Epigenome-wide association study of household air pollution exposure in an area with high lung cancer incidence

Lung cancer incidence among never‐smoking women in Xuanwei, China, is among the highest worldwide and is primarily attributed to household air pollution (HAP) from smoky (bituminous) coal combustion, with early‐life exposure identified as playing a critical role. We conducted epigenome‐wide DNA methylation (DNAm) analyses of HAP exposure and its polycyclic aromatic hydrocarbon (PAH) constituents across exposure windows. Leukocyte DNAm was measured in 106 never-smoking women, including 23 individuals with repeated measurements. Cooking fuel use and stove type was obtained through questionnaire, and comprehensive personal and environmental air monitoring was conducted. Validated exposure models estimated 43 HAP constituents, predominantly PAHs, across childhood, current, and cumulative exposure windows, and PAH clusters were derived via hierarchical clustering. Generalized estimating equations were used to identify CpG sites associated with HAP exposure and PAH clusters, including 5-methylchrysene, a methylated PAH previously linked to lung cancer. We identified several differentially methylated CpG sites, predominantly hypomethylated with higher HAP exposure. Although some DNAm signatures overlapped with those observed in smoking, the majority were distinct. Notably, higher current exposure to 5-methylchrysene was significantly associated with hypomethylation at cg05575921 (AHRR; p = 2.05x10⁻⁰⁶), an established smoking marker. Life-course analyses indicated lasting DNAm variations with both childhood and cumulative PAH exposures at loci such as SLC43A2. Within the PAH clusters, 5-methylchrysene was a key contributor to DNAm variations. Top CpG sites were linked to immune regulation, G-protein coupled signaling, and molecular mechanisms of cancer and other disease pathways. These findings provide novel insight into HAP-induced DNAm changes and their potential health implications.