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It is important to evaluate the combined effects of low–dose-rate or low-dose radiation with chemicals as humans are exposed to a variety of chemical agents. Here, we applied gpt delta transgenic genotoxicity assay to examine combined genotoxic effects of low-dose-rate radiation and 4-(methylnitrosamino)-1-(3-pyridy1)-1-butanone (NNK), the most carcinogenic tobacco-specific nitrosamine and a methylating agent, in the lung of mice. In this mouse model, base substitutions and deletions can be separately analyzed by gpt and Spi- selections, respectively. Female gpt delta mice were treated either with gamma-irradiation alone at a dose rate of 0.5, 1.0 or 1.5mGy/h for 22 h/day for 31 days or its combination with NNK at a dose of 2mg/mouse/day, i.p. for four consecutive days in the middle course of irradiation. In the gpt selection, the NNK treatments enhanced the mutation frequencies (MFs) significantly, but no obvious combined effects of gamma-irradiation were observable at any given radiation dose. In contrast, NNK treatments appeared to suppress the Spi- large deletions. In the Spi- selection, when NNK treatments were combined, the dose-response curve became bell-shaped where the highest radiation dose decreased substantially. These results suggest that NNK treatments may elicit an adaptive response that eliminates cells bearing radiation-induced double-strand breaks (DSBs) in DNA. We are currently examining the mechanisms underlying the apparent suppressive effects of methylating agent against radiation-induced DSBs with human cells in vitro.
会議概要（会議名, 開催地, 会期, 主催者等）
The 7th Japan-France Workshop on Radiation Biology
gpt delta transgenic mice for in vivo genotoxicity assays: application for analysis of combined effects of radiation and chemicals
