title: Polycyclic aromatic hydrocarbons as skin carcinogens: comparison of benzo[a]pyrene, dibenzo[def,p]chrysene and three environmental mixtures in the FVB/N mouse.
abstract: The polycyclic aromatic hydrocarbon (PAH), benzo[a]pyrene (BaP), was compared to dibenzo[def,p]chrysene (DBC) and combinations of three environmental PAH mixtures (coal tar, diesel particulate and cigarette smoke condensate) using a two stage, FVB/N mouse skin tumor model. DBC (4nmol) was most potent, reaching 100% tumor incidence with a shorter latency to tumor formation, less than 20 weeks of 12-O-tetradecanoylphorbol-13-acetate (TPA) promotion compared to all other treatments. Multiplicity was 4 times greater than BaP (400 nmol). Both PAHs produced primarily papillomas followed by squamous cell carcinoma and carcinoma in situ. Diesel particulate extract (1 mg SRM 1650b; mix 1) did not differ from toluene controls and failed to elicit a carcinogenic response. Addition of coal tar extract (1 mg SRM 1597a; mix 2) produced a response similar to BaP. Further addition of 2 mg of cigarette smoke condensate (mix 3) did not alter the response with mix 2. PAH-DNA adducts measured in epidermis 12 h post initiation and analyzed by ³²P post-labeling, did not correlate with tumor incidence. PAH-dependent alteration in transcriptome of skin 12 h post initiation was assessed by microarray. Principal component analysis (sum of all treatments) of the 922 significantly altered genes (p<0.05), showed DBC and BaP to cluster distinct from PAH mixtures and each other. BaP and mixtures up-regulated phase 1 and phase 2 metabolizing enzymes while DBC did not. The carcinogenicity with DBC and two of the mixtures was much greater than would be predicted based on published Relative Potency Factors (RPFs).
authors.affiliation: Department of Environmental and Molecular Toxicology, Oregon State University, USA.
authors.forename: Lisbeth K
authors.initials: LK
authors.lastname: Siddens
authors.forename: Andrew
authors.initials: A
authors.lastname: Larkin
authors.forename: Sharon K
authors.initials: SK
authors.lastname: Krueger
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Bradfield
authors.forename: Katrina M
authors.initials: KM
authors.lastname: Waters
authors.forename: Susan C
authors.initials: SC
authors.lastname: Tilton
authors.forename: Cliff B
authors.initials: CB
authors.lastname: Pereira
authors.forename: Christiane V
authors.initials: CV
authors.lastname: Löhr
authors.forename: Volker M
authors.initials: VM
authors.lastname: Arlt
authors.forename: David H
authors.initials: DH
authors.lastname: Phillips
authors.forename: David E
authors.initials: DE
authors.lastname: Williams
authors.forename: William M
authors.initials: WM
authors.lastname: Baird
mesh_terms: D000818:Animals; D001564:Benzo(a)pyrene / Q000378:metabolism / Q000633:toxicity*; D001580:Benzopyrenes / Q000378:metabolism / Q000633:toxicity*; D002274:Carcinogens, Environmental / Q000378:metabolism / Q000633:toxicity*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D051379:Mice; D008815:Mice, Inbred Strains; D015394:Molecular Structure; D025341:Principal Component Analysis; D040081:Protein Array Analysis; D012878:Skin Neoplasms / Q000139:chemically induced* / Q000378:metabolism; D059467:Transcriptome
chemical_list: D001580:Benzopyrenes; D002274:Carcinogens, Environmental; D001564:Benzo(a)pyrene; C041517:dibenzo(a,l)pyrene