Long-term exposure to ambient fine particulate elements and leukocyte epigenome-wide DNA Methylation in older men: the Normative Aging Study

Abstract

Background and Aim: Several epigenome-wide association studies of ambient fine particulate matter (PM2.5) have been reported. However, none have been done on long-term exposure to PM2.5 elements (PEs). We hypothesized that significant changes in DNA methylation (DNAm) may vary by long-term exposure to PEs. Methods: We repeatedly collected blood samples in the Normative Aging Study and measured leukocyte DNAm with the Illumina HumanMethylation450K BeadChip. We predicted 15 PEs based on an ensemble of machine-learning algorithms. The spatial resolution was 50m × 50m for urban areas (majority in this study) and 1km × 1km for non-urban areas. We applied median regression with subject-specific intercepts for each of the 15 PEs and DNAm at individual cytosine-phosphate-guanine site, adjusting for PM2.5 mass. Significantly differentially methylated probes (DMPs) were identified by Bonferroni correction. We further conducted regional analyses and pathway analyses to identify differentially methylated regions (DMRs) and pathways. We also used nonnegative matrix factorization to identify source factors and obtained the source-specific effect estimates. Results: We included 672 men with 1,181 visits between 1999 and 2013. The significant DMPs, DMRs, and pathways varied by PEs. For example, lead was associated with one DMP and one pathway whereas organic carbon was associated with 45 DMPs and 30 pathways. The identified pathway by lead was involved in cardiovascular disease, whereas the pathways associated with organic carbon were related with reproductive function, nervous system, inflammation, etc. In addition, we identified four independent source factors, which had varied associations with DMPs, DMRs, and pathways. For example, source factor 1 (nitrate, ammonium) was associated with 43 pathways involved in cardiovascular disease, cancer, diabetes, aging, inflammation, etc. Conclusions: Long-term exposure to different PEs were differentially associated with DNAm changes at multiple probes, regions, and along multiple pathways. Keywords: PM2.5 elements; Source factors; DNA methylation; Epigenome-wide association study; Pathway analyses