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; 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.

项目摘要 自发早产（SPTB）包括大多数早产（60％），是主要案例 新生儿的发病率和死亡以及不良健康结果的预测指标。尽管患病率很高，但仍有 对Utero环境如何促进SPTB的病因的有限理解。邻苯二甲酸盐是 无处不在的内分泌破坏化学物质，诱导基因表达和生理变化 胎盘。流行病学研究确定了邻苯二甲酸酯暴露之间的一致正相关 和早产。这项研究的目的是开发可用于用于的胎盘分子特征 机械上将产前邻苯二甲酸盐暴露和SPTB连接起来。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措施的目标，包括 可修改的风险因素，例如环境暴露。我们的研究团队产生了最大的胎盘 转录组学数据集迄今（n = 760个样本），并已使用它来开发转录组签名 产前邻苯二甲酸盐和SPTB。这项研究将扩大我们现有的转录组特征，包括 microRNA对于完全分子签名至关重要，因为它们是高度稳定的，已经是 与许多环境暴露有关，并被分泌到孕产妇的流通中 作为生物标志物。候选microRNA研究确定了邻苯二甲酸酯暴露之间的相关性 和表达胎盘microRNA，但需要进行全面的评估以充分了解角色 邻苯二甲酸酯介导的毒性中的胎盘microRNA。而且，尽管胎盘的重要性可能 MicroRNA作为SPTB的生物标志物，尚未进行全面分析。在此提案中，我们寻求 填补这些研究空白，并使用严格的流行病学应用创新的计算生物学策略 方法可以深入了解产前邻苯二甲酸盐暴露，胎盘功能， 和SPTB。在AIM 1中，我们将生成有关胎盘样品的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测序数据来构建全局 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产物有关。在AIM二，我们将开发一个多 使用我们的胎盘MicroRNA-MRNA网络的SPTB的Omic分子特征。在AIM 3中，我们将检查 胎盘作为邻苯二甲酸酯暴露与SPTB之间的机械联系的作用 包括综合途径分析和正式中介分析的策略。这项研究的结果 将为化学毒理风险评估和政策提供信息，以减少邻苯二甲酸盐的影响 在怀孕。 SPTB的microRNA特征可以用作SPTB的功能性生物标志物，因为它们可以是 将来分泌成母亲的循环，并成为临床和治疗干预的靶标。