Relative activities of methyl methanesulphonate (MMS) as a genotoxin, clastogen and gene mutagen to the liver and bone marrow of Muta™Mouse mice

Abstract

The mutagenicity of the rodent carcinogen methyl methanesulphonate (MMS) to the liver and bone marrow of MutaMouse lacZ- transgenic mice was evaluated. A single intraperitoneal (i.p.) dose of 100 mg/kg MMS gave a strong positive response in the liver UDS and bone marrow micronucleus assays conducted 2 hr and 30 hr, respectively, after dosing. A single i.p. administration of 100 mg/kg of MMS, or five daily administrations of 20 mg/kg MMS, failed to increase significantly the lacZ- --> lacZ+ mutation frequency (MF) in either the liver or the bone marrow, albeit some evidence of weak mutagenicity was observed for the liver. The gene mutation analyses were undertaken 14 days after the final chemical exposure. Administration of the liver mitogens dimethylnitrosamine (DMN), or 4-acetylaminofluorene (4AAF), subsequent to multiple (five) exposures of 20 mg/kg MMS, foiled to enhance the mutagenicity of MMS to the liver, thereby eliminating the possibility that MMS produced promutagenic lesions in the liver that were not transformed to mutations because of the absence of MMS-induced cell division. In the latter experiments, DMN gave a strong mutagenic response and 4AAF a weak mutagenic response. Possible reasons for this selective mutagenicity of MMS (DNA damage and micronuclei induction in the absence of gene mutations) are discussed, but no clear outcome emerges. It is concluded that transgenic mutation assays should not be employed for defining genetic toxicity in vivo, but rather should be reserved for mechanistic studies on previously established rodent genotoxins and/or carcinogens.