Comparison of the mutational spectra of the lacZ transgene in four organs of the Muta (TM) Mouse treated with benzo[a]pyrene: target organ specificity

We recently demonstrated that not all organs with a high rate of induction of mutation in the lacZ transgene develop tumors in the lambda lacZ transge nic mice (Muta(TM) Mouse) used for a long-term carcinogenicity study with b enzo[a]pyrene (BP). To better understand the role of chemical-induced in vi vo mutations in carcinogenesis, we compared the mutational spectra of the l acZ transgene in four organs of the Muta(TM)Mouse obtained 2 weeks after fi ve daily consecutive oral treatments with 125 mg/kg/day BP. lacZ transgenes were analyzed in two target organs (forestomach and spleen) and two non-ta rget organs (colon and glandular stomach) for BP-induced carcinogenesis in Muta(TM)Mouse, and all of these organs were highly mutated in the lacZ tran sgene. The sequence data showed similar mutational spectra of the lacZ tran sgene between the two target organs; the predominant mutations were G:C --> T:A transversions (55% and 50% for forestomach and spleen, respectively), followed by deletions (20% and 21% for forestomach and spleen, respectively ) mainly at G:C site. The frequent G:C --> T:A transversions are consistent with reports of the mutational spectra produced in the p53 gene in tumors generated in rats and mice exposed to BP. In contrast, the mutational spect ra of the lacZ transgene in the two non-target organs are different from th ose in the target organs, and are also suggested to differ from one another . These findings suggest an organ/tissue-specific mechanism of mutagenesis. (C) 2000 Elsevier Science B.V. All rights reserved.