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Benzo[ a ]pyrene carcinogenicity is lost in mice lacking the aryl hydrocarbon receptor

2000; National Academy of Sciences; Volume: 97; Issue: 2 Linguagem: Inglês

10.1073/pnas.97.2.779

1091-6490

Yasuhito Shimizu, Yoko Nakatsuru, Masao Ichinose, Yoshihisa Takahashi, Haruki Kume, Junsei Mimura, Yoshiaki Fujii‐Kuriyama, Takatoshi Ishikawa,

Effects and risks of endocrine disrupting chemicals

The contribution of the aryl hydrocarbon receptor (AhR) in induction of a battery of xenobiotic-metabolizing enzymes has been studied extensively. However, no direct proof has been obtained that it plays a role in modulating carcinogenesis. To address the question of whether AhR is required for tumor induction, we have investigated the response of AhR-deficient mice to benzo[ a ]pyrene (B[ a ]P), a widely distributed environmental carcinogen. B[ a ]P treatment induced expression of the cytochrome P450 gene Cyp1a1 in the skin and liver of AhR-positive mice bearing +/+ and +/− genotypes and did not induce expression of the cytochrome P450 gene Cyp1a1 in AhR-null mice in either skin or liver. In contrast, Cyp1a2 gene expression was positive in liver irrespective of the presence or absence of the AhR gene, or B[ a ]P treatment, although its inducibility was lost in the AhR(−/−) mouse. All AhR-positive male mice of both +/+ and +/− genotypes that received subcutaneous injection of B[ a ]P (2 mg) on the first and the eighth days had developed subcutaneous tumors at the site of injection at the end of the 18-week experiment. In contrast, no tumors were apparent in any of the AhR-deficient mice. Likewise, topical application of B[ a ]P (200 μg) at weekly intervals to the skin of female mice for 25 weeks produced skin tumors only in the AhR-positive mice. Thus the carcinogenic action of B[ a ]P may be determined primarily by AhR, a transcriptional regulator of the gene for CYP1A1. The results of the present study provide direct evidence that AhR is involved in carcinogenesis.