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Short-term carcinogenesis bioassay of genotoxic procarcinogens in PIM® transgenic mice
1Safety Assessment West Point, PA 19486, USA
2Research, Merck Research Laboratories West Point, PA 19486, USA
Departments of Genetic and Cellular Toxicology (WP45-311) West Point, PA 19486, USA
3whom correspondence should be addressed
Eµ-pim-1 transgenic mice, which overexpress the pim 1 oncogene in lymphoid tissues, have shown increased susceptibility to induction of T cell lymphomas by N-ethyl N-nitrosourea, a direct-acting chemical carcinogen (Nature, 340, 61–63, 1989). We sought to further evaluate Eµ-pim-1 transgenic mice as a potential test animal for a short-term carcinogenesis bioassay. We chose to test four genotoxic procarcinogens; 2-acetylaminofluorene (2-AAF), N-nitro sodiethylamine (NDEA), 1, 2-dichloroethane (1, 2-DCE) and benzene (BEN). These compounds require metabolic activa tion and, with the exception of benzene, are not mouse lymphomagens. Compounds were administered by gavage daily for 38 (NDEA and 2-AAF) or 40 (BEN and 1, 2-DCE) weeks to groups of 25–29 male and female PIM® mice at 1 and 3 mg/kg for NDEA, 50 and 100 mg/kg for BEN, 25–100 mg/kg for Small but statistically significant increases in the incidence of malignant lymphoma were seen for three of the four carcinogens tested; in high dose males treated with 2-AAF, high and low dose females treated with NDEA and high dose females treated with 1, 2-DCE. Results for BEN, the only mouse lymphomagen tested, did not show a statistic ally significant increase in the incidence of malignant lymphomas in transgenic mice within the 40 week duration of the study. NDEA also produced a high incidence (>70%) of hepatic hemangiosarcomas in both sexes at the low and high dose levels. These results demonstrate that over expression of the pim-1 oncogene in lymphoid tissue can confer susceptibility of this tissue to chemical carcinogenesis by genotoxic procarcinogens. However, whereas potent genotoxic carcinogens produced only small increases in the incidence of lymphoma and since BEN, a mouse lymphomagen, was negative, PIM® transgenic mice may lack sufficient sensitivity to established carcinogens to justify their routine use in a short-term carcinogenesis screening assay.
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