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

The contribution of the aryl hydrocarbon receptor (AhR) in induction of a b attery of xenobiotic-metabolizing enzymes has been studied extensively. How ever, no direct proof has been obtained that it plays a role in modulating carcinogenesis. To address the question of whether AhR is required for tumo r induction, we have investigated the response of AhR-deficient mice to ben zo[a] pyrene (B[a]P), a widely distributed environmental ca rcinogen. B[a]P treatment induced expression of the cytochrome P450 gene Cyp1a1 in the ski n and liver of AhR-positive mice bearing + / + and + / -genotypes and did n ot 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 tre atment, although its inducibility was lost in the AhR(- / -) mouse. All AhR -positive male mice of both + / + and + / - genotypes that received subcuta neous injection of B[a]P (2 mg) on the first and the eighth days had develo ped 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-deficien t mice. Likewise, topical application of B[a]P (200 mu g) at weekly interva ls 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 i n carcinogenesis.