Mutagenesis induced by oral carcinogens in lacZ mouse (Muta(TM)Mouse) tongue and other oral tissues

Animal models for carcinogenesis of the oral cavity are limited, although this disease is often fatal or disfiguring and its incidence in the USA is ~ 30,000 cases/year. Short-term whole-animal models for this disease should prove valuable in the investigation of factors affecting oral carcinogenesis. In this study we observed that a group of oral carcinogens are clearly mutagenic in the lacZ transgenic mouse oral cavity. The carcinogens 4-nitroquinoline-N-oxide (4-NQO), benzo[a]pyrene (B[a]P), N-nitroso-N-methylurea (NMU), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), nitrosonornicotine (NNN) and 7,12-dimethylbenzanthracene (DMBA) were all mutagenic in a mixture of pooled oral tissues (gingival, buccal, pharyngeal and sublingual) and in the tongue. All agents except DMBA (which was swabbed in the oral cavity) and B[a]P (by gavage) were given in drinking water for 2-4 weeks followed by a 2 week expression period before killing. With one exception, groups of 4-5 female mice were treated. The doses and mutant fractions (MF) in DNA isolated from pooled oral tissues (in mutants/10⁵ p.f.u. ± SD) were: 4-NQO (20-80 μg/ml, over 4 weeks) 78 ± 16; B[a]P (five doses of 125 mg/ml) 33.2 ± 10.9; NMU (20-80 μg/ml over 4 weeks) 7.8 ± 2.6; NNK (0.1 mg/ml, weeks 1-2, 0.2 mg/ ml, weeks 3-4) 9.1 ± 3.0; NNN (same dose as NNK) 9.2 ± 1.6 and DMBA (0.5 mg/ml in corn oil, 3 weeks) 7.1 ± 2.7, The corresponding value for untreated controls was 3.2 ± 1.8. Values for induced mutagenesis in tongue from the same animals were similar except for 4-NQO which was about twice as potent in tongue. Mutagenesis by several compounds was compared in other organs. B[a]P was assayed in lung and kidney and was about twice as mutagenic in oral tissues as in lung, but several times less mutagenic in kidney. Lung, but not kidney is a target organ for B[a]P-induced carcinogenesis in the mouse. NNK was somewhat more mutagenic in lung (MF of 15.0 ± 5.5) than in oral tissues, corresponding with previous reports on carcinogenesis by NNK. Mutagenesis induced by NNN was also assayed in esophagus, a target organ in rodents, and was similar to that in oral tissue. In all cases the MF in untreated control group was about 3-4. These results suggest that: (i) the oral cavity has a significant capacity for metabolic activation of carcinogens; (ii) DNA damage in the oral cavity can be converted to mutations; and (iii) there is significant target organ specificity. The results also tend to support the concept that the anatomical components of the upper aerodigestive tract, in general, behave similarly with respect to genotoxicity. As carcinogenesis is believed to involve mutagenesis, this study demonstrates the utility of the lacZ mouse for investigations involving initiation of carcinogenesis of the oral cavity.