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 two-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 to 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<0.05) 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.This is an author's peer-reviewed final manuscript, as accepted by the publisher. The published article is copyrighted by Oxford University Press and can be found at: http://toxsci.oxfordjournals.org/.Keywords: mixtures, toxicogenomics, skin cancer, polycyclic aromatic hydrocarbons, modelin
