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

• 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
• 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

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.

项目摘要 与交通相关的空气污染（TRAP）是一种无处不在的环境暴露，一直与 动物和人类研究中的不良神经发育效应。但是，这些机制 效果目前尚不清楚，限制了我们的生物学理解并延迟介入和治疗 保护儿童免受这种广泛暴露的努力。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 陷阱影响对发育中大脑的影响的主要中介。 RNA的转录后修饰， 即，同一参考组，既对胎盘发展和至关重要 功能，因此提供了尚未开发的大道，以识别陷阱神经毒性的新机制。 N6- 甲基腺苷（M6A）是Messenger RNA（mRNA）和A的最普遍的表演体修饰 mRNA剪接，稳定性和翻译的调节剂。 M6A阅读器，作家和橡皮擦（RWE）蛋白质 从mRNA中解释，添加和去除M6A标记也对有毒物质高度敏感。我们的团队最近 表明陷阱到达人胎盘，从而表明局部陷阱的积累可能直接 更改胎盘的表面参考组和功能。但是，迄今尚无研究调查 胎盘暴露于陷阱与M6A上皮分类组学之间的关系，也没有任何先前的研究 研究了陷阱诱导的M6a上表面转录组与未来的儿童神经发育有关的变化。 我们假设胎盘负荷通过胎盘的变化对认知产生不利影响 M6A的表演组。为了研究这一假设，我们提出了一系列人类和体外 研究。对于人类研究，我们将利用总部位于纽约市哥伦比亚中心的两个队列 -Hermanos队列，作为发现和复制 套。在AIM 1中，我们将确定与产前相关的人胎盘中的M6A同幕书改变 陷阱。我们将使用一种创新的方法直接在胎盘和环境空气污染上量化BC 整个怀孕的评估。我们将使用M6A序列来剖面胎盘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学 与陷阱相关的胎盘功能障碍涉及的途径。在AIM 2中，我们将确定M6A的表面翻译组 与儿童认知相关的人胎盘的改变，年龄在5-6岁之间，通过一杯金来测量 标准神经心理学测试。在AIM 3中，我们将对滋养细胞进行体外研究，以鉴定陷阱 诱导的M6A表演组的改变及其对mRNA稳定性，剪接和翻译的影响。 这些目的共同发现陷阱对胎盘表演组和随后的影响 对儿童神经发育的影响。这项研究将导致对联系起来的机制的新颖洞察力 儿童神经发育的产前环境。