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

Hill, III, Thomas; Conolly, Rory B.

doi:10.1093/toxsci/kfz185

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 »« less

Authors:

Hill, III, Thomas ^[1];

^[2]

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
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:: Mon Aug 12 00:00:00 EDT 2019

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.

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                    Hill, III, Thomas, & Conolly, Rory B. Development of a Novel AOP for Cyp2F2-Mediated Lung Cancer in Mice.  United States.  https://doi.org/10.1093/toxsci/kfz185

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                    Hill, III, Thomas, and Conolly, Rory B. Mon .  
"Development of a Novel AOP for Cyp2F2-Mediated Lung Cancer in Mice".  United States.  https://doi.org/10.1093/toxsci/kfz185.

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@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         = {Mon Aug 12 00:00:00 EDT 2019},

  month        = {Mon Aug 12 00:00:00 EDT 2019}

}

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G.; Cranz, D. L.; Kemp, L.</span> </li> <li> Experimental Lung Research, Vol. 13, Issue 1</li> <li> <span class="text-muted related-url">DOI: <a href="https://doi.org/10.3109/01902148709064309" class="text-muted" target="_blank" rel="noopener noreferrer">10.3109/01902148709064309<span class="fa fa-external-link" aria-hidden="true"></span></a></span> </li> </ul> <hr/> </div> <div> <h2 class="title" style="margin-bottom:0;" data-apporder=""> <a href="https://doi.org/10.1073/pnas.1319051111" target="_blank" rel="noopener noreferrer" class="name">T helper 17 cells play a critical pathogenic role in lung cancer<span class="fa fa-external-link" aria-hidden="true"></span></a> <small class="text-muted" style="text-transform:uppercase; font-size:0.75rem;"><br/> <span class="type">journal</span>, <span class="date" data-date="2014-03-31">March 2014</span></small> </h2> <ul class="small references-list" style="list-style-type:none; margin-top: 0.5em; padding-left: 0; line-height:1.8em;"> <li> <span style="color:#5C7B2D;"> Chang, S. H.; Mirabolfathinejad, S. G.; Katta, H.</span> </li> <li> Proceedings of the National Academy of Sciences, Vol. 111, Issue 15</li> <li> <span class="text-muted related-url">DOI: <a href="https://doi.org/10.1073/pnas.1319051111" class="text-muted" target="_blank" rel="noopener noreferrer">10.1073/pnas.1319051111<span class="fa fa-external-link" aria-hidden="true"></span></a></span> </li> </ul> <hr/> </div> <div> <h2 class="title" style="margin-bottom:0;" data-apporder=""> <a href="https://doi.org/10.1093/mutage/ger033" target="_blank" rel="noopener noreferrer" class="name">Styrene exposure and risk of cancer<span class="fa fa-external-link" aria-hidden="true"></span></a> <small class="text-muted" style="text-transform:uppercase; font-size:0.75rem;"><br/> <span class="type">journal</span>, <span class="date" data-date="2011-07-01">July 2011</span></small> </h2> <ul class="small references-list" style="list-style-type:none; margin-top: 0.5em; padding-left: 0; line-height:1.8em;"> <li> <span style="color:#5C7B2D;"> Huff, J.; Infante, P. F.