Molecular Atlas of PM _2.5 Chemical Constituents on Cardiac Conduction: A Multiomics Landscape in Older Adults

Ambient fine particulate matter (PM_2.5) exposure is well-documented for cardiovascular risks, however, limited evidence regarding the underlying mechanisms on cardiac conduction in the elderly, especially regarding longitudinal impacts. We aimed to identify key toxic inorganic elemental constituents in PM_2.5 linked to cardiac electrophysiological abnormalities, DNA methylation-mediated pathways and the complex interplay with gene expression. The associations of PM_2.5 and its inorganic chemical constituents with electrocardiography (ECG) parameters were analyzed in 348 measurements of the healthy elderly by mixture exposure models. Epigenomic analyses and bidirectional mediation analyses were conducted to explore the effect patterns of epigenetic changes. Integrated analysis were performed to identify the potential biological pathways. Mixture exposure models identified S and Pb as major contributors to prolonged QRS duration and QTc interval. Bidirectional mediation analysis combined high-dimension mediating analysis revealed 43 cytosine-phosphoguanine sites (CpGs) significantly mediated the association between exposure to PM_2.5, Pb, and S and ECG parameters, with about 90% showing weaker reverse mediation. Cis-eQTM analysis showed that PM_2.5 and S elements associated DMPs modulated downstream gene expression, influencing ECG parameters. Specifically, four CpGs and their annotated gene expressions (<i>HMBOX1</i>, <i>C1orf109</i>, <i>ATAD3A</i>, and <i>RINL</i>) showed consistent effects on these associations, collectively involving multiple pathways, including the antigen presentation, ceramide accumulation, and circadian rhythm. This study elucidates that the incorporation of integrated epigenomic and transcriptomic profiles may provide novel insights into environmental origins and promising biomarkers for the clinical treatment of cardiovascular diseases.