Mechanism-based classification of PAH mixtures to predict carcinogenic potential

Tilton, Susan C.; Siddens, Lisbeth K.; Krueger, Sharon K.; Larkin, Andrew J.; Löhr, Christiane V.; Williams, David E.; Baird, William M.; Waters, Katrina M.

doi:10.1093/toxsci/kfv080

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 »« less

Authors:

Tilton, Susan C. ^[1]; Siddens, Lisbeth K. ^[1]; Krueger, Sharon K. ^[1]; Larkin, Andrew J. ^[1]; Löhr, Christiane V. ^[1]; Williams, David E. ^[1]; Baird, William M. ^[1]; Waters, Katrina M. ^[2]

Oregon State Univ., Corvallis, OR (United States)
Pacific Northwest National Lab. (PNNL), Richland, WA (United States)

Publication Date:: Wed Apr 22 00:00:00 EDT 2015

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.

Copy to clipboard


                    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

Copy to clipboard


                    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.

Copy to clipboard


                    
@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}

}

Copy to clipboard

Journal Article:

Free Publicly Available Full Text

Accepted Manuscript (DOE)

Publisher's Version of Record

https://doi.org/10.1093/toxsci/kfv080

Other availability

Search WorldCat to find libraries that may hold this journal

Citation Metrics:

Cited by: 18 works

Citation information provided by
Web of Science

Save / Share:

Export Metadata

Save to My Library

Works referenced in this record:

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

Atiya, Amir F.
Neural Computation, Vol. 17, Issue 3
DOI: 10.1162/0899766053019971

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

Beagley, Nathaniel; Stratton, Kelly G.; Webb-Robertson, Bobbie-Jo M.
Bioinformatics, Vol. 26, Issue 2
DOI: 10.1093/bioinformatics/btp639

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

Bolstad, B. M.; Irizarry, R. A.; Astrand, M.
Bioinformatics, Vol. 19, Issue 2
DOI: 10.1093/bioinformatics/19.2.185

The influence of diesel exhaust on polycyclic aromatic hydrocarbon-induced DNA damage, gene expression, and tumor initiation in Sencar mice in vivo
journal, June 2008

Courter, Lauren A.; Luch, Andreas; Musafia-Jeknic, Tamara
Cancer Letters, Vol. 265, Issue 1
DOI: 10.1016/j.canlet.2008.02.017

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

Dix, David J.; Gallagher, Kathryn; Benson, William H.
Nature Biotechnology, Vol. 24, Issue 9
DOI: 10.1038/nbt0906-1108

Genomic Models of Short-Term Exposure Accurately Predict Long-Term Chemical Carcinogenicity and Identify Putative Mechanisms of Action
journal, July 2014

Gusenleitner, Daniel; Auerbach, Scott S.; Melia, Tisha
PLoS ONE, Vol. 9, Issue 7
DOI: 10.1371/journal.pone.0102579

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

Huang, Yuh-Chin T.
Journal of Toxicology and Environmental Health, Part B, Vol. 16, Issue 6
DOI: 10.1080/10937404.2013.832649

Interactions between polycyclic aromatic hydrocarbons in complex mixtures and implications for cancer risk assessment
journal, July 2014

Jarvis, Ian W. H.; Dreij, Kristian; Mattsson, Åse
Toxicology, Vol. 321
DOI: 10.1016/j.tox.2014.03.012

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

Kerr, M. Kathleen; Martin, Mitchell; Churchill, Gary A.
Journal of Computational Biology, Vol. 7, Issue 6
DOI: 10.1089/10665270050514954

Automated Dose-Response Analysis and Comparative Toxicogenomic Evaluation of the Hepatic Effects Elicited by TCDD, TCDF, and PCB126 in C57BL/6 Mice
journal, August 2010

Kopec, Anna K.; Burgoon, Lyle D.; Ibrahim-Aibo, Daher
Toxicological Sciences, Vol. 118, Issue 1
DOI: 10.1093/toxsci/kfq236

Non-additive hepatic gene expression elicited by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and 2,2′,4,4′,5,5′-hexachlorobiphenyl (PCB153) co-treatment in C57BL/6 mice
journal, October 2011

Kopec, Anna K.; D'Souza, Michelle L.; Mets, Bryan D.
Toxicology and Applied Pharmacology, Vol. 256, Issue 2
DOI: 10.1016/j.taap.2011.08.002

