Combined Effect of Ionizing Radiation and N-Ethyl-N-Nitrosourea on Mutation Induction and Lymphoma Development

Abstract

Carcinogenesis in humans is thought to result from exposure to numerous environmental factors. Little is known, however, about how these different factors work in combination to cause cancer. Mouse thymic lymphoma is a good model for research on radiation and chemical carcinogenesis. We examined here the occurrence of thymic lymphoma and mutation induction following exposure to both X-rays and N-ethyl-N-nitrosourea (ENU) in B6C3F1 mice. Mice were exposed weekly to whole-body X-irradiation (0.2 or 1.0 Gy per each exposure) for 4 consecutive weeks, ENU (200 ppm) in the drinking water for 4 weeks, or X-irradiation followed by ENU treatment. The incidence of lymphoma after 0.2 and 1.0 Gy were 0% and 10%, respectively. ENU treatment induced lymphoma in 20% of exposed mice. When ENU was combined with 1.0 Gy, lymphoma incidence increased up to 94%, showing a synergistic effect. In contrast, combination of ENU with 0.2 Gy resulted in a decrease in lymphoma incidence, that is, an antagonistic effect. Mutant frequency of the reporter transgene gpt after ENU exposure alone increased by tenfold compared to untreated controls. Combined exposure of ENU with 0.2 Gy X-rays dramatically decreased mutant frequency. In contrast, 1.0 Gy X-rays combined with ENU further enhanced mutant frequency and accelerated clonal expansion of mutated cells. In conclusion, the mutagenic and carcinogenic effect of combined exposure of X-rays with ENU is dose dependent.