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

项目总结 自发性早产(SPTB)占早产的60%，是主要的早产病例。 新生儿发病率和死亡率以及不良健康后果的预测因子。尽管其流行率很高，但有 对子宫内环境如何导致肺结核的病因认识有限。邻苯二甲酸酯是 无处不在的内分泌干扰化学物质，可在体内诱导基因表达和生理变化 胎盘。流行病学研究发现，产前邻苯二甲酸酯暴露与 还有早产。这项研究的目标是开发胎盘分子签名，可用于 从机制上讲，产前邻苯二甲酸盐暴露与sPTB有关。胎盘分子特征可以解释 与肺结核相关的功能差异，并确定临床和治疗干预的目标，包括 可更改的风险因素，如环境暴露。我们的研究团队制造了世界上最大的胎盘 到目前为止的转录转录数据集(N=760个样本)，并利用这一数据开发了 产前邻苯二甲酸盐暴露和肺结核。这项研究将扩展我们现有的转录签名，以包括 MicroRNAs对于完整的分子签名是必不可少的，因为它们高度稳定，一直以来 与许多环境暴露有关，并被分泌到母体循环中，在那里它们可能会服务于 作为生物标志物。候选的microRNA研究已经确定了产前邻苯二甲酸酯暴露之间的相关性 和胎盘microRNAs的表达，但需要进行全面的评估才能充分了解其作用 胎盘微RNA在邻苯二甲酸盐介导的毒性中的作用。此外，尽管胎盘的潜在重要性 MicroRNAs作为sPTB的生物标志物，目前还没有一个全面的分析。在这项建议中，我们寻求 填补这些研究空白，并应用创新的计算生物学策略和严格的流行病学 了解产前邻苯二甲酸盐暴露、胎盘功能、 和sPTB。在目标1中，我们将生成关于胎盘样本的microRNA数据，并使用该数据生成签名 出生前接触邻苯二甲酸盐的风险。我们将使用匹配的microRNA-mRNA测序数据来构建全局 胎盘microRNA-mRNA网络，我们将应用该网络来识别microRNA和基因之间的联系 其胎盘表达与不同的邻苯二甲酸盐代谢产物有关。在目标二中，我们将开发一种多 用我们的胎盘microRNA-mRNA网络研究sPTB的基因组分子特征。在目标3中，我们将研究 胎盘作为产前邻苯二甲酸盐暴露和sPTB之间的机械联系的作用 战略，包括综合途径分析和正式调解分析。这项研究的发现 将为化学毒理学风险评估和政策提供信息，以减少邻苯二甲酸盐暴露对健康的影响 在怀孕期间。SPTB的microRNA签名可以作为sPTB的功能生物标志物，因为它们可以 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.