Initial experiences and future directions for transgenic mouse mutation assays

Transgenic mice have introduced new possibilities in the field of mutation research and safety testing. Using lacZ transgenic mice (MutaTMMouse), we have combined in the peripheral blood micronucleus assay with the transgenic mouse mutation assay, enabling the concomitant detection of gene mutations and micronucleus induction in vivo in the same animals (Suzuki et al., 1993). Several mutagens, i.e., mitomycin C (MMC), ethyl nitrosourea (ENU), ethyl methanesulfonate (EMS) and diethyl nitrosamine (DEN), were tested in this combined assay. All of them increased the lacZ mutant frequency in bone marrow or liver, and all except DEN induced micronuclei in peripheral blood. These initial studies demonstrated that genotoxicity in vivo could be detected with these two endpoints and, more importantly, that some specificity exists among these tissues analyzed. Although transgenic mouse mutation assays have many potential applications in in vivo mutation research, several problems stand in the way of wider use. Paramount among these are cost and labor intensiveness. The color screening systems for lacZ or lacI mutation detection require large numbers of plates and tedious scoring processes. In order to make significant advances in this field, it will be necessary to use positive selection for induced mutants, such as has been described recently for the laZ and lacI transgenic mouse models.