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

评估产前邻苯二甲酸盐暴露如何扰乱胎盘转录调节并导致妊娠长度的变化

• 批准号: 10578186
• 负责人: Alison Genevieve Paquette
• 金额: $ 66.01万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-11 至 2027-10-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10578186
• 关键词: Address; Assessment tool; Big Data; Biological Markers; Black race; Cessation of life; Chemicals; Circulation; Clinical; Computational Biology; Data; Data Set; Development; Endocrine Disruptors; Environment; Environmental Exposure; Epidemiology; Etiology; Exposure to; Fatty Acids; Functional disorder; Future; Gene Expression; General Population; Genes; Goals; Health; High Prevalence; Inflammation; Length; Link; Mediating; Mediation; Medical; Medical Research; Messenger RNA; Metabolic Pathway; Metabolism; MicroRNAs; Minerals; Molecular; Molecular Profiling; Morbidity - disease rate; Multiomic Data; National Institute of Environmental Health Sciences; Newborn Infant; Outcome; Overlapping Genes; Participant; Pathway Analysis; Pathway interactions; Physiological; Placenta; Policies; Population; Pregnancy; Pregnancy Trimesters; Pregnant Women; Premature Birth; Public Policy; Research; Risk; Risk Assessment; Risk Factors; Role; Sampling; Second Pregnancy Trimester; Signal Transduction; Steroid biosynthesis; Therapeutic Intervention; Third Pregnancy Trimester; Toxic effect; Toxicology; Transcriptional Regulation; Underrepresented Populations; absorption; cohort; environmental chemical; epidemiology study; high risk; in utero; innovation; insight; knowledge translation; mRNA sequencing; modifiable risk; multiple omics; notch protein; novel; perinatal outcomes; phthalates; potential biomarker; prenatal; prenatal exposure; repaired; targeted treatment; transcriptomics; urinary

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.

项目概要 自发性早产 (sPTB) 占早产的大多数 (60%)，是早产的一个主要案例 新生儿发病率和死亡以及不良健康结果的预测因素。尽管患病率很高，但 对宫内环境如何影响 sPTB 的病因学了解有限。邻苯二甲酸盐是 普遍存在的内分泌干扰化学物质，可诱导体内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盐暴露之间存在一致的正相关关系 和早产。这项研究的目的是开发胎盘分子特征，可用于 从机制上将产前邻苯二甲酸盐暴露与 SPTB 联系起来。胎盘分子特征可以解释 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，例如环境暴露。我们的研究团队已经产生了最大的胎盘 迄今为止的转录组学数据集（N = 760 个样本），并使用它来开发转录组学特征 产前邻苯二甲酸盐暴露和 SPTB。这项研究将扩展我们现有的转录组特征，包括 microRNA 对于完整的分子特征至关重要，因为它们高度稳定，已被 与许多环境暴露有关，并分泌到母体循环中，在那里它们可以发挥作用 作为生物标志物。候选 microRNA 研究已确定产前邻苯二甲酸盐暴露之间的相关性 和胎盘 microRNA 的表达，但需要进行全面评估才能充分了解其作用 胎盘 microRNA 在邻苯二甲酸盐介导的毒性中的作用。此外，尽管胎盘具有潜在的重要性 microRNAs作为sPTB的生物标志物，目前尚未有全面的分析。在本提案中，我们力求 填补这些研究空白，并应用严格的流行病学创新计算生物学策略 深入了解产前邻苯二甲酸盐暴露、胎盘功能、 和 SPTB。在目标 1 中，我们将生成胎盘样本的 microRNA 数据，并使用它来生成签名 产前邻苯二甲酸盐暴露。我们将使用匹配的 microRNA-mRNA 测序数据构建全局 胎盘 microRNA-mRNA 网络，我们将应用它来识别 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 网络分析 sPTB 的组学分子特征。在目标 3 中，我们将检查 跨学科研究胎盘作为产前邻苯二甲酸盐暴露与 sPTB 之间机制联系的作用 策略包括综合路径分析和正式中介分析。这项研究的结果 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 特征可以作为 sPTB 的功能生物标志物，因为它们可以 分泌到母体循环中，并成为未来临床和治疗干预的目标。