| Although an extensive history links radiation exposure to an elevated incidence of cancer, the mechanisms of radiation-induced carcinogenesis are not completely understood. Genetic events leading to the loss of heterozygosity (LOH) have been shown to play a crucial role in the development of cancer. We have used B6C3F1 mice heterozygous at Aprt (adenine phosphoribosyltransferase) as a model for study of in vivo LOH in normal splenic T lymphocytes. In this animal model, rare in vivo LOH events can be quantitated, and possible mutational pathways of LOH can also be discriminated.; To study the effect of radiation on induction of LOH at both the intragenic and chromosomal levels in normal tissues, B6C3F1 Aprt heterozygous mice were whole-body irradiated with a single dose or fractionated doses of X-rays and tested for LOH at the Aprt and flanking loci in T lymphocytes. We observed that, while the radiation-induced small-scale, intragenic mutations are dependent on total exposure dose, radiation-induced large-scale chromosomal alterations, in particular interstitial deletion/gene conversion, are more dependent on exposure scheme.; We also irradiated p53-deficient Aprt heterozygous mice to determine the role of p53, a tumor suppressor protein involved in cell proliferation and cell death in response to radiation, in radiation-induced LOH. We showed that radiation-induced in vivo LOH in p53-deficient mice was greater than that of their wild-type counterparts and was caused by selective increase of certain components of LOH pathways, such as interstitial deletion/gene conversion, mitotic recombination, intragenic alterations and epigenetic inactivation. These results strongly support the idea that p53 plays a critical role in maintenance of genetic stability.; Our findings are strongly correlated with the previous observations that the incidence and latent period of radiation-induced lymphoma in mice varies with the dose fractionation of radiation and p53 status. Therefore, these results have important implications for understanding carcinogenesis induced by radiation, the treatment of tumors with radiation, and establishing human radiation exposure guidelines. For instance, our findings support the idea that the p53 status of a tumor may be a significant factor in choosing whether or not to use radiation therapy. |
