Title: Oral benzo[a]pyrene-induced cancer: two distinct types in different target organs depend on the mouse Cyp1 genotype.
Authors: Shi, Zhanquan; Dragin, Nadine; Miller, Marian L; Stringer, Keith F; Johansson, Elisabet; Chen, Jing; Uno, Shigeyuki; Gonzalez, Frank J; Rubio, Carlos A; Nebert, Daniel W
Published In Int J Cancer, (2010 Nov 15)
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.
PubMed ID: 20127859
MeSH Terms: Adenocarcinoma/chemically induced*; Adenocarcinoma/enzymology; Adenocarcinoma/genetics; Administration, Oral; Animals; Aryl Hydrocarbon Hydroxylases/genetics; Benzo(a)pyrene/administration & dosage*; Carcinoma, Squamous Cell/chemically induced*; Carcinoma, Squamous Cell/enzymology; Carcinoma, Squamous Cell/genetics; Cytochrome P-450 CYP1A1/genetics*; Cytochrome P-450 CYP1B1; Female; Genotype; Inbreeding; Intestinal Neoplasms/chemically induced*; Intestinal Neoplasms/enzymology; Intestinal Neoplasms/genetics; Intestine, Small/drug effects; Intestine, Small/pathology; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Scent Glands/drug effects