Dibenzo[A,L]pyrene-induced genotoxic and carcinogenic responses are dramatically suppressed in aryl hydrocarbon receptor-deficient mice.
Dibenzo[a,l]pyrene (DB[a,l]P), a notorious air pollutant, is the most powerful carcinogenic polycyclic aromatic hydrocarbon (PAH) ever tested. Although the carcinogenicity of PAH may be primarily mediated by the aryl hydrocarbon receptor (AhR), the in vivo role of AhR in skin carcinogenesis remains to be defined. In this context, we investigated the genotoxic and carcinogenic responses of the AhR-deficient mouse skin to DB[a,l]P. A single painting resulted in a striking epidermal hyperplasia in AhR+/+ mice but not in AhR-/- mice. Bromodeoxyuridine-labeling index and accumulation of p53 protein in epidermal cells of AhR+/+ mice were 8- and 33-fold higher than those of AhR-/- mice, respectively. 32P-Postlabeling assay for DB[a,l]P-DNA adducts displayed a 2-fold increase in the AhR+/+ mouse skin. After DB[a,l]P exposure, AhR-/- mice arranged a nearly 60% reduction in the induction of epidermal cytochrome P450 (CYP)1A1, but CYP1B1 was constitutively expressed in both genotypes of mice, irrespective of DB[a,l]P treatment. As compared with AhR+/+ mice, AhR-/- mice had both significantly lower incidence (100% vs. 33%) and multiplicity (2.7 vs. 0.46) of skin tumors by the complete carcinogenesis study. These observations indicate that a reduced tumor yield in AhR-/- mice may be secondary to reduction of inducible CYP1A1 activation and subsequent DNA adduction. It is evident from our continuous work that although AhR is likely to play a central role in epidermal proliferation and possibly neoplastic transformation, the relative importance of AhR for carcinogenesis may be different among PAH examined.
Nakatsuru
Yoko
Y
Department of Pathology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
Wakabayashi
Keiji
K
Fujii-Kuriyama
Yoshiaki
Y
Ishikawa
Takatoshi
T
Kusama
Kaoru
K
Ide
Fumio
F
D000279:Administration, Cutaneous; D000818:Animals; D001580:Benzopyrenes / Q000008:administration & dosage / Q000633:toxicity*; D002273:Carcinogens / Q000008:administration & dosage / Q000633:toxicity*; D002471:Cell Transformation, Neoplastic; D018736:DNA Adducts; D005260:Female; D005838:Genotype; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics* / Q000502:physiology*; D012878:Skin Neoplasms / Q000139:chemically induced* / Q000503:physiopathology / Q000662:veterinary
D001580:Benzopyrenes; D002273:Carcinogens; D018736:DNA Adducts; D018336:Receptors, Aryl Hydrocarbon; C041517:dibenzo(a,l)pyrene