Gamma radiation at a human relevant low dose rate is genotoxic in mice

Abstract

Even today, 70 years after Hiroshima and accidents like in Chernobyl and Fukushima, we still have limited knowledge about the health effects of low dose rate (LDR) radiation. Despite their human relevance after occupational and accidental exposure, only few animal studies on the genotoxic effects of chronic LDR radiation have been performed. Selenium (Se) is involved in oxidative stress defence, protecting DNA and other biomolecules from reactive oxygen species (ROS). It is hypothesised that Se deficiency, as it occurs in several parts of the world, may aggravate harmful effects of ROS-inducing stressors such as ionising radiation. We performed a study in the newly established LDR-facility Figaro on the combined effects of Se deprivation and LDR γ exposure in DNA repair knockout mice (Ogg1−/−) and control animals (Ogg1+/−). Genotoxic effects were seen after continuous radiation (1.4 mGy/h) for 45 days. Chromosomal damage (micronucleus), phenotypic mutations (Pig-a gene mutation of RBCCD24−) and DNA lesions (single strand breaks/alkali labile sites) were significantly increased in blood cells of irradiated animals, covering three types of genotoxic activity. This study demonstrates that chronic LDR γ radiation is genotoxic in an exposure scenario realistic for humans, supporting the hypothesis that even LDR γ radiation may induce cancer.

The Pig‐a Gene Mutation Assay in Mice and Human Cells: A Review

“…If not removed, the DNA polymerases may misincorporate adenine opposite 8‐oxoG, which may be removed by MutY that excises adenine from 8oxoG:A base pairs, giving a new chance for Ogg1 to remove 8‐oxoG. Studies of Ogg1‐deficient mice have shown no significant elevation of the spontaneous Pig‐a mutation frequency , which correlates well with the lack of cancer phenotype in this mouse model. The Ogg1‐deficient mice have been subjected to BaP, to Se deficiency and to low dose rate gamma irradiation without the Pig‐a ‐mutant cell frequency exceeding the wild‐type levels, suggesting that the DNA damage levels induced are being repaired via other backup DNA repair systems.…”

“…We recently published a study on single and combined effects of continuous chronic low dose rate gamma exposure and selenium deprivation via diet in a mouse model with deficient repair of oxidized DNA (8‐oxoguanine DNA glycosylase‐deficient mice; Ogg1 −/− ) and control animals. The main result of this study was that gamma radiation given in a more environmentally relevant exposure manner (1.48 mGy/hr for 45 days to a total dose of 1.5 Gy) is indeed genotoxic in mice . One of several methods used to determine genotoxic effects was the Pig‐a gene mutation analyses.…”

“…Mutagenic effects of ionizing radiation such as X‐rays and gamma irradiation have been studied and provide valuable information concerning timing of mutant induction and elimination in mice, as well as responses after acute versus protracted/chronic exposure to mutagens. Moreover, in contrast to many chemicals, ionizing radiation does not depend on metabolic activation to exert its effects.…”

“…In mice, the maximum response after protracted exposures seems to occur later than after acute exposures , so in the study by Graupner et al . , an additional measurement time‐point at 4 weeks after exposure cessation would have given valuable information. Acute exposure to ionizing radiation, on the other hand, clearly induces Pig‐a mutants .…”

“…Mice exhibiting different deficiencies in DNA repair proteins involved in protection of the genome from oxidized DNA have been studied [, Rolseth et al ., unpublished]. The DNA repair proteins investigated are involved in base excision repair eliminating oxidized DNA damage and comprise 8‐oxoguanine DNA glycosylase (Ogg1), the MutY DNA glycosylase (MutY) and three endonuclease VIII‐like DNA glycosylases (Neil1, Neil2 and Neil3) as well as the tumour protein p53 (p53).…”