Proton-induced genetic damage in lacZ transgenic mice.

The plasmid-based lacZ transgenic mouse model system was used to evaluate the mutagenic and genotoxic potential of 250 MeV/nucleon proton radiation by evaluating the frequency of micronucleated polychromatic reticulocytes in peripheral blood and bone marrow and the mutant frequencies of the lacZ reporter transgene in spleen and brain, respectively. Doses of 0.1-2 Gy produced dose- and time-dependent changes in the frequency of micronucleated polychromatic reticulocytes within 48 h, with peak induction up to sixfold above control levels. The frequency of micronucleated polychromatic reticulocytes returned to control levels within 1 week after exposure. With doses of 4 Gy, the elevation in the frequency of micronucleated polychromatic reticulocytes was delayed up to 1 week after exposure, but complete recovery to control levels was observed at 16 weeks postirradiation. Significant increase in mutant frequencies in brain tissue was observed at 8 week after proton exposure at doses as low of 0.1 Gy. Mutant frequencies in spleen increased up to twofold above spontaneous mutant frequencies at 8 weeks after exposure to 0.5-1 Gy. These effects appeared saturated at doses >1 Gy for both tissues, possibly due to elimination of damaged cells from the tissue systems. These in vivo results highlight the importance of considering tissue specificity, dose and temporal dependence when assessing radiation effects.