Detection of gene mutation in skin, stomach and liver of MutaMouse following oral or topical treatment with N-methyl-N'-nitro-N-nitrosoguanidine or 1-chloromethylpyrene: some preliminary observations.

Abstract

Transgenic mouse assays, such as MutaMouse, provide a method to predict the potential target organ carcinogenicity of chemical compounds. As part of a validation study, the effects of the direct-acting mutagens, N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and 1-chloromethyl-pyrene (CMP), were investigated for gene mutation in the tissues of MutaMice after a single oral or topical exposure. MNNG (50 or 100 mg/kg) or CMP (25 or 50 mg/kg) were administered as a single oral dose and the mice killed after 3, 7 or 10 days. Mutation frequencies were determined in stomach DNA from both MNNG and CMP-treated animals and in liver DNA from the MNNG-treated animals only. The results, although obtained from a limited number of animals, consistently showed that MNNG increased the mutation frequency in stomach DNA, but not apparently in liver DNA, at each exposure time; no clear increase in mutation frequency was seen in the stomach DNA of CMP-treated animals. Also, MNNG (250 or 500 micrograms) or CMP (5 or 10 micrograms) in acetone were applied as a single dose to the shorn skin of mice 7, 14 or 21 days prior to death. A positive control group was similarly given dimethyl-benz[a]anthracene (DMBA, 40 micrograms) and sacrificed after 14 days. Mutation frequencies were determined in the skin DNA extracted from all animals and in the stomach DNA from MNNG-painted animals only. The results, again obtained from a limited number of animals, clearly showed that all test compounds consistently increased the mutation frequency of skin DNA and that these increases were far greater in the DMBA- and MNNG-treated mice than the CMP-treated mice. No apparent increases were seen in the stomach DNA from the MNNG-painted mice.