Mutational landscape induced by chronic exposure to environmental PM and PM in A549 lung epithelial cell.

Exposure to particulate matter (PM) has been linked to an increased risk of multiple diseases, primarily lung cancer, through various molecular mechanisms. However, the mutagenic potential of PM remains unclear. This study aimed to provide a comprehensive description of genetic mutations and mutagenic signatures resulting from chronic exposure to PM or PM. Using whole exome sequencing, we identified driver mutations and mutational signatures in A549 cells, a lung epithelial cell model subjected to weekly exposure to either PM or PM for a period of 28 weeks. The number of single nucleotide variations, insertions, and deletions increased depending on the duration of exposure. PM generated the highest number of genomic alterations. Amplifications in SYK (oncogene) and mutations in NCOR1 (tumor suppressor gene) were prevalent in cells exposed to either PM or PM; however, other mutations were exclusive, such as TP53 and ANK3 for PM, and ERCC1 and ERCC2 for PM. Different p53-related signaling pathways were most enriched by driver mutations upon exposure to both PM and PM, particularly the glucose deprivation pathway. Exposure to either PM or PM resulted in high frequencies of C > A substitutions and one-base insertions/deletions in microhomology sites. The single-base substitution (SBS) signature SBS05, related to the nucleotide excision DNA repair pathway, contributed the most to both PM-and PM-exposed cells. The contribution of signature SBS18, related to oxidative stress, was observed in cells exposed to either PM or PM, but a greater contribution was observed in PM-exposed cells. In addition, SBS03 and SBS36, which are related to different DNA damage repair mechanisms, were observed more frequently in PM-exposed cells. We assessed the mutagenic potential of PM and PM, as a complete mixture, identifying mutated driver genes and mutational signatures generated by chronic PM exposure, which could contribute to the development of cancer, cardiovascular, and digestive diseases.