Prenatal Traffic-Related Air Pollutants, Placental Epitranscriptomics, and Child Cognition

产前交通相关空气污染物、胎盘表观转录组学和儿童认知

基本信息

批准号：
10366988
负责人：
Andrea Baccarelli
金额：
$ 68.43万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-10 至 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10366988
关键词：
Address Age Air Pollutants Animals Attention Biological Blood Brain Carbon Black Child Cognition Data Development Environment Environmental Exposure Exposure to Fetal Growth Functional disorder Future Genetic Transcription Gold Growth and Development function Health Fairs Hispanic Human In Vitro Intelligence Intelligence Tests Intervention Life Link Low income Measures Mediating Mediator of activation protein Mental Health Messenger RNA Methods Modification Molecular Target Mothers Names Neuropsychological Tests Neurosecretory Systems Organ Pathway Analysis Pathway interactions Performance Placenta Placentation Post-Transcriptional RNA Processing Pregnancy Prevention Proteins RNA Splicing RNA Stability RNA, Messenger, Splicing Reader Regulation Reporting Research Role Series Short-Term Memory Siblings Signal Transduction Therapeutic Time Tissues Translations Work ambient air pollution base cohort design epitranscriptome epitranscriptomics executive function experimental study fetal follow-up in vitro Model innovation insight neurodevelopment neurodevelopmental effect neurotoxicity novel novel strategies population based postnatal prenatal prenatal influence recruit therapeutic target toxicant traffic-related air pollution trophoblast

项目摘要

PROJECT SUMMARY Traffic-related air pollution (TRAP) is a ubiquitous environmental exposure that has been consistently linked to adverse neurodevelopmental effects in animal and human studies. However, definitive mechanism(s) for these effects is currently unknown, limiting our biological understanding and delaying interventional and therapeutic efforts to protect children from this widespread exposure. The placenta oversees prenatal neurodevelopment through regulation of fetal growth and its neuroendocrine functions and has been consistently indicated as a primary mediator of the effects of TRAP on the developing brain. Post-transcriptional modifications of RNA, i.e., the epitranscriptome, are both environmentally sensitive and critical to placental development and functions, hence providing a yet unexplored avenue to identify new mechanisms of TRAP neurotoxicity. N6- methyladenosine (m6A) is the most prevalent epitranscriptomic modification on messenger RNA (mRNA) and a regulator of mRNA splicing, stability, and translation. The m6A reader, writer, and eraser (RWE) proteins that interpret, add, and remove m6A marks from mRNA are also highly sensitive to toxicants. Our team recently showed that TRAP reaches the human placenta, thereby indicating that local TRAP accumulation may directly alter the placental epitranscriptome and function. However, no research to date has investigated the relationships between placental exposure to TRAP and m6A epitranscriptomics, nor has any previous study investigated TRAP-induced m6A epitranscriptomic alterations in relation to future child neurodevelopment. We hypothesize that placental TRAP load adversely impacts cognition via changes in the placental m6A epitranscriptome. To investigate this hypothesis, we propose a coordinated series of human and in vitro studies. For the human studies, we will leverage two cohorts within the NYC-based Columbia Center for -Hermanos cohorts, as discovery and replication sets. In Aim 1, we will identify m6A epitranscriptome alterations in human placenta associated with prenatal TRAP. We will use an innovative method to quantify BC directly on the placenta and ambient air pollution assessment throughout pregnancy. We will use m6A-sequencing to profile placental m6A and measure protein and mRNA expression of 18 placental m6A RWEs. We will use data-driven approaches to identify biological pathways implicated in TRAP-related placental dysfunction. In Aim 2, we will identify m6A epitranscriptome alterations in human placenta associated with child cognition at ages 5-6 measured through a battery of gold- standard neuropsychological tests. In Aim 3, we will conduct in vitro studies of trophoblasts to identify TRAP- induced alterations of the m6A epitranscriptome and their impact on mRNA stability, splicing, and translation. Together, these aims will uncover the impacts of TRAP on the placental epitranscriptome and the ensuing effects on child neurodevelopment. This research will lead to novel insight into the mechanisms linking the prenatal environment to child neurodevelopment.

项目概要交通相关空气污染 (TRAP) 是一种普遍存在的环境暴露，一直与动物和人类研究中的不良神经发育影响。然而，这些的明确机制目前的影响尚不清楚，限制了我们的生物学理解并延迟了介入和治疗努力保护儿童免受这种广泛的接触。胎盘监督产前神经发育通过调节胎儿生长及其神经内分泌功能，并一直被认为是 TRAP 对大脑发育的影响的主要调节因素。 RNA转录后修饰，即表观转录组，对环境敏感并且对胎盘发育和功能，因此提供了一个尚未探索的途径来识别 TRAP 神经毒性的新机制。 N6- 甲基腺苷 (m6A) 是信使 RNA (mRNA) 上最常见的表观转录组修饰， mRNA 剪接、稳定性和翻译的调节因子。 m6A 读取器、写入器和擦除器 (RWE) 蛋白质从 mRNA 中解释、添加和删除 m6A 标记也对有毒物质高度敏感。我们团队最近表明 TRAP 到达人胎盘，从而表明局部 TRAP 积累可能直接改变胎盘表观转录组和功能。然而，迄今为止还没有研究调查过胎盘暴露于 TRAP 和 m6A 表观转录组学之间的关系，也没有任何先前的研究研究了 TRAP 诱导的 m6A 表观转录组改变与未来儿童神经发育的关系。我们假设胎盘 TRAP 负荷通过胎盘的变化对认知产生不利影响。 m6A 表观转录组。为了研究这一假设，我们提出了一系列协调一致的人类和体外实验研究。对于人类研究，我们将利用纽约哥伦比亚中心的两个队列 - Hermanos 队列，作为发现和复制套。在目标 1 中，我们将鉴定与产前相关的人类胎盘中 m6A 表观转录组的改变陷阱。我们将使用创新方法直接量化胎盘和环境空气污染中的 BC 整个怀孕期间的评估。我们将使用 m6A 测序来分析胎盘 m6A 并测量蛋白质和 18 个胎盘 m6A RWE 的 mRNA 表达。我们将使用数据驱动的方法来识别生物与 TRAP 相关的胎盘功能障碍有关的途径。在目标 2 中，我们将鉴定 m6A 表观转录组通过金电池测量与 5-6 岁儿童认知相关的人类胎盘变化标准神经心理学测试。在目标 3 中，我们将对滋养层进行体外研究，以确定 TRAP- 诱导 m6A 表观转录组的改变及其对 mRNA 稳定性、剪接和翻译的影响。这些目标将共同揭示 TRAP 对胎盘表观转录组的影响以及随后的结果对儿童神经发育的影响。这项研究将对连接机制产生新的见解产前环境对儿童神经发育的影响。