Particulate air pollution, pregnancy outcomes, and the role of placental extracellular microRNAs

项目摘要 早产和低出生体重与婴儿期发病率和死亡率的增加有关， 慢性疾病的影响因素。产妇在分娩期间暴露于颗粒空气污染 妊娠与这些不良妊娠结局有关。虽然暴露在空气污染中 每天都在变化，大多数研究都集中在平均累积暴露的影响上， 在怀孕期间。将空气污染与不良妊娠结局联系起来的潜在途径是 然而，不完全理解，越来越多的证据支持表观遗传失调，包括改变 microRNA（miRNA）表达，作为一种假定的机制。在妊娠期间，胎盘来源的miRNAs 可以被包装成囊泡，并被运输到母体和胎儿系统中的远距离目标， 被认为在蜂窝通信中发挥着关键作用。然而，胎盘miRNAs在空气中的潜在作用 污染与妊娠结局的关系尚不清楚。本研究的目的是：（1） 调查产前对颗粒空气污染暴露的敏感性窗口，以及2）检查是否 胎盘来源和胎盘组织的细胞外囊泡（EV）包裹的miRNAs发生改变， 在这些关系中的作用。在辅导K99阶段，科威尔博士将利用800名母亲的数据， 新生儿对登记在城市，主要是少数民族的跨代压力的编程 机制（PRISM）妊娠队列研究空间（1x 1 km）和时间（每日）分辨良好 颗粒物（PM2.5）暴露与胎儿生长、出生体重和胎龄的关系。完成 为此，考威尔博士将培训识别易感性窗口的方法，包括分布滞后模型 （DLM）和最近开发的用于检查交互的DLM扩展（例如，PM2.5中性）。她还将 培训用于分析转录组数据的计算方法，她将在R 00阶段应用这些方法。期间 在这一阶段，Cowell博士将研究使用RNA-seq测量的胎盘miRNAs是否作为一种联系， 空气污染暴露和怀孕结果之间的中介分析，并将研究对 胎盘miRNA-mRNA调控网络。她还将描述胎盘EV miRNAs的变化 并检查PM2.5暴露与变化的关系。这项研究的结果将提供信息， 减少接触和减轻其影响的公共卫生战略 发展时期。拟议的研究还将提供关于PM2.5如何在生物环境中运作的见解。 水平，并可能有助于识别早期和怀孕风险的信息生物标志物。博士 科威尔的指导团队在空气污染暴露、易感性建模、转录组学、 胎盘信号传导和胎盘学。该小组将提供针对拟议研究的现场培训 目标，并将指导科威尔博士的过渡到独立和她建立一个研究计划， 将“大数据”分析纳入儿童环境健康和分子流行病学研究。

PROJECT SUMMARY Preterm birth and low birthweight are associated with increased morbidity and mortality in infancy and are risk factors for chronic disease across the life course. Maternal exposure to particulate air pollution during pregnancy has been associated with these adverse pregnancy outcomes. Although exposure to air pollution varies on a daily basis, the majority of studies have focused on the effects of cumulative exposure averaged across pregnancy. The underlying pathways linking air pollution with adverse pregnancy outcomes are incompletely understood, however, growing evidence supports epigenetic dysregulation, including altered microRNA (miRNA) expression, as one putative mechanism. During pregnancy, miRNAs of placental origin can be packaged into vesicles and trafficked to distant targets in the maternal and fetal systems, where they are thought to play a key role in cellular communication. However, the potential role of placental miRNAs in air pollution-pregnancy outcome relationships is unknown. The goals of the proposed research are to 1) investigate windows of prenatal susceptibility to particulate air pollution exposure, and 2) examine whether altered extracellular vesicle (EV) encapsulated miRNAs of placental origin and placenta tissue miRNAs play a role in these relationships. During the mentored K99 phase, Dr. Cowell will leverage data from 800 mother- newborn pairs enrolled in the urban, predominantly minority PRogramming of Intergenerational Stress Mechanisms (PRISM) pregnancy cohort to investigate spatially (1x1 km) and temporally (daily) resolved fine particulate matter (PM2.5) exposure in relation to fetal growth, birthweight, and gestational age. To accomplish this, Dr. Cowell will train in methods for identifying windows of susceptibility, including distributive lag models (DLMs) and recently developed DLM extensions for examining interactions (e.g., PM2.5 х sex). She will also train in computational methods for analyzing transcriptomic data, which she will apply in the R00 phase. During this phase, Dr. Cowell will investigate whether placental miRNAs, measured using RNA-seq, serve as a link between air pollution exposure and pregnancy outcomes using mediation analysis and will examine effects on the placental miRNA-mRNA regulatory network. She will also characterize changes in placental EV miRNAs across pregnancy and examine PM2.5 exposure in relation to change. Results from this research will inform public health strategies for reducing exposure and mitigating its impact during the most sensitive developmental periods. The proposed studies will also provide insight on how PM2.5 operates at the biological level and may contribute to the identification of early and informative biomarkers of pregnancy risk. Dr. Cowell's mentoring team has expertise in air pollution exposure, susceptibility modeling, transcriptomics, placental signaling and neonatology. This team will provide on-site training tailored to the proposed research aims and will guide Dr. Cowell's transition to independence and her establishment of a research program that integrates `big data' analytics into children's environmental health and molecular epidemiology research.