Application of a fuzzy neural network model in predicting polycyclic aromatic hydrocarbon-mediated perturbations of the Cyp1b1 transcriptional regulatory network in mouse skin
journal, March 2013

Larkin, Andrew; Siddens, Lisbeth K.; Krueger, Sharon K.
Toxicology and Applied Pharmacology, Vol. 267, Issue 2
DOI: 10.1016/j.taap.2012.12.011

Systems Approaches in Risk Assessment
journal, February 2013

Lesko, L. J.; Zheng, S.; Schmidt, S.
Clinical Pharmacology & Therapeutics, Vol. 93, Issue 5
DOI: 10.1038/clpt.2013.29

Functional Analysis of OMICs Data and Small Molecule Compounds in an Integrated “Knowledge-Based” Platform
book, January 2009

Nikolsky, Yuri; Kirillov, Eugene; Zuev, Roman
Methods in Molecular Biology
DOI: 10.1007/978-1-60761-175-2_10

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

Sen, B.; Mahadevan, B.; Demarini, D.
Mutation Research/Reviews in Mutation Research, Vol. 636, Issue 1-3
DOI: 10.1016/j.mrrev.2007.08.002

Cytoscape: A Software Environment for Integrated Models of Biomolecular Interaction Networks
journal, November 2003

Shannon, P.
Genome Research, Vol. 13, Issue 11
DOI: 10.1101/gr.1239303

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

Siddens, Lisbeth K.; Larkin, Andrew; Krueger, Sharon K.
Toxicology and Applied Pharmacology, Vol. 264, Issue 3
DOI: 10.1016/j.taap.2012.08.014

Identification of molecular signatures predicting the carcinogenicity of polycyclic aromatic hydrocarbons (PAHs)
journal, July 2012

Song, Mi-Kyung; Song, Mee; Choi, Han-Seam
Toxicology Letters, Vol. 212, Issue 1
DOI: 10.1016/j.toxlet.2012.04.013

Works referencing / citing this record:

A novel, integrated in vitro carcinogenicity test to identify genotoxic and non-genotoxic carcinogens using human lymphoblastoid cells
journal, November 2017

Wilde, Eleanor C.; Chapman, Katherine E.; Stannard, Leanne M.
Archives of Toxicology, Vol. 92, Issue 2
DOI: 10.1007/s00204-017-2102-y

Cytochrome P450 1b1 in polycyclic aromatic hydrocarbon (PAH)-induced skin carcinogenesis: Tumorigenicity of individual PAHs and coal-tar extract, DNA adduction and expression of select genes in the Cyp1b1 knockout mouse
journal, September 2015

Siddens, Lisbeth K.; Bunde, Kristi L.; Harper, Tod A.
Toxicology and Applied Pharmacology, Vol. 287, Issue 2
DOI: 10.1016/j.taap.2015.05.019

The State-of-the Art of Environmental Toxicogenomics: Challenges and Perspectives of “Omics” Approaches Directed to Toxicant Mixtures
journal, November 2019

Martins,
International Journal of Environmental Research and Public Health, Vol. 16, Issue 23
DOI: 10.3390/ijerph16234718

Similar Records in DOE PAGES and OSTI.GOV collections:

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 Article Siddens, Lisbeth K. ; Larkin, Andrew ; Superfund Research Center, Oregon State University ; ... - Toxicology and Applied Pharmacology

The polycyclic aromatic hydrocarbon (PAH), benzo[a]pyrene (BaP), was compared to dibenzo[def,p]chrysene (DBC) and combinations of three environmental PAH mixtures (coal tar, diesel particulate and cigarette smoke condensate) using a two stage, FVB/N mouse skin tumor model. DBC (4 nmol) was most potent, reaching 100% tumor incidence with a shorter latency to tumor formation, less than 20 weeks of 12-O-tetradecanoylphorbol-13-acetate (TPA) promotion compared to all other treatments. Multiplicity was 4 times greater than BaP (400 nmol). Both PAHs produced primarily papillomas followed by squamous cell carcinoma and carcinoma in situ. Diesel particulate extract (1 mg SRM 1650b; mix 1) did notmore »« less
https://doi.org/10.1016/J.TAAP.2012.08.014
Cytochrome P450 1b1 in polycyclic aromatic hydrocarbon (PAH)-induced skin carcinogenesis: Tumorigenicity of individual PAHs and coal-tar extract, DNA adduction and expression of select genes in the Cyp1b1 knockout mouse

