Assessing how Prenatal Phthalate Exposure Disrupts Placental Transcriptional Regulation and Contributes to Changes in Gestational Length

项目摘要 自发性早产（sPTB）占早产的大多数（60%），是早产的主要病例。 新生儿发病率和死亡率以及不良健康后果的预测因素。尽管发病率很高， 对子宫内环境如何导致sPTB病因学的理解有限。二甲酸盐是 普遍存在的内分泌干扰化学品，诱导基因表达和生理变化， 胎盘流行病学研究确定了产前邻苯二甲酸酯暴露与 和早产这项研究的目的是开发胎盘分子标记，可用于 产前邻苯二甲酸酯暴露与sPTB之间存在机械联系。胎盘的分子特征可以解释 与sPTB相关的功能差异，并确定临床和治疗干预的目标，包括 可改变的风险因素，如环境暴露。我们的研究小组已经制造出了世界上最大的胎盘 迄今为止的转录组学数据集（N=760个样本），并已使用该数据集开发以下转录组学特征： 产前邻苯二甲酸酯暴露和sPTB。这项研究将扩大我们现有的转录组签名，包括 microRNA是一个完整的分子特征所必需的，因为它们非常稳定， 与许多环境暴露有关，并分泌到母体循环中， 作为生物标志物。候选microRNA研究已经确定了产前邻苯二甲酸酯暴露与 胎盘microRNA的表达，但需要全面评估，以充分了解其作用 胎盘microRNA在邻苯二甲酸酯介导的毒性中的作用。此外，尽管胎盘的潜在重要性 microRNA作为sPTB的生物标志物，尚未有全面的分析。在本建议中，我们力求 填补这些研究空白，并应用创新的计算生物学策略， 了解产前邻苯二甲酸酯暴露，胎盘功能， 和sPTB。在目标1中，我们将生成胎盘样本的microRNA数据并使用其生成签名 产前邻苯二甲酸酯暴露我们将使用匹配的microRNA-mRNA测序数据构建一个全球性的 胎盘microRNA-mRNA网络，我们将应用于识别microRNA和基因之间的连接 其胎盘表达与不同的邻苯二甲酸酯代谢物有关。在目标二中，我们将开发一个多- 使用我们的胎盘microRNA-mRNA网络的sPTB的组学分子特征。在目标3中，我们将研究 胎盘作为产前邻苯二甲酸酯暴露和sPTB之间机制联系的作用 战略，包括综合途径分析和正式调解分析。从这个研究结果 将告知化学毒理学风险评估和政策，以减少邻苯二甲酸酯暴露对健康的影响 怀孕期间sPTB的microRNA特征可以作为sPTB的功能性生物标志物，因为它们可以被 分泌到母体循环中，并成为未来临床和治疗干预的目标。

PROJECT SUMMARY Spontaneous preterm birth (sPTB) comprises the majority of preterm births (60%) and is a leading case of newborn morbidity and death and a predictor of adverse health outcomes. Despite its high prevalence, there is a limited understanding of how the in-utero environment contributes to the etiology of sPTB. Phthalates are ubiquitous endocrine disrupting chemicals that induce gene expression and physiological changes within the placenta. Epidemiological studies identify a consistent positive relationship between prenatal phthalate exposure and preterm birth. The goal of this study is to develop placental molecular signatures that can be used to mechanistically link prenatal phthalate exposure and sPTB. Placental molecular signatures can explain functional differences related to sPTB and identify targets for clinical and therapeutic interventions, including modifiable risk factors such as environmental exposures. Our research team has generated the largest placental transcriptomics dataset to date (N=760 samples) and has used this to develop transcriptomic signatures of prenatal phthalate exposure and sPTB. This study will expand our existing transcriptomic signatures to include microRNAs, which are essential to a complete molecular signature because they are highly stable, have been linked to a number of environmental exposures, and are secreted into maternal circulation where they may serve as biomarkers. Candidate microRNA studies have identified correlations between prenatal phthalate exposure and expression of placental microRNAs, but a comprehensive assessment is needed to fully understand the role of placental microRNAs in phthalate mediated toxicity. Moreover, despite the potential importance of placental microRNAs as a biomarker of sPTB, there has not been a comprehensive analysis. In this proposal, we seek to fill these research gaps and apply innovative computational biology strategies with rigorous epidemiological approaches to gain insight into the mechanistic links between prenatal phthalate exposure, placental function, and sPTB. In aim 1, we will generate microRNA data on placental samples and use this to generate a signature of prenatal phthalate exposure. We will use the matched microRNA-mRNA sequencing data to construct a global placental microRNA-mRNA network, which we will apply to identify connections between microRNAs and genes whose placenta expression is associated with different phthalate metabolites. In Aim two, we will develop a multi- omic molecular signature of sPTB using our placental microRNA-mRNA network. In aim 3, we will examine the role of the placenta as a mechanistic link between prenatal phthalate exposure and sPTB by interdisciplinary strategies including an integrated pathway analysis and a formal mediation analysis. Findings from this study will inform chemical toxicological risk assessment and policy to reduce health impacts due to phthalate exposure in pregnancy. microRNA signatures of sPTB may serve as functional biomarkers of sPTB since they can be secreted into maternal circulation and be targets for clinical and therapeutic intervention in the future.