</span> </li> <li> Mutagenesis, Vol. 26, Issue 5</li> <li> <span class="text-muted related-url">DOI: <a href="https://doi.org/10.1093/mutage/ger033" class="text-muted" target="_blank" rel="noopener noreferrer">10.1093/mutage/ger033<span class="fa fa-external-link" aria-hidden="true"></span></a></span> </li> </ul> <hr/> </div> <div> <h2 class="title" style="margin-bottom:0;" data-apporder=""> <a href="https://doi.org/10.1016/0009-2797(82)90152-1" target="_blank" rel="noopener noreferrer" class="name">Evidence for cytochrome P-450 mediated metabolism in the bronchiolar damage by naphthalene<span class="fa fa-external-link" aria-hidden="true"></span></a> <small class="text-muted" style="text-transform:uppercase; font-size:0.75rem;"><br/> <span class="type">journal</span>, <span class="date" data-date="1982-07-01">July 1982</span></small> </h2> <ul class="small references-list" style="list-style-type:none; margin-top: 0.5em; padding-left: 0; line-height:1.8em;"> <li> <span style="color:#5C7B2D;"> Warren, D. L.; Brown, D. L.; Buckpitt, A. R.</span> </li> <li> Chemico-Biological Interactions, Vol. 40, Issue 3</li> <li> <span class="text-muted related-url">DOI: <a href="https://doi.org/10.1016/0009-2797(82)90152-1" class="text-muted" target="_blank" rel="noopener noreferrer">10.1016/0009-2797(82)90152-1<span class="fa fa-external-link" aria-hidden="true"></span></a></span> </li> </ul> <hr/> </div> <div> <h2 class="title" style="margin-bottom:0;" data-apporder=""> <a href="https://doi.org/10.1177/41.8.8331282" target="_blank" rel="noopener noreferrer" class="name">Quantitative comparison of intracellular concentration and volume of Clara cell 10 KD protein in rat bronchi and bronchioles based on laser scanning confocal microscopy.<span class="fa fa-external-link" aria-hidden="true"></span></a> <small class="text-muted" style="text-transform:uppercase; font-size:0.75rem;"><br/> <span class="type">journal</span>, <span class="date" data-date="1993-08-01">August 1993</span></small> </h2> <ul class="small references-list" style="list-style-type:none; margin-top: 0.5em; padding-left: 0; line-height:1.8em;"> <li> <span style="color:#5C7B2D;"> Dodge, D. E.; Rucker, R. B.; Singh, G.</span> </li> <li> Journal of Histochemistry & Cytochemistry, Vol. 41, Issue 8</li> <li> <span class="text-muted related-url">DOI: <a href="https://doi.org/10.1177/41.8.8331282" class="text-muted" target="_blank" rel="noopener noreferrer">10.1177/41.8.8331282<span class="fa fa-external-link" aria-hidden="true"></span></a></span> </li> </ul> <hr/> </div> <div> <h2 class="title" style="margin-bottom:0;" data-apporder=""> <a href="https://doi.org/10.1080/15287390306386" target="_blank" rel="noopener noreferrer" class="name">In Vitro Metabolism of Styrene to Styrene Oxide in Liver and Lung of Cyp2E1 Knockout Mice<span class="fa fa-external-link" aria-hidden="true"></span></a> <small class="text-muted" style="text-transform:uppercase; font-size:0.75rem;"><br/> <span class="type">journal</span>, <span class="date" data-date="2003-01-01">January 2003</span></small> </h2> <ul class="small references-list" style="list-style-type:none; margin-top: 0.5em; padding-left: 0; line-height:1.8em;"> <li> <span style="color:#5C7B2D;"> Carlson, Gary</span> </li> <li> Journal of Toxicology and Environmental Health, Part A, Vol. 66, Issue 9</li> <li> <span class="text-muted related-url">DOI: <a href="https://doi.org/10.1080/15287390306386" class="text-muted" target="_blank" rel="noopener noreferrer">10.1080/15287390306386<span class="fa fa-external-link" aria-hidden="true"></span></a></span> </li> </ul> <hr/> </div> <div> <h2 class="title" style="margin-bottom:0;" data-apporder=""> <a href="https://doi.org/10.1016/j.toxlet.2004.06.007" target="_blank" rel="noopener noreferrer" class="name">Impaired recovery from naphthalene-induced bronchiolar epithelial injury in mice exposed to aged and diluted sidestream cigarette smoke<span class="fa fa-external-link" aria-hidden="true"></span></a> <small class="text-muted" style="text-transform:uppercase; font-size:0.75rem;"><br/> <span class="type">journal</span>, <span class="date" data-date="2004-12-01">December 2004</span></small> </h2> <ul class="small references-list" style="list-style-type:none; margin-top: 0.5em; padding-left: 0; line-height:1.8em;"> <li> <span style="color:#5C7B2D;"> Van Winkle, Laura S.; Brown, Collette D.; Shimizu, Judith A.