The development and testing of transgenic rat lines for genotoxicity testing during Phase I, demonstrate the overall project feasibility for developing an efficient multi-species system for monitoring in vivo mutations. These transgenic rat lines have been used to provide the first direct comparisons on mutant frequencies between two species utilizing the identical target gene. This proposal extends this preliminary work through the development of additional high copy number transgenic animals to reduce assay cost. In addition, this Phase II proposal will directly address the effects of chromosomal position on mutant frequency. Finally, the systems developed in this proposal will be used to test the mutagenic potential of species-specific carcinogens. The lambda phage shuttle vectors used in these transgenic animals permits the rapid in vivo screening of mutations. These systems allow quantitative tissue specific determination of mutant rates, and coupled with additional quantitative measures (e.g. DNA adduct levels) will allow for direct determination of the contribution of metabolic processes, cell proliferation, detoxification, DNA repair, and the route of dosing to mutagenesis. Currently, human risk assessment is performed through the extrapolation of tumorigenicity data obtained from multiple species testing (usually mouse and rat). The capability of directly monitoring mutations in two different species will provide a novel approach to human risk assessment using mutation data in conjunction with tumor data for an increased mechanistic understanding of how chemicals differentially induce mutations.
| Dycaico, M J; Provost, G S; Kretz, P L et al. (1994) The use of shuttle vectors for mutation analysis in transgenic mice and rats. Mutat Res 307:461-78 |
