title: Toxicogenomic outcomes predictive of forestomach carcinogenesis following exposure to benzo(a)pyrene: relevance to human cancer risk.
abstract: Forestomach tumors are observed in mice exposed to environmental carcinogens. However, the relevance of this data to humans is controversial because humans lack a forestomach. We hypothesize that an understanding of early molecular changes after exposure to a carcinogen in the forestomach will provide mode-of-action information to evaluate the applicability of forestomach cancers to human cancer risk assessment. In the present study we exposed mice to benzo(a)pyrene (BaP), an environmental carcinogen commonly associated with tumors of the rodent forestomach. Toxicogenomic tools were used to profile gene expression response in the forestomach. Adult Muta™Mouse males were orally exposed to 25, 50, and 75 mgBaP/kg-body-weight/day for 28 consecutive days. The forestomach was collected three days post-exposure. DNA microarrays, real-time RT-qPCR arrays, and protein analyses were employed to characterize responses in the forestomach. Microarray results showed altered expression of 414 genes across all treatment groups (± 1.5 fold; false discovery rate adjusted P ≤ 0.05). Significant downregulation of genes associated with phase II xenobiotic metabolism and increased expression of genes implicated in antigen processing and presentation, immune response, chemotaxis, and keratinocyte differentiation were observed in treated groups in a dose-dependent manner. A systematic comparison of the differentially expressed genes in the forestomach from the present study to differentially expressed genes identified in human diseases including human gastrointestinal tract cancers using the NextBio Human Disease Atlas showed significant commonalities between the two models. Our results provide molecular evidence supporting the use of the mouse forestomach model to evaluate chemically-induced gastrointestinal carcinogenesis in humans.
authors.affiliation: Environmental and Radiation Health Sciences Directorate, Health Canada, Ottawa, Ontario K1A 0K9, Canada. Electronic address: Sarah.Labib@hc-sc.gc.ca.
authors.forename: Sarah
authors.initials: S
authors.lastname: Labib
authors.forename: Charles H
authors.initials: CH
authors.lastname: Guo
authors.forename: Andrew
authors.initials: A
authors.lastname: Williams
authors.forename: Carole L
authors.initials: CL
authors.lastname: Yauk
authors.forename: Paul A
authors.initials: PA
authors.lastname: White
authors.forename: Sabina
authors.initials: S
authors.lastname: Halappanavar
mesh_terms: D000818:Animals; D001564:Benzo(a)pyrene / Q000633:toxicity*; D063646:Carcinogenesis / Q000139:chemically induced* / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011237:Predictive Value of Tests; D012307:Risk Factors; D013274:Stomach Neoplasms / Q000139:chemically induced* / Q000235:genetics*; D043922:Toxicogenetics
chemical_list: D001564:Benzo(a)pyrene
keywords: AhR; Antigen processing and presentation; BPDE; BW; BaP; Cancer; FDR; GO; GSH; Gene Ontology; Human relevance; Immunoproteasome; MHC; Microarrays; NKT; PAH; Polycyclic aromatic hydrocarbons; RT-qPCR; aryl hydrocarbon receptor; benzo(a)pyrene; benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide; body weight; false discovery rate; glutathione; major histocompatibility complex; natural killer T cells; polycyclic aromatic hydrocarbon; quantitative real time PCR