</span> </li> <li> Toxicology Letters, Vol. 154, Issue 1-2</li> <li> <span class="text-muted related-url">DOI: <a href="https://doi.org/10.1016/j.toxlet.2004.06.007" class="text-muted" target="_blank" rel="noopener noreferrer">10.1016/j.toxlet.2004.06.007<span class="fa fa-external-link" aria-hidden="true"></span></a></span> </li> </ul> <hr/> </div> <div> <h2 class="title" style="margin-bottom:0;" data-apporder=""> <a href="https://doi.org/10.1093/toxsci/kfu199" target="_blank" rel="noopener noreferrer" class="name">Adverse Outcome Pathway (AOP) Development I: Strategies and Principles<span class="fa fa-external-link" aria-hidden="true"></span></a> <small class="text-muted" style="text-transform:uppercase; font-size:0.75rem;"><br/> <span class="type">journal</span>, <span class="date" data-date="2014-12-01">December 2014</span></small> </h2> <ul class="small references-list" style="list-style-type:none; margin-top: 0.5em; padding-left: 0; line-height:1.8em;"> <li> <span style="color:#5C7B2D;"> Villeneuve, Daniel L.; Crump, Doug; Garcia-Reyero, Natàlia</span> </li> <li> Toxicological Sciences, Vol. 142, Issue 2</li> <li> <span class="text-muted related-url">DOI: <a href="https://doi.org/10.1093/toxsci/kfu199" class="text-muted" target="_blank" rel="noopener noreferrer">10.1093/toxsci/kfu199<span class="fa fa-external-link" aria-hidden="true"></span></a></span> </li> </ul> <hr/> </div> <div> <h2 class="title" style="margin-bottom:0;" data-apporder=""> <a href="https://doi.org/10.1124/jpet.103.062901" target="_blank" rel="noopener noreferrer" class="name">Comparison of Pulmonary/Nasal CYP2F Expression Levels in Rodents and Rhesus Macaque<span class="fa fa-external-link" aria-hidden="true"></span></a> <small class="text-muted" style="text-transform:uppercase; font-size:0.75rem;"><br/> <span class="type">journal</span>, <span class="date" data-date="2004-01-14">January 2004</span></small> </h2> <ul class="small references-list" style="list-style-type:none; margin-top: 0.5em; padding-left: 0; line-height:1.8em;"> <li> <span style="color:#5C7B2D;"> Baldwin, R. Michael; Jewell, William T.; Fanucchi, Michelle V.</span> </li> <li> Journal of Pharmacology and Experimental Therapeutics, Vol. 309, Issue 1</li> <li> <span class="text-muted related-url">DOI: <a href="https://doi.org/10.1124/jpet.103.062901" class="text-muted" target="_blank" rel="noopener noreferrer">10.1124/jpet.103.062901<span class="fa fa-external-link" aria-hidden="true"></span></a></span> </li> </ul> <hr/> </div> <div> <h2 class="title" style="margin-bottom:0;" data-apporder=""> <a href="https://doi.org/10.1093/toxsci/kfj001" target="_blank" rel="noopener noreferrer" class="name">Mode of Action in Relevance of Rodent Liver Tumors to Human Cancer Risk<span class="fa fa-external-link" aria-hidden="true"></span></a> <small class="text-muted" style="text-transform:uppercase; font-size:0.75rem;"><br/> <span class="type">journal</span>, <span class="date" data-date="2005-10-12">October 2005</span></small> </h2> <ul class="small references-list" style="list-style-type:none; margin-top: 0.5em; padding-left: 0; line-height:1.8em;"> <li> <span style="color:#5C7B2D;"> Holsapple, Michael P.; Pitot, Henri C.; Cohen, Samuel H.