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

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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.