Mutagenesis induced by oral carcinogens in lacZ mouse (Muta™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