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Title: Development of a Novel AOP for Cyp2F2-Mediated Lung Cancer in Mice

Abstract

Abstract Traditional methods for carcinogenicity testing rely heavily on the rodent bioassay as the standard for identification of tumorigenic risk. As such, identification of species-specific outcomes and/or metabolism are a frequent argument for regulatory exemption. One example is the association of tumor formation in the mouse lung after exposure to Cyp2F2 ligands. The adverse outcome pathway (AOP) framework offers a theoretical platform to address issues of species specificity that is consistent, transparent, and capable of integrating data from new approach methodologies as well as traditional data streams. A central premise of the AOP concept is that pathway progression from the molecular initiating event (MIE) implies a definable “response-response” (R-R) relationship between each key event (KE) that drives the pathway towards a specific adverse outcome (AO). This article describes an AOP for lung cancer in the mouse from an MIE of Cyp2F2-specific reactive metabolite formation, advancing through KE that include protein and/or nucleic acid adducts, diminished Club Cell 10 kDa (CC10) protein expression, hyperplasia of CC10 deficient Club cells, and culminating in the AO of mixed-cell tumor formation in the distal airways. This tumor formation is independent of route of exposure and our AOP construct is based on overlapping mechanistic events formore » naphthalene, styrene, ethyl benzene, isoniazid, and fluensulfone in the mouse. This AOP is intended to accelerate the explication of an apparent mouse-specific outcome and serve as a starting point for a quantitative analysis of mouse-human differences in susceptibility to the tumorigenic effects of Cyp2F2 ligands.« less

Authors:
 [1]; ORCiD logo [2]
  1. Oak Ridge Institute for Science and Education Fellow at the National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27709
  2. National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27709
Publication Date:
Sponsoring Org.:
USDOE
OSTI Identifier:
1571840
Resource Type:
Published Article
Journal Name:
Toxicological Sciences
Additional Journal Information:
Journal Name: Toxicological Sciences Journal Volume: 172 Journal Issue: 1; Journal ID: ISSN 1096-6080
Publisher:
Oxford University Press
Country of Publication:
United States
Language:
English

Citation Formats

Hill, III, Thomas, and Conolly, Rory B. Development of a Novel AOP for Cyp2F2-Mediated Lung Cancer in Mice. United States: N. p., 2019. Web. doi:10.1093/toxsci/kfz185.
Hill, III, Thomas, & Conolly, Rory B. Development of a Novel AOP for Cyp2F2-Mediated Lung Cancer in Mice. United States. doi:10.1093/toxsci/kfz185.
Hill, III, Thomas, and Conolly, Rory B. Mon . "Development of a Novel AOP for Cyp2F2-Mediated Lung Cancer in Mice". United States. doi:10.1093/toxsci/kfz185.
@article{osti_1571840,
title = {Development of a Novel AOP for Cyp2F2-Mediated Lung Cancer in Mice},
author = {Hill, III, Thomas and Conolly, Rory B.},
abstractNote = {Abstract Traditional methods for carcinogenicity testing rely heavily on the rodent bioassay as the standard for identification of tumorigenic risk. As such, identification of species-specific outcomes and/or metabolism are a frequent argument for regulatory exemption. One example is the association of tumor formation in the mouse lung after exposure to Cyp2F2 ligands. The adverse outcome pathway (AOP) framework offers a theoretical platform to address issues of species specificity that is consistent, transparent, and capable of integrating data from new approach methodologies as well as traditional data streams. A central premise of the AOP concept is that pathway progression from the molecular initiating event (MIE) implies a definable “response-response” (R-R) relationship between each key event (KE) that drives the pathway towards a specific adverse outcome (AO). This article describes an AOP for lung cancer in the mouse from an MIE of Cyp2F2-specific reactive metabolite formation, advancing through KE that include protein and/or nucleic acid adducts, diminished Club Cell 10 kDa (CC10) protein expression, hyperplasia of CC10 deficient Club cells, and culminating in the AO of mixed-cell tumor formation in the distal airways. This tumor formation is independent of route of exposure and our AOP construct is based on overlapping mechanistic events for naphthalene, styrene, ethyl benzene, isoniazid, and fluensulfone in the mouse. This AOP is intended to accelerate the explication of an apparent mouse-specific outcome and serve as a starting point for a quantitative analysis of mouse-human differences in susceptibility to the tumorigenic effects of Cyp2F2 ligands.},
doi = {10.1093/toxsci/kfz185},
journal = {Toxicological Sciences},
number = 1,
volume = 172,
place = {United States},
year = {2019},
month = {8}
}

Journal Article:
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This content will become publicly available on August 12, 2020
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