PM-induced alteration of DNA methylation and RNA-transcription are associated with inflammatory response and lung injury.
Sci Total Environ. 2019 Feb 10 ;650(Pt 1):908-921. Epub 2018 Sep 7. PMID: 30308865
The mechanisms of systemic pulmonary inflammation and toxicity of fine particulate matter (PM) exposure remains unclear. The current study investigated the inflammatory response and lung toxicity of PMin rats following intratracheal instillation of PM. After repeated (treated every 3 days for 30 days) PMexposure, total protein (TP), lactate dehydrogenase (LDH) activity and inflammatory cytokines including interleukin 6 (IL-6), interleukin 1β (IL-1β) and tumor necrosis factor α (TNF-α) levels in bronchoalveolar lavage fluid (BALF) were markedly elevated. The expression levels of IL-6, IL-1β, TNF-α and NF-κB in rat lung tissue and BEAS-2B cells were significantly upregulated after PMexposure. Histopathological evaluation suggested that the major pathological changes were alveolar wall thickening and inflammatory cell infiltration of the lungs. Genome wide DNA methylation and RNA-transcription analysis was performed on human bronchial epithelial cells (BEAS-2B) to explore the potential mechanisms in vitro. PMinduced genome wide DNA methylation and transcription changes. Differentially methylated CpGs were located in gene promoter region linked with CpG islands. Integrated analysis with DNA methylation and transcription data indicated a clear bias toward transcriptional alteration by differential methylation. Disease ontology of differentially methylated and expressed genes addressed their prominent role in respiratory disease. Functional enrichment revealed their involvement in inflammation or immune response, cellular community, cellular motility, cell growth, development and differentiation, signal transduction and responses to exogenous stimuli. Gene expression validation of ACTN4, CXCL1, MARK2, ABR, PSEN1, PSMA3, PSMD1 verified their functional participation in critical biological processes and supported the microarray bioinformatics analysis. Collectively, our data shows that PMinduced genome wide methylome and transcriptome alterations that could be involved in pulmonary toxicity and pathological process of respiratory disease, providing new insight into the toxicity mechanisms of PM.