Concurrent low-dose-rate gamma irradiation and inorganic arsenite: genotoxicity and transcriptional responses in liver and testis in CBA and C57BL/6 mice

Humans in arsenic-endemic and radiologically exposed settings may be co-exposed to inorganic arsenic and ionizing radiation, yet the combined effects of chronic low-dose-rate irradiation and environmentally relevant arsenic are poorly defined. In a single factorial experiment, male CBA and C57BL/6N mice were exposed to sodium arsenite in drinking water (0, 0.3 or 3 mg/L) and chronic γ irradiation (2.5 mGy/h, total 3 Gy), alone and combined. We measured blood genotoxicity (comet and micronucleus assays), characterised 21 circulating miRNAs, and sequenced liver and testis transcriptomes, analysing all endpoints in a factorial model (arsenite × irradiation × strain). Arsenite exposure was accompanied by an increase in oxidative DNA lesions in white blood cells along a slight reduction in single strand breaks. Micronucleus frequency in reticulocytes and erythrocytes was not affected by arsenite. Arsenite was identified as an oxidative rather than a chromosomal genotoxicant. The liver and testis transcriptomes shared a common DNA-repair and oxidative-stress response that diverged between the organs. Irradiation was the dominant stressor while the concurrent arsenite exposure was mainly non-additive or counteracting, but also additive effects were observed. Only two miRNAs responded to arsenite. Baseline strain differences were large but additive, with negligible strain×treatment interaction. Our study contributes new data, experimental design and analysis methods about the genotoxic and transcriptional landscape of multiple stressor exposures.