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 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. Asmore »
- Authors:
-
- Oregon State Univ., Corvallis, OR (United States)
- Pacific Northwest National Lab. (PNNL), Richland, WA (United States)
- Publication Date:
- Research Org.:
- Oregon State Univ., Corvallis, OR (United States)
- Sponsoring Org.:
- USDOE
- OSTI Identifier:
- 1224102
- Grant/Contract Number:
- AC05-76RL01830
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Toxicological Sciences
- Additional Journal Information:
- Journal Volume: 146; Journal Issue: 1; Journal ID: ISSN 1096-6080
- Publisher:
- Oxford University Press
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; polycyclic aromatic hydrocarbons; toxicogenomics; modeling; skin cancer; mixtures
Citation Formats
Tilton, Susan C., Siddens, Lisbeth K., Krueger, Sharon K., Larkin, Andrew J., Löhr, Christiane V., Williams, David E., Baird, William M., and Waters, Katrina M. Mechanism-based classification of PAH mixtures to predict carcinogenic potential. United States: N. p., 2015.
Web. doi:10.1093/toxsci/kfv080.
Tilton, Susan C., Siddens, Lisbeth K., Krueger, Sharon K., Larkin, Andrew J., Löhr, Christiane V., Williams, David E., Baird, William M., & Waters, Katrina M. Mechanism-based classification of PAH mixtures to predict carcinogenic potential. United States. https://doi.org/10.1093/toxsci/kfv080
Tilton, Susan C., Siddens, Lisbeth K., Krueger, Sharon K., Larkin, Andrew J., Löhr, Christiane V., Williams, David E., Baird, William M., and Waters, Katrina M. Wed .
"Mechanism-based classification of PAH mixtures to predict carcinogenic potential". United States. https://doi.org/10.1093/toxsci/kfv080. https://www.osti.gov/servlets/purl/1224102.
@article{osti_1224102,
title = {Mechanism-based classification of PAH mixtures to predict carcinogenic potential},
author = {Tilton, Susan C. and Siddens, Lisbeth K. and Krueger, Sharon K. and Larkin, Andrew J. and Löhr, Christiane V. and Williams, David E. and Baird, William M. and Waters, Katrina M.},
abstractNote = {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. As a result, 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.},
doi = {10.1093/toxsci/kfv080},
journal = {Toxicological Sciences},
number = 1,
volume = 146,
place = {United States},
year = {Wed Apr 22 00:00:00 EDT 2015},
month = {Wed Apr 22 00:00:00 EDT 2015}
}
Web of Science
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