Metabolic effects of air pollution exposure and reversibility

Air pollution involving particulate matter smaller than 2.5 μm in size (PM_2.5) 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 PM_2.5 (~10 times ambient levels/~60–120 μg/m³) or filtered air over a 14-week period. We investigated the effects of PM_2.5 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 PM_2.5 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 PM_2.5 exposure was lower than that observed with a HFD, the degree of alteration in chromatin accessibility after PM_2.5 exposure was significant. The novel chromatin remodeler SMARCA5 (SWI/SNF complex) was regulated in response to PM_2.5 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.