The goal in environmental mutagenesis is to achieve realistic predictions of hazard to human and natural populations from exposure to chemicals introduced by society. A large improvement over the currently available mouse mutation models could be made if in a new model the target gene(s) would be active and analysis could be performed at a single cell level. Only a gain of function assay will be sufficiently sensitive to detect a single mutant cell among normal cells within a tissue sample. The new transgenic mouse mutation models will be based on the expression of the genes encoding beta-galactosidase (lacZ) or enhanced green fluorescent protein (EGFP) as controlled by the expression of the genes encoding the lac repressor protein (lacl) and the reverse tet-controlled transactivator (rtTA), respectively. The method for introducing the transgenes uses homologous recombination in embryonic stem cells having a single copy each transgene integrated into a chosen location in the genome based on a proven principle. This new in vivo model will provide an unique opportunity to study cell type-specific differences in mutagenicity using chemical exposure(s) at levels which do not produce acute symptoms but which may produce detectable effects such as apoptosis and tumors, later.
The development of new drugs and chemicals by pharmaceutical and chemical industries requires that the safety of these new compounds is evaluated as regards to their potential toxic effects. The new transgenic mouse mutation models, combined with an existing lacZ plasmid-based mutation model, is expected to become a standard tool in toxicology testing by industry and academia involved in toxicological testing and cancer risk assessment. As such, these new models have great commercial potential.
