Abstract
Chromosome aberrations as well as point mutations are genomic alterations that play important roles in carcinogenesis. In general, it is thought that radiation efficiently induces chromosome aberrations via DNA strand breaks, and chemical carcinogens and ultraviolet light (UV) irradiation induce point mutations via modification of bases in DNA. To dissect the genotoxic effects of various environmental carcinogenic factors in vivo, we have developed gpt delta transgenic mice, which allow analysis of deletions (chromosome aberrations) and point mutations, and examined the genomic alterations induced by radiation, UV and chemical carcinogens at the molecular level. Heavy-ion irradiation induced large deletions in size more than 1 kb in the liver but no point mutations. In contrast, gamma-ray and X-ray irradiation induced both deletions and point mutations. UV irradiation induced not only base substitutions (G:C to A:T) in the skin but also induced large deletions. Carcinogen PhIP contained in the burnt food induced base substitutions (G:C to T:A) and 1 bp deletions in the colon but no large deletions. Mitomycin C efficiently induced both base substitutions (tandem base substitutions) and large deletions in the bone marrow. These results suggest (1) low LET radiation such as gamma-ray and X-ray induces base substitutions due to modification of bases in DNA along with induction of DNA strand breaks (2) UV irradiation and chemical carcinogens induce deletions via DNA strand breaks by replication stall along with induction of base substitutions via modifications of bases in DNA.
