title: Mechanism-Based Classification of PAH Mixtures to Predict Carcinogenic Potential.
abstract: We have previously shown that relative potency factors and DNA adduct measurements are inadequate for predicting carcinogenicity of certain polycyclic aromatic hydrocarbons (PAHs) and PAH mixtures, particularly those that function through alternate pathways or exhibit greater promotional activity compared to benzo[a]pyrene (BaP). Therefore, we developed a pathway-based approach for classification of tumor outcome after dermal exposure to PAH/mixtures. FVB/N mice were exposed to dibenzo[def,p]chrysene (DBC), BaP, or environmental PAH mixtures (Mix 1-3) following a 2-stage initiation/promotion skin tumor protocol. Resulting tumor incidence could be categorized by carcinogenic potency as DBC >> BaP = Mix2 = Mix3 > Mix1 = Control, based on statistical significance. Gene expression profiles measured in skin of mice collected 12 h post-initiation were compared with tumor outcome for identification of short-term bioactivity profiles. A Bayesian integration model was utilized to identify biological pathways predictive of PAH carcinogenic potential during initiation. Integration of probability matrices from four enriched pathways (P < .05) for DNA damage, apoptosis, response to chemical stimulus, and interferon gamma signaling resulted in the highest classification accuracy with leave-one-out cross validation. This pathway-driven approach was successfully utilized to distinguish early regulatory events during initiation prognostic for tumor outcome and provides proof-of-concept for using short-term initiation studies to classify carcinogenic potential of environmental PAH mixtures. These data further provide a 'source-to-outcome' model that could be used to predict PAH interactions during tumorigenesis and provide an example of how mode-of-action-based risk assessment could be employed for environmental PAH mixtures.
authors.affiliation: *Superfund Research Center, Environmental and Molecular Toxicology Department, susan.tilton@oregonstate.edu.
authors.forename: Susan C
authors.initials: SC
authors.lastname: Tilton
authors.affiliation: *Superfund Research Center, Environmental and Molecular Toxicology Department.
authors.forename: Lisbeth K
authors.initials: LK
authors.lastname: Siddens
authors.affiliation: *Superfund Research Center, Linus Pauling Institute.
authors.forename: Sharon K
authors.initials: SK
authors.lastname: Krueger
authors.affiliation: *Superfund Research Center, Environmental and Molecular Toxicology Department.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Larkin
authors.affiliation: College of Veterinary Medicine, Oregon State University, Corvallis, Oregon 97331, USA and.
authors.forename: Christiane V
authors.initials: CV
authors.lastname: Löhr
authors.affiliation: *Superfund Research Center, Environmental and Molecular Toxicology Department, Linus Pauling Institute.
authors.forename: David E
authors.initials: DE
authors.lastname: Williams
authors.affiliation: *Superfund Research Center, Environmental and Molecular Toxicology Department.
authors.forename: William M
authors.initials: WM
authors.lastname: Baird
authors.affiliation: *Superfund Research Center, Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington 99352, USA.
authors.forename: Katrina M
authors.initials: KM
authors.lastname: Waters
mesh_terms: D000818:Animals; D002273:Carcinogens / Q000145:classification* / Q000633:toxicity*; D051379:Mice; D011084:Polycyclic Aromatic Hydrocarbons / Q000145:classification* / Q000633:toxicity*
chemical_list: D002273:Carcinogens; D011084:Polycyclic Aromatic Hydrocarbons
keywords: mixtures; modeling; polycyclic aromatic hydrocarbons; skin cancer; toxicogenomics