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

项目摘要/摘要 许多流行病学调查都与汽车交通产生的空气污染有关 车辆、来自工业的空气毒素和其他具有不良出生结局措施的环境毒素 包括先兆子痫(PE)、早产(PTB)和宫内生长受限(IUGR)。这些 这些疾病共同构成了缺血性胎盘疾病，与婴儿发病率和 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 导致缺血性胎盘疾病和胎盘并发症的病理生理机制 功能不全有相似的生物起源，早在有缺陷的胎盘植入时就开始了，到目前为止 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或异常的预测。因此，总体目标是 这项建议的目的是开发和评估一套外体微转录和转录 用于预测胎盘功能不全的信号(预测因子)。此外，我们试图使用这些新颖的签名来 评估环境污染暴露对胎盘异常/功能不全的影响及相关因素 结果(PE、PTB和IUGR)(主要结果)。我们的中心假设是，长期接触 与社会经济地位(SES)无关的环境污染会增加胎盘的风险 由于妊娠早期发育不良的胎盘功能而导致的功能不全 通过发展母血来源的胎盘可以无创预测结果 外体微转录型和转录型签名。为了检验这一假设，我们的具体目标是 目的是：目标1：在母体血液中无创发育，胎盘来源的胞外微球 通过三种方法预测体内胎盘功能的转录和转录切割信号 怀孕三个月了。目标2：使用来自目标1的微观转录和转录数据来预测 在本研究过程中收集的环境污染数据。我们将构建模型来 根据这些特征对环境污染状况进行预测，从而可以作为环境污染状况的代理 如果没有这一数据，就会造成污染。目标3：使用DNA进行表观基因组广谱关联研究 来自同一队列的胎盘组织的甲基化。我们将使用我们的简化代表亚硫酸盐 测序以确定其甲基化与胎盘功能不全和环境相关的基因座 曝光。这些研究将有助于识别经转录分析确认的基因，这些基因可能对 空气所致胎盘功能不全高危妇女治疗干预的未来发展 暴露在污染中。识别预测环境污染存在的分子特征 不良妊娠结局可能成为游戏规则的改变者。产科实践可能会接受这些 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.