Mechanisms of oral carcinogenesis induced by dibenzo[a,l]pyrene: An environmental pollutant and a tobacco smoke constituent

Kun Ming Chen, Joseph Guttenplan, Shang Min Zhang, Cesar Aliaga, Timothy K. Cooper, Yuan Wan Sun, Joseph Deltondo, Wieslawa Kosinska, Arun K. Sharma, Kun Jiang, Richard Bruggeman, Kwangmi Ahn, Shantu Amin, Karam El-Bayoumy

Research output: Contribution to journalArticle

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. What's new? Tobacco smoking is the most important carcinogen in the development of oral cancer but molecular studies are hampered by the lack of an adequate animal model. The authors addressed this issue by developing a novel animal model that demonstrates the potent carcinogenicity of (±)-anti-DB[a,l]PDE, a metabolite of the tobacco smoke constituent dibenzo[a,l]pyrene in the oral cavity of mice. They demonstrate that this model is an appropriate platform to explore genetic and epigenetic alterations that can account for the development of oral squamous cell carcinoma. The model may also serve to evaluate the chemopreventive efficacy of agents, which modulate critical molecular mediators such as p53 or COX-2 involved in oral carcinogenesis.

Original languageEnglish (US)
Pages (from-to)1300-1309
Number of pages10
JournalInternational Journal of Cancer
Volume133
Issue number6
DOIs
StatePublished - Sep 15 2013

Fingerprint

Environmental Pollutants
Smoke
Tobacco
Carcinogenesis
Tongue
Squamous Cell Carcinoma
Epoxy Compounds
Carcinogens
Mouth
Animal Models
Bluetongue
Environmental Carcinogens
Estuaries
Mouth Neoplasms
Polycyclic Aromatic Hydrocarbons
Head and Neck Neoplasms
dibenzo(a,l)pyrene
Reporter Genes
Epigenomics
Smoking

Keywords

  • carcinogenesis
  • COX-2
  • mutagenesis
  • oral cancer
  • p53

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Mechanisms of oral carcinogenesis induced by dibenzo[a,l]pyrene : An environmental pollutant and a tobacco smoke constituent. / Chen, Kun Ming; Guttenplan, Joseph; Zhang, Shang Min; Aliaga, Cesar; Cooper, Timothy K.; Sun, Yuan Wan; Deltondo, Joseph; Kosinska, Wieslawa; Sharma, Arun K.; Jiang, Kun; Bruggeman, Richard; Ahn, Kwangmi; Amin, Shantu; El-Bayoumy, Karam.

In: International Journal of Cancer, Vol. 133, No. 6, 15.09.2013, p. 1300-1309.

Research output: Contribution to journalArticle

Chen, KM, Guttenplan, J, Zhang, SM, Aliaga, C, Cooper, TK, Sun, YW, Deltondo, J, Kosinska, W, Sharma, AK, Jiang, K, Bruggeman, R, Ahn, K, Amin, S & El-Bayoumy, K 2013, 'Mechanisms of oral carcinogenesis induced by dibenzo[a,l]pyrene: An environmental pollutant and a tobacco smoke constituent', International Journal of Cancer, vol. 133, no. 6, pp. 1300-1309. https://doi.org/10.1002/ijc.28152
Chen, Kun Ming ; Guttenplan, Joseph ; Zhang, Shang Min ; Aliaga, Cesar ; Cooper, Timothy K. ; Sun, Yuan Wan ; Deltondo, Joseph ; Kosinska, Wieslawa ; Sharma, Arun K. ; Jiang, Kun ; Bruggeman, Richard ; Ahn, Kwangmi ; Amin, Shantu ; El-Bayoumy, Karam. / Mechanisms of oral carcinogenesis induced by dibenzo[a,l]pyrene : An environmental pollutant and a tobacco smoke constituent. In: International Journal of Cancer. 2013 ; Vol. 133, No. 6. pp. 1300-1309.
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AU - Sun, Yuan Wan

AU - Deltondo, Joseph

AU - Kosinska, Wieslawa

AU - Sharma, Arun K.

AU - Jiang, Kun

AU - Bruggeman, Richard

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AU - Amin, Shantu

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