MUTATIONAL RESPONSE AT THE SPLENIC T-LYMPHOCYTE HPRT LOCUS IN MICE TREATED AS NEONATES - CONTRASTING EFFECTS OF THE CARCINOGENS N-ETHYL-N-NITROSOUREA, DIMETHYLNITROSAMINE, AND 2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE

The newborn mouse tumorigenicity assay, which involves the treatment o f animals during the first two weeks after birth and monitoring tumor induction after a year, has been suggested as a cost- and time-effecti ve alternative to the conventional two year rodent bioassay. In order to evaluate whether or not lymphocyte hprt mutant induction is an accu rate predictor of carcinogenicity in the assay, we determined the freq uencies of 6-thioguanine-resistant (TG(r)) lymphocytes in the spleens of mice neonatally treated with the carcinogenic mutagens N-ethyl-N-ni trosourea (ENU), dimethylnitrosamine (DMN), and 2-amino-1-methyl-6-phe nylimidazo[4,5-b]pyridine (PhlP). Male C57BL/6 pups were injected on p ostnatal days 8 and 15, and the frequency of TG(r) T-lymphocytes was m easured in groups of three animals, sacrificed periodically up to 31 w eeks post-treatment. Compared to background frequencies of 1.1-2.9 x 1 0(-6), mutant frequencies (MFS) reached 155.1 x 10(-6) following a cum ulative dose of 49 mg ENU/kg body weight and 172.3 x 10(-6) following a cumulative dose of 142 mg ENU/kg. These results show that TG(r) lymp hocyte mutations can be induced and measured in mice treated as neonat es and that the induced MFs found for mice treated neonatally with ENU are comparable with frequencies reported For the treatment of adult a nimals with the some chemical. In contrast, treatment with the promuta genic and procarcinogenic compounds DMN (at a maximum concentration of 10.5 mg/kg) and PhlP (26.2 mg/kg) did not result in on increase in ly mphocyte MF, suggesting that reactive metabolites of these compounds m ay not be reaching cells that are sensitive for mutation fixation. The results indicate that the lymphocyte hprt assay may fail to predict t he carcinogenicity of some test chemicals in the neonatal mouse bioass ay. (C) 1998 Wiley-Liss, Inc.