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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 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 » 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.« less

Authors:
 [1];  [1];  [1];  [1];  [1];  [1];  [1];  [2]
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  1. Oregon State Univ., Corvallis, OR (United States)
  2. 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:
Journal Article: 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.
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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
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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. 2015. "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.
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@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},
url = {https://www.osti.gov/biblio/1224102}, journal = {Toxicological Sciences},
issn = {1096-6080},
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}
}
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Journal Article:
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Publisher's Version of Record
https://doi.org/10.1093/toxsci/kfv080
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Cited by: 18 works
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Works referenced in this record:

Estimating the Posterior Probabilities Using the K-Nearest Neighbor Rule
journal, March 2005

VIBE 2.0: Visual Integration for Bayesian Evaluation
journal, November 2009

A comparison of normalization methods for high density oligonucleotide array data based on variance and bias
journal, January 2003

A framework for the use of genomics data at the EPA
journal, September 2006

The Role of in Vitro Gene Expression Profiling in Particulate Matter Health Research
journal, August 2013

Analysis of Variance for Gene Expression Microarray Data
journal, December 2000

Systems Approaches in Risk Assessment
journal, February 2013

Transcriptional responses to complex mixtures—A review
journal, November 2007

Polycyclic aromatic hydrocarbons as skin carcinogens: Comparison of benzo[a]pyrene, dibenzo[def,p]chrysene and three environmental mixtures in the FVB/N mouse
journal, November 2012

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