Chromium(VI)-induced mutagenesis in the lungs of big blue transgenic mice

The mutagenic activity of the hexavalent chromium [Cr(VI)] compound potassium dichromate was examined in the Big Blue transgenic mouse lung, the target organ for Cr(VI) carcinogenesis in humans. Mice were exposed to Cr(VI) by intratracheal instillation of a potassium dichromate (K2Cr2O7) solution. Analysis of the deposition of Cr in mouse lungs revealed that the procedure reproducibly resulted in about 5% retention of the Cr in the lung. Lower but measurable levels were detected in kidney and liver. We found a dose-dependent and time-dependent increase in the mutant frequency in the mouse lung. A significant elevation of the mutant frequency above the spontaneous background was observed two weeks after Cr(VI) intratracheal instillation and at doses above 3 mg/kg. Depletion of tissue glutathione (GSH) levels by buthionine sulfoximine (BSO) before Cr(VI) treatment led to a decrease in the Cr(VI)-induced mutant frequency, compared to that in the animals with normal GSH levels, suggesting a role for GSH in the generation of reactive intermediates during the intracellular reduction of Cr(VI). Sequence analysis for the Cr(VI)-induced mutants revealed a similarity to the spontaneous mutational spectrum observed in mouse lungs, consistent with the generation of oxidative-type DNA damage by Cr(VI). These results demonstrate that Cr(VI) is mutagenic in mouse lung, the target organ for human carcinogenesis.