DNA hydroxymethylation landscape and mitochondrial DNA in lung fibroblasts exhibit specific signatures of single- and multi-fraction alpha-particle radiation

We report that SF and MF α-irradiation primarily increased DNAhm levels, with more alterations observed following the MF exposure: the gene body region being more susceptible to these alterations. The genes with increased DNAhm levels due to the MF exposure, contrarily to the SF, led to a profound disruption of the inflammatory response and other cellular pathway-based biomarkers of radiation in the α-irradiated cells.

We also detected DNAhm changes in key genes encoding enzymes involved in DNAm / demethylation processes, which supports the previous DNAm findings. Similar to DNAm, MF α-irradiation induced a greater number of DNAhm aging changes. Compared to equivalent SF doses, the MF pro-oxidant α-irradiation also resulted in more mitochondrial damage, specifically in the hydroxymethylome of nuclear-encoded mitochondrial genes and the mitochondrial DNA copy number.

Although at equivalent doses, SF and MF α-radiation exposures induce radically different effects on the DNAhm and mitochondrial DNA. The DNAhm changes help explain the effects observed in our 2023 methylome study. These findings prove that environmental exposure regimens are a major consideration when assessing DNAm and DNAhm biomarkers and the potential health effects of a pro-oxidant such as α-radiation.