Impact of Arsenite on Transient and Persistent Histone H3 Modifications and Transcriptional Response

Arsenite-contaminated groundwater poses a major health concern affecting millions of people. Chronic exposure to elevated levels of inorganic arsenic is implicated in carcinogenesis, with impaired DNA repair and dysregulated DNA and histone modifications as key factors. Using human A549 lung carcinoma cells, we investigated the persistence of acute arsenite-induced cellular stress at the epigenetic and transcriptional levels after 24 h of exposure to 1–25 μM NaAsO$_2$, reflecting low to high acute exposure scenarios, followed by a 48 h arsenite-free postincubation period. The primary objective was to analyze alterations in acetylation and methylation marks on both bulk histone H3 and specific DNA repair gene loci. We conducted immunochemical and proteomic analyses to assess alterations in histone modification patterns. Transient effects were observed at both methylated and acetylated residues, with hypoacetylation specifically detected at promoters of certain DNA repair genes, including MLH1, MSH2, MPG, and XPA. Among all modifications analyzed, H3K18ac exhibited the most pronounced decline, suggesting its preferential sensitivity toward arsenite. ... mehrH3 hypoacetylation was further observed in noncancerous human BEAS-2B lung cells, indicating that this effect is not cancer cell-specific. Mechanistically, in A549 cells, increased total HDAC or decreased HAT activity could be excluded. Instead, a persistent moderate decline in HDAC activity and a delayed, pronounced induction of HAT activity suggest targeted arsenite interactions with specific enzymes of the histone acetylation regulatory network.