Short-Term PM_2.5 Exposure Impairs Cognitive Function and the DNA Methylation Signatures of Circadian Rhythm Genes

Fine particulate matter (PM_2.5) is a recognized contributor to cognitive decline, but the biological mechanisms by which circadian rhythms mediate short-term PM_2.5 exposure remain unclear. Using data from the Guangxi Eco-Environmental Health and Aging Study (GEHAS), which included 3554 observations from 1777 middle-aged and older adults, we examined whether DNA methylation of circadian rhythm genes mediates this association. A 5 μg/m³ increase in the 28-day average PM_2.5 exposure was significantly associated with a 0.474-point reduction in Mini-Mental State Examination (MMSE) scores (95% CI: -0.618, -0.329). Subgroup analyses showed stronger associations in women (β = -0.649; 95% CI: -0.830, -0.67) and middle-aged individuals (β = -0.382; 95% CI: -0.556, -0.208), whereas the association was attenuated and nonsignificant in men. Among 552 participants with DNA methylation data, we identified 44 CpG sites associated with PM_2.5 exposure (FDR < 0.05). Among these, cg25579477 in PRKAG2 mediated 10.04% of the PM_2.5 effect on cognitive function (P < 0.05), although no robust cis-mQTLs were detected. These findings suggest that short-term PM_2.5 exposure may impair cognitive function through epigenetic alterations of circadian rhythm genes, revealing a potentially modifiable pathway for mitigating air pollution's neurological impacts and informing public health interventions.