The Nature of the Heterozygous Trp53 Knockout Model for Identifi cation of Mutagenic Carcinogens

Abstract

The heterozygous Trp 53 null allele C57BL/6 (N5) mouse is susceptible to the rapid development of neoplasia by mutagenic carcinogens relative to control strains. This mouse model of chemical carcinogenesis demonstrates 1) dose-related rapid induction of tumors (26 wks), 2) multiple sites of carcinogen-specifi c tissue susceptibility, and 3) carcinogen-induced loss of heterozygosity involving the Trp53 wild-type allele or a p53 haploinsufficiency permitting mutation of other critical protooncogenes and/or inactivation of tumor suppressor genes driving tumorigenesis. Demonstration of mutation or loss ofheterozygosity involving the Trp53 locus is consistent with a common finding in human cancers and supports extrapolation between rodents and humans. Using diverse experimental protocols, almost all mutagenic rodent carcinogens (including all mutagens that are carcinogenic to humans), but not nonmutagenic rodent carcinogens, induce tumors within 26 weeks of continuous exposure. These characteristics and results indicate that the mouse heterozygous for the Trp53 null allele may be of significant use for the prospective identification of mutagenic carcinogens of potential risk to human health.