Evaluation of the transgenic p53+/- mouse for detecting genotoxic liver carcinogens in a short-term bioassay.
The transgenic p53-deficient heterozygous (p53+/-) mouse is prone to both spontaneous and induced tumors and has been proposed for use in a sensitive, short-term (6 months) assay for identifying genotoxic, multispecies carcinogens. It is not clear, however, if a short-term assay with p53+/- mice detects agents that target certain organs, in particular, the liver. In this study, we treated neonatal male p53+/- and p53+/+ mice with the genotoxic carcinogens dimethylnitrosamine (DMN), 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP), and 6-nitrochrysene (6-NC). In keeping with the methodology of the proposed short-term assay, the p53+/- mice were evaluated for tumors 7 months after treatment. Wild-type neonatal mice treated with genotoxic carcinogens are known to develop tumors within 1 year; hence, the p53+/+ animals used as controls were subjected to pathological examination at 1 year of age. Our results showed that PhIP was not tumorigenic in either group of mice. Liver tumor incidence increased significantly in the p53+/+ mice treated with DMN and 6-NC, indicating that the conditions of the bioassay were conducive to the promotion of liver tumorigenesis. On the other hand, these two chemicals failed to induce a significant increase in liver tumors in the p53+/- mice by seven months. This result suggests that a deficiency in the amount of p53 protein does not lead to accelerated liver tumorigenesis in mice, and contrasts with previous reports that show a decreased latency of tumors in non-liver targets.
Dass
S B
SB
Division of Genetic and Reproductive Toxicology, National Center for Toxicological Research, Jefferson, AR 72079, USA.
Bucci
T J
TJ
Heflich
R H
RH
Casciano
D A
DA
D000236:Adenoma / Q000139:chemically induced* / Q000235:genetics / Q000473:pathology; D000818:Animals; D000831:Animals, Newborn; D015197:Carcinogenicity Tests; D002273:Carcinogens / Q000633:toxicity*; D002911:Chrysenes / Q000633:toxicity; D004128:Dimethylnitrosamine / Q000633:toxicity; D007093:Imidazoles / Q000633:toxicity; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency* / Q000235:genetics
D002273:Carcinogens; D002911:Chrysenes; D007093:Imidazoles; D016159:Tumor Suppressor Protein p53; C035986:6-nitrochrysene; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine; D004128:Dimethylnitrosamine