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

项目总结 交通相关空气污染(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利神经发育影响。然而，对这些的最终机制(S) 影响目前尚不清楚，限制了我们对生物学的理解，并推迟了干预和治疗 保护儿童免受这种广泛接触的努力。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，一直被认为是一种 TRAP对发育中的大脑影响的主要介体。RNA的转录后修饰， 即表位转录组，既对环境敏感，又对胎盘发育和 因此，为确定TRAP神经毒性的新机制提供了一条尚未探索的途径。N6- 甲基腺苷(M6A)是信使RNA(MRNAs)上最常见的表观转录修饰。 信使核糖核酸剪接、稳定性和翻译的调节。M6A读写器和擦除器(RWE)蛋白 解释、添加和移除m6A标记也对毒物高度敏感。我们的团队最近 表明陷阱到达人的胎盘，从而表明局部陷阱的积累可能直接 改变胎盘表位编码组和功能。然而，到目前为止还没有研究调查过 胎盘暴露于TRAP与m6A表位转录之间的关系，此前也没有任何研究 研究了TRAP诱导的m6A表位转录改变与未来儿童神经发育的关系。 我们假设胎盘陷阱负荷通过胎盘的变化对认知产生不利影响。 M6A表位转录组。为了研究这一假设，我们提出了一系列协调的人体和体外实验。 学习。对于人体研究，我们将利用位于纽约的哥伦比亚中心内的两个队列来进行 -Hermanos队列，作为发现和复制 布景。在目标1中，我们将确定人类胎盘中与产前相关的m6A表位编码组改变。 陷阱。我们将使用一种创新的方法来直接量化胎盘和环境空气污染中的BC 在整个怀孕期间进行评估。我们将使用m6A-测序来分析胎盘组织中的m6A并测量蛋白质 18例胎盘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通路。在目标2中，我们将确定m6A表位转录组 通过一组金电池测量与5-6岁儿童认知相关的人类胎盘变化- 标准的神经心理测试。在目标3中，我们将进行滋养层细胞的体外研究，以确定TRAP- 诱导m6A表位转录组的改变及其对信使核糖核酸稳定性、剪接和翻译的影响。 总之，这些目标将揭示TRAP对胎盘表位转录组的影响以及随后的 对儿童神经发育的影响。这项研究将导致对连接机制的新见解 产前环境对儿童神经发育的影响。

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.