Air pollution involving particulate matter smaller than 2.5 μm in size (PM2.5) is the world’s leading environmental risk factor contributing to mortality through cardiometabolic pathways. In this study, we modeled early life exposure using chow-fed C57BL/6J male mice that were exposed to real-world inhaled, concentrated PM2.5 (~10 times ambient levels/~60–120 μg/m3) or filtered air over a 14-week period. We investigated the effects of PM2.5 on phenotype, the transcriptome, and chromatin accessibility and compared these with the effects of a prototypical high-fat diet (HFD) as well as cessation of exposure on phenotype reversibility. Exposure to PM2.5 impaired glucose and insulin tolerance and reduced energy expenditure and 18FDG-PET uptake in brown adipose tissue. Multiple differentially expressed gene clusters in pathways involving metabolism and circadian rhythm were noted in insulin-responsive tissues. Although the magnitude of transcriptional change detected with PM2.5 exposure was lower than that observed with a HFD, the degree of alteration in chromatin accessibility after PM2.5 exposure was significant. The novel chromatin remodeler SMARCA5 (SWI/SNF complex) was regulated in response to PM2.5 exposure, the cessation of which was associated with a reversal of insulin resistance and restoration of chromatin accessibility and nucleosome positioning near transcription start sites, as well as a reversal of exposure-induced changes in the transcriptome, including SMARCA5. These changes indicate pliable epigenetic control mechanisms following cessation of exposure.
Sanjay Rajagopalan, Bongsoo Park, Rengasamy Palanivel, Vinesh Vinayachandran, Jeffrey A. Deiuliis, Roopesh Singh Gangwar, Lopa Das, Jinhu Yin, Youngshim Choi, Sadeer Al-Kindi, Mukesh K. Jain, Kasper D. Hansen, Shyam Biswal
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