Oral benzo[a]pyrene‐induced cancer: Two distinct types in different target organs depend on the mouse Cyp1 genotype |
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Authors: | Marian L. Miller Keith F. Stringer Elisabet Johansson Jing Chen Shigeyuki Uno Frank J. Gonzalez Carlos A. Rubio Daniel W. Nebert |
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Affiliation: | 1. Department of Environmental Health and Center for Environmental Genetics (CEG), University of Cincinnati Medical Center, Cincinnati, OH;2. Department of Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH;3. Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD;4. Gastrointestinal and Liver Pathology Research Laboratory, Karolinska Institute, Stockholm, Sweden;5. Department of Environmental Health and Center for Environmental Genetics (CEG), University of Cincinnati Medical Center, Cincinnati, OHTel.: +513‐821‐4664, Fax: +513‐558‐0925 |
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Abstract: | Benzo[a]pyrene (BaP) is a prototypical polycyclic aromatic hydrocarbon (PAH) found in combustion processes. Cytochrome P450 1A1 and 1B1 enzymes (CYP1A1 and CYP1B1) can both detoxify PAHs and activate them to cancer‐causing reactive intermediates. Following high dosage of oral BaP (125 mg/kg/day), ablation of the mouse Cyp1a1 gene causes immunosuppression and death within ~28 days, whereas Cyp1(+/+) wild‐type mice remain healthy for >12 months on this regimen. In this study, male Cyp1(+/+) wild‐type, Cyp1a1(?/?) and Cyp1b1(?/?) single‐knockout and Cyp1a1/1b1(?/?) double‐knockout mice received a lower dose (12.5 mg/kg/day) of oral BaP. Tissues from 16 different organs—including proximal small intestine (PSI), liver and preputial gland duct (PGD)—were evaluated; microarray cDNA expression and >30 mRNA levels were measured. Cyp1a1(?/?) mice revealed markedly increased CYP1B1 mRNA levels in the PSI, and between 8 and 12 weeks developed unique PSI adenomas and adenocarcinomas. Cyp1a1/1b1(?/?) mice showed no PSI tumors but instead developed squamous cell carcinoma of the PGD. Cyp1(+/+) and Cyp1b1(?/?) mice remained healthy with no remarkable abnormalities in any tissue examined. PSI adenocarcinomas exhibited striking upregulation of the Xist gene, suggesting epigenetic silencing of specific genes on the Y‐chromosome; the Rab30 oncogene was upregulated; the Nr0b2 tumor suppressor gene was downregulated; paradoxical overexpression of numerous immunoglobulin kappa‐ and heavy‐chain variable genes was found—although the adenocarcinoma showed no immunohistochemical evidence of being lymphatic in origin. This oral BaP mouse paradigm represents an example of “gene‐environment interactions” in which the same exposure of carcinogen results in altered target organ and tumor type, as a function of just 1 or 2 globally absent genes. |
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Keywords: | oral benzo[a]pyrene CYP1 enzymes Cyp1a1 gene Cyp1b1 gene adenocarcinoma of proximal small intestine immunoglobulin‐secreting tumor squamous cell carcinoma of preputial gland duct Xist gene Rab30 oncogene Nr0b2 tumor suppressor gene nonagouti locus Olfr genes |
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