Identification and characterization of potential human carcinogens using B6.129tm1Trp53 heterozygous null mice and loss of heterozygosity at the Trp53 locus.

Abstract

Rodent models are often used as surrogates for humans in toxicology and cancer research. Transgenic mice have been useful for studying gene function by loss of function or gain of function through mutation or overexpression. Thus, transgenic or genetically altered mouse models could play an important role in understanding environment-gene interactions. Wild-type Trp53 protein is critical for cell function and maintaining integrity of the genome, which suppresses cancer in humans and rodents. Mice heterozygous for a Trp53 null and a wild-type allele are p53 haplo-insufficient. This reduction in p53 protein results in deficiencies in cell cycle check-point control and induction of apoptosis. p53 Haplo-insufficient mice do not immediately develop neoplasia as a result of this signalling dysregulation. However, exposure to mutagenic carcinogens induces neoplasia during the period in which unexposed, co-isogenic haplo-insufficient and homozygous wild-type mice are free from neoplasia. These observations provide a basis for evaluation of p53 haplo-insufficient mice for mechanism-based identification of carcinogens. Maximum tolerated doses (MTD) determined and used for 2-year NCI/NTP cancer bioassays and/or by 28-day toxicokinetic studies to predict MTD for subchronic studies were, generally, effective in inducing neoplasia with reduced latency in 26-week exposure studies in p53 haplo-insufficient mice. The latency of tumour development may be shortened by requiring only an additional genetic alteration (or alterations) in p53 (mutation or loss of heterozygosity (LOH) involving the Trp53 locus) or in other tumour-suppressor genes by mutation or inactivation. LOH is a loss of genetic loci through chromosomal aberrations and reduction to homozygosity that often results in loss of tumour-suppressor genes. Interspecies extrapolation between rodents and humans is difficult owing to the possibility of species differences, but demonstration of an operational mechanism, such as mutation or loss of p53 function through LOH, may help in reducing uncertainty and, thus, lead to identification of carcinogens of presumed risk to humans.