トランスジェニックマウス変異原性試験の有用性に関する研究

抄録

The transgenic mouse mutation assay was developed as a striking new tool for mutation research in 1990. This assay enables the detection of mutations in a transgene in multiple organs including germinal tissues and thus reveals organ-specific genotoxicity of the mutagen. Following its introduction in MutaMouse and Big Blue mouse systems, modification of the methodology, mainly the introduction of the positive selection system and development of other transgenic animal models including rat, improved and assured the relevance of the assay. Accumulation of experimental data suggests the transgenic mouse mutation assay can be used as a standard in vivo test for mutagenesis.
We have developed a multi-endpoint test, by combining the peripheral blood micronucleus assay with the transgenic mouse mutation assay. This test allows simultaneous detection of clastogenecity and mutagenecity in vivo. Since these two endpoints indicate different characteristics of the mutagen, data from many chemicals suggest the importance of detecting both endpoints. With this approach, the transgenic assay could detect the mutagenecity of diethylnitrosamine, which failed to be detected in micronucleus assay.
Another important advantage of this assay is its suitability for sequence analysis. Sequencing of the transgene enables to draw mutagen-specific mutation spectrum, a molecular signature of the mutagen, and is very useful to deduce the mechanism of mutagenesis. In this regard, we have intensively used a positively selectable target gene ‘cII’. This gene is relatively short (300 bp) which made the sequencing process easier and less time consuming and enables us to generate data on mutagenesis of several mutagens. We hope the database will be useful for molecular epidemiology in future.
A quantitative comparison of carcinogenic and mutagenic potency of chemicals revealed a good correlation with transgenic mutation assay and therefore suggesting a usefulness of this assay for the quantitative risk assessment.