DiversitySupp-ONES-Prenatal Phthalate Exposure

项目摘要 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，产前邻苯二甲酸酯与 暴露和早产。这项研究的目标是开发胎盘分子签名， 用于将产前邻苯二甲酸盐暴露与sPTB机械联系起来。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。我们的研究团队产生了世界上最大的 迄今的胎盘转录学数据集(N=760个样本)，并已使用该数据集开发转录学 出生前邻苯二甲酸盐暴露和肺结核的特征。这项研究将扩展我们现有的转录本 签名包括microRNAs，这对完整的分子签名是必不可少的，因为它们是 高度稳定，与许多环境暴露有关，并被分泌到母体 它们可以作为生物标志物的循环。候选的microRNA研究已经确定了相关性 产前邻苯二甲酸盐暴露与胎盘microRNAs表达之间的关系 需要评估以充分了解胎盘microRNAs在邻苯二甲酸盐介导的毒性中的作用。 此外，尽管胎盘微RNA作为sPTB的生物标记物具有潜在的重要性，但还没有 进行了全面的分析。在这项提案中，我们试图填补这些研究空白，并应用创新 计算生物学策略与严格的流行病学方法，以深入了解机制 产前邻苯二甲酸盐暴露、胎盘功能和单纯性肺结核之间的联系。在目标1中，我们将生成microRNA 胎盘样本的数据，并用它来生成产前邻苯二甲酸盐暴露的特征。我们将使用 匹配microRNA-mRNA测序数据构建全球胎盘microRNA-mRNA网络，该网络 我们将应用于确定microRNAs和其胎盘表达相关的基因之间的联系 含有不同的邻苯二甲酸盐代谢物。在第二个目标中，我们将开发一种sPTB的多组分子标记 利用我们的胎盘microRNA-mRNA网络。在目标3中，我们将研究胎盘作为一种 跨学科策略在产前邻苯二甲酸盐暴露和sPTB之间的机制联系 综合路径分析和正式中介分析。这项研究的发现将为化学公司 减少孕期邻苯二甲酸盐暴露对健康影响的毒理学风险评估和政策。 SPTB的microRNA特征可以作为sPTB的功能生物标志物，因为它们可以分泌到 母体循环，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 placneta 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.