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Toxicol Sci. 2015 Jul;146(1):135-45. doi: 10.1093/toxsci/kfv080. Epub 2015 Apr 22.

Mechanism-Based Classification of PAH Mixtures to Predict Carcinogenic Potential.

Author information

1
*Superfund Research Center, Environmental and Molecular Toxicology Department, susan.tilton@oregonstate.edu.
2
*Superfund Research Center, Environmental and Molecular Toxicology Department.
3
*Superfund Research Center, Linus Pauling Institute.
4
College of Veterinary Medicine, Oregon State University, Corvallis, Oregon 97331, USA and.
5
*Superfund Research Center, Environmental and Molecular Toxicology Department, Linus Pauling Institute.
6
*Superfund Research Center, Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington 99352, USA.

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.

KEYWORDS:

mixtures; modeling; polycyclic aromatic hydrocarbons; skin cancer; toxicogenomics

PMID:
25908611
PMCID:
PMC4476464
DOI:
10.1093/toxsci/kfv080
[Indexed for MEDLINE]
Free PMC Article

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