Journal Article Siddens, Lisbeth K. ; Superfund Research Center, Oregon State University, Corvallis, OR 97331 ; Bunde, Kristi L. ; ... - Toxicology and Applied Pharmacology

FVB/N mice wild-type, heterozygous or null for Cyp 1b1 were used in a two-stage skin tumor study comparing PAH, benzo[a]pyrene (BaP), dibenzo[def,p]chrysene (DBC), and coal tar extract (CTE, SRM 1597a). Following 20 weeks of promotion with TPA the Cyp 1b1 null mice, initiated with DBC, exhibited reductions in incidence, multiplicity, and progression. None of these effects were observed with BaP or CTE. The mechanism of Cyp 1b1-dependent alteration of DBC skin carcinogenesis was further investigated by determining expression of select genes in skin from DBC-treated mice 2, 4 and 8 h post-initiation. A significant reduction in levels of Cyp 1a1,more »« less
https://doi.org/10.1016/J.TAAP.2015.05.019
Application of a fuzzy neural network model in predicting polycyclic aromatic hydrocarbon-mediated perturbations of the Cyp1b1 transcriptional regulatory network in mouse skin

Journal Article Larkin, Andrew ; Department of Statistics, Oregon State University ; Superfund Research Center, Oregon State University ; ... - Toxicology and Applied Pharmacology

Polycyclic aromatic hydrocarbons (PAHs) are present in the environment as complex mixtures with components that have diverse carcinogenic potencies and mostly unknown interactive effects. Non-additive PAH interactions have been observed in regulation of cytochrome P450 (CYP) gene expression in the CYP1 family. To better understand and predict biological effects of complex mixtures, such as environmental PAHs, an 11 gene input-1 gene output fuzzy neural network (FNN) was developed for predicting PAH-mediated perturbations of dermal Cyp1b1 transcription in mice. Input values were generalized using fuzzy logic into low, medium, and high fuzzy subsets, and sorted using k-means clustering to create Mamdanimore »« less
https://doi.org/10.1016/J.TAAP.2012.12.011
Competitive Metabolism of Polycyclic Aromatic Hydrocarbons (PAHs): An Assessment Using In Vitro Metabolism and Physiologically Based Pharmacokinetic (PBPK) Modeling

Journal Article Smith, Jordan N. ; Gaither, Kari A. ; Pande, Paritosh - International Journal of Environmental Research and Public Health

Humans are routinely exposed to complex mixtures such as polycyclic aromatic hydrocarbons (PAHs) rather than to single compounds, as are often assessed for hazards. Cytochrome P450 enzymes (CYPs) metabolize PAHs, and multiple PAHs found in mixtures can compete as substrates for individual CYPs (e.g., CYP1A1, CYP1B1, etc.). The objective of this study was to assess competitive inhibition of metabolism of PAH mixtures in humans and evaluate a key assumption of the Relative Potency Factor approach that common human exposures will not cause interactions among mixture components. To test this objective, we co-incubated binary mixtures of benzo[a]pyrene (BaP) and dibenzo[def,p]chrysene (DBC)more »« less
https://doi.org/10.3390/ijerph19148266

Full Text Available
Translating dosimetry of Dibenzo[def,p]chrysene (DBC) and metabolites across dose and species using physiologically based pharmacokinetic (PBPK) modeling

Journal Article Pande, Paritosh ; Madeen, Erin P. ; Williams, David E. ; ... - Toxicology and Applied Pharmacology

We report that Dibenzo[def,p]chrysene (DBC) is an environmental polycyclic aromatic hydrocarbon (PAH) that causes tumors in mice and has been classified as a probable human carcinogen by the International Agency for Research on Cancer. Animal toxicity studies often utilize higher doses than are found in relevant human exposures. Additionally, like many PAHs, DBC requires metabolic bioactivation to form the ultimate toxicant, and species differences in DBC and DBC metabolite metabolism have been observed. To understand the implications of dose and species differences, a physiologically based pharmacokinetic model (PBPK) for DBC and major metabolites was developed in mice and humans. Metabolismmore »« less
https://doi.org/10.1016/j.taap.2021.115830

