N-Nitrosodi- n-propylamine induces organ specific mutagenesis with specific expression times in lacZ transgenic mice

The mutagenic and clastogenic effects of N-nitrosodi- n-propylamine (NDPA) in lacZ transgenic mice (Muta™Mouse) were investigated as a part of the second collaborative study of the transgenic mouse mutation assay by a subgroup of the Mammalian Mutagenesis Study Group, a suborganization of the Environmental Mutagen Society of Japan. Male Muta™Mouse mice were administered NDPA intraperitoneally at a dose of 250 mg/kg, which is half of the LD 50 of the compound. The clastogenicity of NDPA was examined by the peripheral blood micronucleus test just before and at 24, 48 and 72 h after the treatment. The mutant frequencies in the bone marrow, liver, lung, kidney and urinary bladder were examined by the positive selection method for lacZ mutations on days 7, 14 and 28 after treatment and in the testis on day 28. NDPA did not cause a significant increase in micronucleated reticulocytes in peripheral blood. In the mutation assay, NDPA showed a statistically significant increase in mutant frequencies in the liver, lung and kidney. No biologically meaningful increase in mutant frequency was observed in the bone marrow, urinary bladder or testis. The mutant frequency in the liver increased in a time-dependent manner, whereas in the lung and kidney the mutant frequencies on days 14 and 28 were almost equal. The order of mutagenic potency of NDPA was liver>lung> kidney. These findings demonstrate that NDPA induces organ-specific mutagenesis with specific expression times, and that the mutagenicity of NDPA in lacZ transgenic mice is consistent with its carcinogenicity.