Mutagenesis and carcinogenesis induced by dibenzo[a,l]pyrene in the mouse oral cavity: a potential new model for oral cancer

Abstract

Cancer of the oral cavity is a serious disease, affecting about 30,000 individuals in US annually. There are several animal models of oral cancer, but each has certain disadvantages. As a new model, we investigated whether topical application of the tobacco smoke carcinogen, dibenzo[a,l]pyrene (DB[a,l]P) is mutagenic and carcinogenic in the oral cavity of the B6C3F1 lacI and B6C3F1 mouse, respectively. B6C3F1 lacI mice received DB[a,l]P (0, 3, 6, 12 nmol) 3× per week. B6C3F1 mice received the same doses and also 24 nmol. At 38 weeks mutagenesis was measured in oral tissues in lacI mice. For the high dose group, the mutant fraction (MF) in upper mucosa and tongue increased about twofold relative to that in vehicle-alone. The increases were statistically significant. The mutational profile in the DB[a,l]P-induced mutants was compared with that induced by benzo[a]pyrene (BaP) in oral tissue. BaP is mutagenic in many tissues when administered by gavage. The mutational profile for DB[a,l]P was more similar to that reported for p53 mutations in head and neck cancers than was that of BaP. At 47 weeks, oral squamous cell carcinomas (OSCC) were found in 31% of the high-dose B6C3F1 group. Elevations of p53 and COX-2 protein were observed in tumor and dysplastic tissue. As DB[a,l]P induces mutations and tumors in the oral cavity, and has a mutational profile in oral tissue similar to that found in p53 in human OSCC, the treatment protocol described here may represent a new and relevant model for cancer of the oral cavity.

Simultaneous Detection of Deoxyadenosine and Deoxyguanosine Adducts in the Tongue and Other Oral Tissues of Mice Treated with Dibenzo[a,l]pyrene

“…In our previous report, we showed that DB[ a , l ]P-induced SCC in oral tissues but not in the tongue after direct application of DB[ a , l ]P into the oral cavity; 11 however, DB[ a , l ]PDE is a potent carcinogen in both oral tissues and tongue. 13 Toward this end, we initially focused on DB[ a , l ]P-induced genotoxic effects in this target organ.…”

“…11 Therefore, in the present study we have compared the levels of dA and dG adducts in oral and tongue tissues of mice treated with DB[ a , l ]P (Figures 6B and C). The levels of (−)- anti - trans -DB[ a , l ]PDE-dA adduct in oral tissues exceeded those in tongue at all time points.…”

Effects of Black Raspberry Extract and Protocatechuic Acid on Carcinogen-DNA Adducts and Mutagenesis, and Oxidative Stress in Rat and Human Oral Cells

“…Previously we reported that the tobacco smoke carcinogen, dibenzo[a,l]pyrene (DBP) (also known as Dibenzo[def,p]chrysene) and its ultimate carcinogenic metabolite, (±)-anti-11,12-dihydroxy-13,14-epoxy-11,12,13,14-tetrahydrodibenzo[a,l]pyrene (DBPDE), are mutagenic and carcinogenic in the mouse oral cavity (12, 13) (see Fig. 1).…”

Effects of chronic alcohol consumption on DNA damage and immune regulation induced by the environmental pollutant dibenzo[a,l]pyrene in oral tissues of mice

“…Furthermore, previous studies showed that alcohol can contribute to epigenetic regulation of oncogenes or tumor suppressor genes (33). Finally, alcohol can suppress and skew aspects of both the innate and adaptive immune system, providing a window of opportunity for loss of immune surveillance (9, 10). …”

“…The mechanisms by which alcohol consumption enhances oral carcinogenesis remain under investigation; however, numerous lines of research have implicated ethanol-induced oxidative stress/damage as an important component. Other potential mechanisms include possible induction of carcinogen activation pathways and suppression of both innate and adaptive immune systems, providing a window of opportunity for loss of immune surveillance (9, 10). …”