Short-Term PM_2.5 Exposure and DNA Methylation Changes of Circadian Rhythm Genes: Evidence from Two Experimental...

The circadian rhythm regulates many crucial physiological processes, impacting human aging and aging-related outcomes. Observational evidence links circadian rhythm disturbance to PM_2.5 exposure, yet the underlying DNA methylation mechanisms remain unclear due to limited PM_2.5-dominated experimental settings. Therefore, we investigated the associations between short-term PM_2.5 exposure and DNA methylation changes of 1188 CpG candidates across circadian genes among 32 young adults in the FDU study, with the validation in 26 individuals from the PKU study. Further mediation analyses tested whether DNA methylation of circadian genes could mediate the influence of PM_2.5 on aging measured by three epigenetic ages: DNAmGrimAge, DunedinPoAm, and the mortality risk score. We identified three CpG sites associated with personal PM_2.5 exposure: cg01248361 (CSNK2A2), cg17728065 (RORA), and cg22513396 (PRKAG2). Acute effects of PM_2.5 on the three loci could be mediated by several circulating biomarkers, including MDA and EGF, with up to ∼30% of mediated proportions. Three loci further showed varying potentials in mediating the aging acceleration effect of PM_2.5. Locus cg17728065 is the key site exhibiting a robust mediating effect (7.54-12.52%) on PM_2.5-induced aging acceleration. Our findings demonstrated that PM_2.5, even short-term peaks, could leave imprints on human aging via inducing aberrant temporal fluctuation in circadian homeostasis captured by DNA methylation profiles.