功能正常与异常的预测。因此，总体目标 这项建议的目的是开发和评估一套外泌体微转录组学和转录组学 特征（预测因子）用于预测胎盘功能不全。此外，我们试图利用这些新颖的签名， 评估环境污染暴露对胎盘异常/功能不全及相关疾病的影响 结局（PE、PTB和IUGR）（主要结局）。我们的中心假设是，长期暴露于 环境污染，独立于社会经济地位（SES），增加了胎盘风险 由于妊娠早期不良胎盘功能的发展，这些 结果可以通过开发母体血液来源的胎盘富集的 外泌体微转录组和转录组标记。为了验证这一假设，我们的具体目标是 目的1：在母体血液中非侵入性地开发胎盘来源的外泌体微 转录组和转录组特征通过所有三个预测体内胎盘功能 三个月目的2：使用目的1中的微转录组和转录组数据预测 在本研究过程中收集的环境污染数据。我们将建立模型， 基于这些特征来预测环境污染状态，使得它们可以用作环境污染的代理。 污染，如果没有这些数据。目的3：使用DNA进行表观基因组广泛关联研究 来自同一队列的胎盘组织的甲基化。我们将使用还原型亚硫酸氢盐 测序以鉴定其甲基化与胎盘功能不全和环境相关的基因座 暴露。这些研究将有助于确定转录组学分析证实的基因，这些基因可能在以下方面有用： 对空气致胎盘功能不全高危妇女的治疗干预措施的未来发展 污染暴露。识别预测环境污染存在的分子特征 不良的妊娠结局可能会改变游戏规则。产科实践可能包括这些 实时监测策略，以预测并可能逆转胎盘异常/功能不全。

PROJECT SUMMARY/ABSTRACT Many epidemiological investigations have associated exposure to traffic-derived air pollution from motor vehicles, air toxins from industry, and other environmental toxins with measures of poor birth outcomes consisting of preeclampsia (PE), preterm birth (PTB) and intra-uterine growth restriction (IUGR). These conditions, which collectively constitute ischemic placental disease, correlate strongly with infant morbidity and a host of adult diseases, ranging from coronary artery disease to cancer. Although it is widely believed that the pathophysiological mechanisms leading to complications of ischemic placental disease and placental insufficiency have similar biological origins, starting as early as defective placental implantation, to date there are no predictive studies that prospectively examine placental function. Thus, non-invasive assessment and prediction of normalcy versus aberrancy of placental function are lacking. Therefore, the overarching objective of this proposal is to develop and evaluate a suite of exosomal micro-transcriptomic and transcriptomic signatures (predictor) for predicting placental insufficiency. Moreover, we seek to use these novel signatures to assess the impact of environmental pollution exposure on placental aberrancy/insufficiency and related outcomes (PE, PTB and IUGR) (primary outcome). Our central hypothesis is that chronic exposure to environmental pollution, independent of socio-economic status (SES), increases the risk of placental insufficiency due to early gestational development of adverse placental function, and that these outcomes can be predicted non-invasively by developing maternal blood derived placental-enriched exosomal micro-transcriptomic and transcriptomic signatures. To test this hypothesis, our specific aims are to: AIM 1: Develop non-invasively in maternal blood, placenta-derived exosomal micro- transcriptomic and transcriptomic signatures that predict in-vivo placental function through all three trimesters. AIM 2: Use the micro-transcriptomic and transcriptomic data from Aim 1 to predict environmental pollution data collected during the course of this study. We will construct models to predict the environmental pollution state based on these signatures, so that they may be used as proxy of the pollution when this data is not available. AIM 3: Perform Epigenome Wide Association Studies using DNA methylation from placental tissues of the same cohort. We will use our Reduced Representation Bisulfite Sequencing to identify loci whose methylation is associated with placental insufficiency and environmental exposures. These studies will help identify genes confirmed by transcriptomic analysis that may be useful in future development of therapeutic interventions for women at high risk of placental insufficiency due to air pollution exposures. Identification of molecular signatures that predict the presence of environmental pollution and adverse pregnancy outcomes may become a game-changer. Obstetric practices may embrace these surveillance tactics in real-time to predict and perhaps reverse placental aberrancy/insufficiency.