Full Text Available

Similar Records

Title: Mechanism-based classification of PAH mixtures to predict carcinogenic potential

Abstract

Citation Formats

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

The influence of diesel exhaust on polycyclic aromatic hydrocarbon-induced DNA damage, gene expression, and tumor initiation in Sencar mice in vivo journal, June 2008

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

Genomic Models of Short-Term Exposure Accurately Predict Long-Term Chemical Carcinogenicity and Identify Putative Mechanisms of Action journal, July 2014

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

Interactions between polycyclic aromatic hydrocarbons in complex mixtures and implications for cancer risk assessment journal, July 2014

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

Automated Dose-Response Analysis and Comparative Toxicogenomic Evaluation of the Hepatic Effects Elicited by TCDD, TCDF, and PCB126 in C57BL/6 Mice journal, August 2010

Non-additive hepatic gene expression elicited by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and 2,2′,4,4′,5,5′-hexachlorobiphenyl (PCB153) co-treatment in C57BL/6 mice journal, October 2011

Application of a fuzzy neural network model in predicting polycyclic aromatic hydrocarbon-mediated perturbations of the Cyp1b1 transcriptional regulatory network in mouse skin journal, March 2013

Systems Approaches in Risk Assessment journal, February 2013

Functional Analysis of OMICs Data and Small Molecule Compounds in an Integrated “Knowledge-Based” Platform book, January 2009

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

Cytoscape: A Software Environment for Integrated Models of Biomolecular Interaction Networks journal, November 2003

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

Identification of molecular signatures predicting the carcinogenicity of polycyclic aromatic hydrocarbons (PAHs) journal, July 2012

A novel, integrated in vitro carcinogenicity test to identify genotoxic and non-genotoxic carcinogens using human lymphoblastoid cells journal, November 2017

Cytochrome P450 1b1 in polycyclic aromatic hydrocarbon (PAH)-induced skin carcinogenesis: Tumorigenicity of individual PAHs and coal-tar extract, DNA adduction and expression of select genes in the Cyp1b1 knockout mouse journal, September 2015

The State-of-the Art of Environmental Toxicogenomics: Challenges and Perspectives of “Omics” Approaches Directed to Toxicant Mixtures journal, November 2019

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

The influence of diesel exhaust on polycyclic aromatic hydrocarbon-induced DNA damage, gene expression, and tumor initiation in Sencar mice in vivo
journal, June 2008

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

Genomic Models of Short-Term Exposure Accurately Predict Long-Term Chemical Carcinogenicity and Identify Putative Mechanisms of Action
journal, July 2014

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

Interactions between polycyclic aromatic hydrocarbons in complex mixtures and implications for cancer risk assessment
journal, July 2014

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

Automated Dose-Response Analysis and Comparative Toxicogenomic Evaluation of the Hepatic Effects Elicited by TCDD, TCDF, and PCB126 in C57BL/6 Mice
journal, August 2010

Non-additive hepatic gene expression elicited by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and 2,2′,4,4′,5,5′-hexachlorobiphenyl (PCB153) co-treatment in C57BL/6 mice
journal, October 2011

Application of a fuzzy neural network model in predicting polycyclic aromatic hydrocarbon-mediated perturbations of the Cyp1b1 transcriptional regulatory network in mouse skin
journal, March 2013

Systems Approaches in Risk Assessment
journal, February 2013

Functional Analysis of OMICs Data and Small Molecule Compounds in an Integrated “Knowledge-Based” Platform
book, January 2009

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

Cytoscape: A Software Environment for Integrated Models of Biomolecular Interaction Networks
journal, November 2003

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

Identification of molecular signatures predicting the carcinogenicity of polycyclic aromatic hydrocarbons (PAHs)
journal, July 2012

A novel, integrated in vitro carcinogenicity test to identify genotoxic and non-genotoxic carcinogens using human lymphoblastoid cells
journal, November 2017

Cytochrome P450 1b1 in polycyclic aromatic hydrocarbon (PAH)-induced skin carcinogenesis: Tumorigenicity of individual PAHs and coal-tar extract, DNA adduction and expression of select genes in the Cyp1b1 knockout mouse
journal, September 2015

The State-of-the Art of Environmental Toxicogenomics: Challenges and Perspectives of “Omics” Approaches Directed to Toxicant Mixtures
journal, November 2019