High LET ⁵⁶Fe ion irradiation induces tissue‐specific changes in DNA methylation in the mouse

Abstract

DNA methylation is an epigenetic mechanism that drives phenotype and that can be altered by environmental exposures including radiation. The majority of human radiation exposures occur in a relatively low dose range; however, the biological response to low dose radiation is poorly understood. Based on previous observations, we hypothesized that in vivo changes in DNA methylation would be observed in mice following exposure to doses of high linear energy transfer (LET) (56) Fe ion radiation between 10 and 100 cGy. We evaluated the DNA methylation status of genes for which expression can be regulated by methylation and that play significant roles in radiation responses or carcinogenic processes including apoptosis, metastasis, cell cycle regulation, and DNA repair (DAPK1, EVL, 14.3.3, p16, MGMT, and IGFBP3). We also evaluated DNA methylation of repeat elements in the genome that are typically highly methylated. No changes in liver DNA methylation were observed. Although no change in DNA methylation was observed for the repeat elements in the lungs of these same mice, significant changes were observed for the genes of interest as a direct effect and a delayed effect of irradiation 1, 7, 30, and 120 days post exposure. At delayed times, differences in methylation profiles among genes were observed. DNA methylation profiles also significantly differed based on dose, with the lowest dose frequently affecting the largest change. The results of this study are the first to demonstrate in vivo high LET radiation-induced changes in DNA methylation that are tissue and locus specific, and dose and time dependent.

Late-occurring chromosome aberrations and global DNA methylation in hematopoietic stem/progenitor cells of CBA/CaJ mice exposed to silicon (28Si) ions

“…Changes in 5mC patterns of specific genes (e.g. DAPK1 and p16) were detected in the lung, but not in the liver, of C3H/HeN mice at various times up to 120 d post-exposure to 600 MeV/n 56 Fe ions [55]. It was observed that abnormal patterns of 5mC (hypomethylation) at specific loci are frequently associated with microsatellite instability (MSI), which is often associated with deficiency in the mismatch repair (MMR) system found in human diseases such as cancers and abnormalities in the central nervous system (e.g.…”

“…Even though it is known that exposure to low LET radiation (such as X or ␥ rays) induces changes in the patterns of DNA methylation [49][50][51][52][53][54][55][56][57], little is known about the effects of high LET radiation (such as HZE particles found in the space environment) on global or gene-specific DNA methylation patterns [54,55]. Changes in 5mC patterns of specific genes (e.g.…”

Low-Dose Ionizing Radiation Exposure, Oxidative Stress and Epigenetic Programing of Health and Disease

“…Recently published studies indicate that LDIR exposure affects DNA methylation patterns. Using mouse model systems, LDIR exposure has been shown to demonstrate dose-dependent, sex and tissuespecific effects on global hypomethylation (83). For example, breast cancer cells treated with fractionated doses demonstrated locus-specific DNA hypomethylation at TRAPC1, FOXC1 and LINE1 genes (20,84).…”

Space Environmental Factor Impacts upon Murine Colon Microbiota and Mucosal Homeostasis

“…Low LET radiation, such as gamma and x-rays, is more likely to have indirect effects on cells through the generation of free radicals (e.g., H•, •OH, H 2 O 2 , and e - aq ), while high LET radiation can physically damage DNA and proteins [5, 6]. Both high and low LET radiation exposure can compromise plasma and organelle membrane integrity and cause DNA damage and DNA methylation [5, 7].…”