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.
Cheng
L
L
Department of Environmental Health, University of Cincinnati College of Medicine, OH 45267-0056, USA.
Sonntag
D M
DM
de Boer
J
J
Dixon
K
K
D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D002273:Carcinogens / Q000633:toxicity*; D004247:DNA / Q000187:drug effects / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D005978:Glutathione / Q000378:metabolism; D007322:Instillation, Drug; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D008175:Lung Neoplasms / Q000139:chemically induced* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016296:Mutagenesis / Q000187:drug effects* / Q000235:genetics; D009153:Mutagens / Q000633:toxicity*; D009154:Mutation / Q000235:genetics; D011192:Potassium Dichromate / Q000633:toxicity*; D014132:Trachea
D000963:Antimetabolites; D002273:Carcinogens; D009153:Mutagens; D019328:Buthionine Sulfoximine; D004247:DNA; D005978:Glutathione; D011192:Potassium Dichromate