Exposure to environmental toxicants reduces global N6-methyladenosine RNA methylation and alters expression of RNA methylation modulator genes

The epitranscriptome comprises more than 100 forms of RNA modifications. Of these, N6-methyladenosine (m⁶A) is the most abundantform of RNA methylation, with roles in modulating mRNA transcript processing and regulation. The aims of the study weretoexamine changes inm⁶A RNA methylation in A549 lung epithelial cells in response to environmental toxicants, anddifferential gene expression of m⁶A modulator genes ('readers', 'writers' and 'erasers') in human subjects exposed toparticulate matter (PM) and in lung cancer tissueusing publicly-available microarray datasets. Global m⁶A methylation levelsweremeasured in total RNA after exposuretotwo carcinogens (PM and sodium arsenite) for 24- and 48-h, and totwo endocrine disruptors (bisphenol A and vinclozolin)for 24-h.Global m⁶A methylation level significantly decreased with exposure to >62 μg/mlPM, >1 μM sodium arsenite, >1  μM bisphenol A (BPA), and0.1  μM vinclozolin. In an analysis of a published dataset derived from a population study, we observed that m⁶A writers (METTL3 and WTAP), erasers (FTO and ALKBH5) and readers (HNRPC) showed significantly higher expression among participants in the high-PM_2.5exposure group compared to those in the low-exposure control group (all p < 0.05). Further, the m⁶A writer METTL3shows reduced expression in lung tumors in comparison to normal lung epithelia (p < 0.0001). Our findings reveal that m⁶A RNA methylation can be modified by exposure to environmental toxicants, and exposure to particulate matter is associated with differential expression level of m⁶A RNA methylation modification machinery.