COMPARISON OF IN-VIVO MUTAGENESIS IN THE ENDOGENOUS HPRT GENE AND THELACI TRANSGENE OF BIG BLUE(R) RATS TREATED WITH 7,12-DIMETHYLBENZ[A]ANTHRACENE

The lacI transgene of Big Blue(R) (BB) rats was evaluated as a reporte r of in vivo mutation by comparing mutant frequencies (MFs) in it and in the endogenous Hprt gene. Seven-week old female BE rats were given single doses of 0, 20, 75 and 130 mg/kg of 7,12-dimethylbenz(a)anthrac ene (DMBA) by gavage, and Hprt and lacI MFs in splenic lymphocytes wer e measured over a period of 18 weeks. The Hprt MFs in treated rats inc reased for 10 weeks and then declined; 130 mg/kg of DMBA produced a ma ximum Hprt MF of 168 +/- 11.4 x 10(-6) clonable lymphocytes, while the MF in control rats was 7.4 +/- 1.5 x 10(-6). DMBA exposure of generic F344 rats resulted in a similar time-course of mutant induction but p roduced about 50% higher Hprt MFs with the 75 and 130 mg/kg doses. In contrast, the lacI MFs increased for 6 weeks and then remained relativ ely constant; 130 mg/kg of DMBA produced a maximum increase in lacI MF of 341 +/- 83 x 10(-6) PFU compared with 25 +/- 5 x 10(-6) PFU in con trol rats. The Hprt mutant frequencies in DMBA-treated BB and F344 rat s were significantly increased over control values for every dose-time combination examined, while only the 130 mg/kg dose consistently prod uced lacI MFs that were significantly above the controls. In addition, the fold-increase in MF for treated vs. control rats was two times hi gher for the Hprt gene than the lacI gene due to the higher MFs in the lacI gene of control rats. Differences between the lacI and Hprt gene s in the kinetics of mutant induction, in the frequency of induced mut ants, and in the sensitivity of mutant detection could be explained at least partially by the properties of these two genes. (C) 1998 Elsevi er Science B.V. All rights reserved.