PARENT SESSION

Ion Beams from Physics to Therapy

(SY014) Transgenic mouse mutation models and heavy ion effects.

Chang, Polly^*,1, ¹ Molecular and Genetic Toxicology/Biosciences Division, Menlo Park, CA, USA

ABSTRACT- The study of genetic mechanisms of mutation in different tissues in vivo is difficult because of the lack of adequate selectable somatic target genes in many mammalian systems, and the limited clonogenic potential of most somatic cells. Transgenic mouse mutation model systems have been constructed so that every cell of the animal contains multiple copies of an integrated target transgene. The use of these systems allows us to efficiently quantify statistically reliable mutations in any tissue of the body without prior drug selection or clonal expansion of the target cells. These models are accepted by regulatory agencies and have been used successfully in a variety of GLP toxicology studies to access the carcinogenic potential of drug candidates or medical devices. The central focus of our research is to evaluate the mutagenic potential of heavy ion irradiation in tissues using a plasmid-based transgenic mouse model system. Animals were exposed to a range of doses from 10 – 200 cGy with particle beams of LETs ranging from 0.24 keV/m to 180 keV/m. Analysis of the brain and spleen tissues from irradiated animals up to 16 weeks post irradiation showed that transgene mutant frequencies are tissue-specific, dose-dependent and temporally-regulated. Kinetic changes in the level of micronucleated reticulocytes in the peripheral blood from the same experimental animals showed that early cytogenetic damages to the hematopoietic stem cell population were responsive to low doses of radiation and also highly dependent on radiation quality. Protracted exposures of iron particle radiation induced an overall sparing effect in cytogenetic toxicity. HZE-induced transgenic mutant frequencies after such exposures were highly dose-dependent and tissue-specific. These results have important implications for both short- and long-term risks estimations in planned manned space missions as well as in hadron therapy. The work presented in this workshop is supported by NSBRI/NASA cooperative agreement NCC9-58-163 and NASA project NAG2-1630.

Key words: heavy ions, transgenic, mutation, radiation