PM2.5 Constituents and Cardiopulmonary Dysfunctions in Older Adults: A Multiomics Approach Unveiling Molecular Pathways

Abstract The cardiopulmonary risks of fine particulate matter (PM2.5) are linked to its constituents, yet key constituents and underlying molecular pathways driving cardiopulmonary dysfunctions in older adults remain elusive. In a longitudinal panel study of 313 measurements, we assessed associations between PM2.5 constituents and cardiopulmonary functions and explored mediation effects by DNA methylation and gene transcription using personal monitoring data. We combined a linear mixed-effects model with three machine-learning methods to identify key PM2.5 constituents, and employed mediation analysis and Ingenuity Pathway Analysis to explore potential epigenetic and transcriptional mediators and biological pathways. Our findings revealed that chloride ion (Cl–), nickel (Ni), barium, and selenium were the key constituents of PM2.5 inducing cardiopulmonary dysfunction. Interquartile range (IQR) increases in Cl– and Ni were associated with a 3.48% (95% CI: 1.50%, 5.46%) increase in diastolic blood pressure and a 0.09% (95% CI: 0.05%, 0.12%) decrease in FEV1/FVC, respectively. Mediation analysis identified 212 cytosine-phosphate-guanine (CpG) sites that regulated both cardiovascular and pulmonary dysfunctions, and 7 genes mediating more than two distinct constituent-function associations. Neurotransmission, metabolism, and cardiovascular function-related pathways were primarily enriched, among which 22 CpG sites (e.g., cg07115148, cg26409134, and cg26613778) were identified as key epigenetic mediators. Expression quantitative trait methylation analysis revealed that these CpG sites were associated with 14 protein-coding genes including CERS6 and LRCH3. Our findings suggest that short-term exposure to PM2.5 constituents triggers cardiopulmonary dysfunctions via DNA methylation-gene transcription axes and related disruption of neurotransmission, metabolism, and cardiovascular signaling pathways.