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Dibenzo[A,L]pyrene-induced genotoxic and carcinogenic responses are dramatically suppressed in aryl hydrocarbon

Yoko Nakatsuru1, Keiji Wakabayashi, Yoshiaki Fujii-Kuriyama

  • 1Department of Pathology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.

International Journal of Cancer
|September 8, 2004
PubMed

Insights

The aryl hydrocarbon receptor (AhR) is crucial for skin cancer development from the air pollutant Dibenzo[a,l]pyrene (DB[a,l]P). AhR deficiency significantly reduces DB[a,l]P-induced skin tumors and DNA damage in mice.

Area of Science:

  • Environmental Health
  • Toxicology
  • Carcinogenesis

Background:

  • Dibenzo[a,l]pyrene (DB[a,l]P) is a potent carcinogenic polycyclic aromatic hydrocarbon (PAH) found in air pollution.
  • The aryl hydrocarbon receptor (AhR) is implicated in PAH carcinogenicity, but its in vivo role in skin cancer is not fully understood.

Purpose of the Study:

  • To investigate the role of AhR in the genotoxic and carcinogenic effects of DB[a,l]P in mouse skin.
  • To compare the responses of AhR-deficient (AhR-/-) and wild-type (AhR+/+) mice to DB[a,l]P exposure.

Main Methods:

  • Exposure of AhR+/+ and AhR-/- mice to DB[a,l]P.
  • Assessment of epidermal hyperplasia, cell proliferation (BrdU labeling), p53 protein accumulation, and DNA adduct formation.
  • Measurement of cytochrome P450 (CYP) enzyme induction (CYP1A1, CYP1B1).
  • Evaluation of skin tumor incidence and multiplicity in a complete carcinogenesis study.

Main Results:

  • DB[a,l]P induced significant epidermal hyperplasia, increased cell proliferation, p53 accumulation, and DNA adducts in AhR+/+ mice, but not in AhR-/- mice.
  • AhR-/- mice showed a marked reduction (approx. 60%) in inducible CYP1A1 expression, while CYP1B1 was constitutively expressed in both genotypes.
  • AhR-/- mice exhibited significantly lower skin tumor incidence (33% vs. 100%) and multiplicity (0.46 vs. 2.7) compared to AhR+/+ mice.

Conclusions:

  • AhR plays a critical role in DB[a,l]P-induced skin carcinogenesis, likely mediated by inducible CYP1A1 activation and subsequent DNA adduction.
  • Reduced tumor yield in AhR-deficient mice is associated with decreased genotoxicity and impaired epidermal proliferation.
  • The findings highlight the importance of AhR in mediating the carcinogenic effects of specific PAHs and suggest varying roles for AhR across different PAHs.

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