title: Mechanisms of oral carcinogenesis induced by dibenzo[a,l]pyrene: an environmental pollutant and a tobacco smoke constituent.
abstract: We previously reported that dibenzo[a,l]pyrene (DB[a,l]P), the most potent known environmental carcinogen among polycyclic aromatic hydrocarbons (PAH) congeners, is carcinogenic in the oral tissues of mice. We have now developed a new mouse model which employs the oral application of the fjord region diol epoxide, (±)-anti-11,12-dihydroxy-13,14-epoxy-11,12,13,14-tetrahydrodibenzo[a,l]pyrene (DB[a,l]PDE), a metabolite of the tobacco smoke constituent DB[a,l]P, and we show its specific induction of oral squamous cell carcinoma (OSCC) in both tongue and other oral tissues. Groups of B6C3F1 mice (20/group) received 6 or 3 nmol of (±)-anti-DB[a,l]PDE administered into the oral cavity; 3 times per week for 38 weeks. Additional groups received the vehicle alone or were left untreated. Mice were sacrificed 42 weeks after the first carcinogen administration. The high dose induced 74 and 100% OSCC in the tongue and other oral tissues, respectively; the corresponding values at the lower dose were 45 and 89%. Using immunohistochemistry, we showed that DB[a,l]PDE resulted in overexpression of p53 and COX-2 proteins in malignant tissues when compared to normal oral tissues and tongues. Consistent with the carcinogenicity, we demonstrated powerful mutagenicity in cII gene in B6C3F1 (Big Blue) mouse tongue. The mutational profile in lacI reporter gene is similar to those detected in human head and neck cancer, and p53 mutations were observed in mouse oral tumor tissues. Taken together, we conclude that the formation of diol epoxides plays a major role among the mechanisms by which DB[a,l]P exerts its oral mutagenicity and tumorigenicity.
authors.affiliation: Department of Biochemistry and Molecular Biology, Penn State College of Medicine, Hershey, PA, USA.
authors.forename: Kun-Ming
authors.initials: KM
authors.lastname: Chen
authors.forename: Joseph B
authors.initials: JB
authors.lastname: Guttenplan
authors.forename: Shang-Min
authors.initials: SM
authors.lastname: Zhang
authors.forename: Cesar
authors.initials: C
authors.lastname: Aliaga
authors.forename: Timothy K
authors.initials: TK
authors.lastname: Cooper
authors.forename: Yuan-Wan
authors.initials: YW
authors.lastname: Sun
authors.forename: Joseph
authors.initials: J
authors.lastname: DelTondo
authors.forename: Wieslawa
authors.initials: W
authors.lastname: Kosinska
authors.forename: Arun K
authors.initials: AK
authors.lastname: Sharma
authors.forename: Kun
authors.initials: K
authors.lastname: Jiang
authors.forename: Richard
authors.initials: R
authors.lastname: Bruggeman
authors.forename: Kwangmi
authors.initials: K
authors.lastname: Ahn
authors.forename: Shantu
authors.initials: S
authors.lastname: Amin
authors.forename: Karam
authors.initials: K
authors.lastname: El-Bayoumy
mesh_terms: D000818:Animals; D001580:Benzopyrenes / Q000633:toxicity*; D002274:Carcinogens, Environmental / Q000633:toxicity*; D005260:Female; D016158:Genes, p53; D007150:Immunohistochemistry; D051379:Mice; D009062:Mouth Neoplasms / Q000139:chemically induced*; D009154:Mutation; D012906:Smoke / Q000032:analysis*
chemical_list: D001580:Benzopyrenes; D002274:Carcinogens, Environmental; D012906:Smoke; C041517:dibenzo(a,l)pyrene
keywords: COX-2; carcinogenesis; mutagenesis; oral cancer; p53