DNA methylome signatures as epigenetic biomarkers of hexanal associated with lung toxicity

Abstract

Background. Numerous studies have investigated the relationship of environmental exposure, epigenetic effects, and human diseases. These linkages may contribute to the potential toxicity mechanisms of environmental chemicals. Here, we investigated the epigenetic pulmonary response of hexanal, a major indoor irritant, following inhalation exposure in F-344 rats. Methods. Based on DNA methylation profiling in gene promoter regions, we identified hexanal-characterized methylated sites and target genes using an unpaired t-test with a fold-change cutoff of > 3.0 and a p-value < 0.05. We also conducted an integrated analysis ofDNAmethylation andmRNAexpression data to identify core anti-correlated target genes of hexanal exposure. To further investigate the potential key biological processes and pathways of coreDNAmethylated target genes, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis were performed. Results. Thirty-six dose-dependent methylated genes and anti-correlated target genes of DNA methylation and mRNA in lung tissue of hexanal exposed F-344 rats were identified. These genes were involved in diverse biological processes such as neuroactive ligand-receptor interaction, protein kinase cascade, and intracellular signaling cascade associated with pulmonary toxicity. These results suggest that novel DNA methylation- based epigenetic biomarkers of exposure to hexanal and elucidate the potential pulmonary toxicological mechanisms of action of hexanal.