RELATIVE ACTIVITIES OF METHYL METHANESULFONATE (MMS) AS A GENOTOXIN, CLASTOGEN AND GENE MUTAGEN TO THE LIVER AND BONE-MARROW OF MUTA(TM)MOUSE MICE

The mutagenicity of the rodent carcinogen methyl methanesulphonate (MM S) to the liver and bone marrow of Muta(TM)Mouse lacZ(-) transgenic mi ce was evaluated. A single intraperitoneal (i.p.) dose of 100 mg/kg MM S gave a strong positive response in the liver UDS and bone marrow mic ronucleus assays conducted 2 hr and 30 hr, respectively, after dosing. A single i.p. administration of 100 mg/kg of MMS, or five daily admin istrations 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 th e liver. The gene mutation analyses were undertaken 14 days after the final chemical exposure. Administration of the liver mitogens dimethyl nitrosamine (DMN), or 4-acetylaminofluorene (4AAF), subsequent to mult iple (five) exposures of 20 mg/kg MMS, failed to enhance the mutagenic ity of MMS to the liver, thereby eliminating the possibility that MMS produced promutagenic lesions in the liver that were not transformed t o mutations because of the absence of MMS-induced cell division. In th e latter experiments, DMN gave a strong mutagenic response and 4AAF a weak mutagenic response. Possible reasons for this selective mutagenic ity of MMS (DNA damage and micronuclei induction in the absence of gen e mutations) are discussed, but no clear outcome emerges. It is conclu ded that transgenic mutation assays should not be employed for definin g genetic toxicity in vivo, but rather should be reserved for mechanis tic studies on previously established rodent genotoxins and/or carcino gens. (C) 1998 Wiley-Liss, Inc.