</span> </li> <li> Toxicological Sciences, Vol. 89, Issue 1</li> <li> <span class="text-muted related-url">DOI: <a href="https://doi.org/10.1093/toxsci/kfj001" class="text-muted" target="_blank" rel="noopener noreferrer">10.1093/toxsci/kfj001<span class="fa fa-external-link" aria-hidden="true"></span></a></span> </li> </ul> <hr/> </div> <div> <h2 class="title" style="margin-bottom:0;" data-apporder=""> <a href="https://doi.org/10.1021/ci0600915" target="_blank" rel="noopener noreferrer" class="name">QSAR Modeling of in Vitro Inhibition of Cytochrome P450 3A4<span class="fa fa-external-link" aria-hidden="true"></span></a> <small class="text-muted" style="text-transform:uppercase; font-size:0.75rem;"><br/> <span class="type">journal</span>, <span class="date" data-date="2006-08-17">August 2006</span></small> </h2> <ul class="small references-list" style="list-style-type:none; margin-top: 0.5em; padding-left: 0; line-height:1.8em;"> <li> <span style="color:#5C7B2D;"> Mao, Boryeu; Gozalbes, Rafael; Barbosa, Frédérique</span> </li> <li> Journal of Chemical Information and Modeling, Vol. 46, Issue 5</li> <li> <span class="text-muted related-url">DOI: <a href="https://doi.org/10.1021/ci0600915" class="text-muted" target="_blank" rel="noopener noreferrer">10.1021/ci0600915<span class="fa fa-external-link" aria-hidden="true"></span></a></span> </li> </ul> <hr/> </div> <div> <h2 class="title" style="margin-bottom:0;" data-apporder=""> <a href="https://doi.org/10.1289/EHP1304" target="_blank" rel="noopener noreferrer" class="name">Application of Adverse Outcome Pathways to U.S. EPA’s Endocrine Disruptor Screening Program<span class="fa fa-external-link" aria-hidden="true"></span></a> <small class="text-muted" style="text-transform:uppercase; font-size:0.75rem;"><br/> <span class="type">journal</span>, <span class="date" data-date="2017-09-22">September 2017</span></small> </h2> <ul class="small references-list" style="list-style-type:none; margin-top: 0.5em; padding-left: 0; line-height:1.8em;"> <li> <span style="color:#5C7B2D;"> Browne, Patience; Noyes, Pamela D.; Casey, Warren M.</span> </li> <li> Environmental Health Perspectives, Vol. 125, Issue 9</li> <li> <span class="text-muted related-url">DOI: <a href="https://doi.org/10.1289/EHP1304" class="text-muted" target="_blank" rel="noopener noreferrer">10.1289/EHP1304<span class="fa fa-external-link" aria-hidden="true"></span></a></span> </li> </ul> <hr/> </div> </div> <div class="pagination-container small"> <a class="pure-button prev page" href="#" rel="prev"><span class="sr-only">Previous Page</span><span class="fa fa-angle-left"></span></a> <ul class="pagination d-inline-block" style="padding-left:.2em;"></ul> <a class="pure-button next page" href="#" rel="next"><span class="sr-only">Next Page</span><span class="fa fa-angle-right"></span></a> </div> </div> </div> <div class="col-sm-3 order-sm-3"> <ul class="nav nav-stacked"> <li class="active"><a href="" class="reference-type-filter tab-nav" data-tab="biblio-references" data-filter="type" data-pattern=""><span class="fa fa-angle-right"></span> All References</a></li> <li class="small" style="margin-left:.75em; 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float:none;">[ × clear filter / sort ]</a> </div> <input type="submit" id="sort_submit_references" name="submit" aria-label="submit" style="display: none;"/> </form> </div> </div> </div> </section> <section id="biblio-related" class="tab-content tab-content-sec " data-tab="biblio"> <div class="row"> <div class="col-sm-9 order-sm-9"> <section id="biblio-similar" class="tab-content tab-content-sec active" data-tab="related"> <div class="padding"> <p class="lead text-muted" style="font-size: 18px; margin-top:0px;">Similar Records in DOE PAGES and OSTI.GOV collections:</p> <aside> <ul class="item-list" itemscope itemtype="http://schema.org/ItemList" style="padding-left:0; list-style-type: none;"> <li> <div class="article item document" itemprop="itemListElement" itemscope itemtype="http://schema.org/WebPage"><meta itemprop="position" content="0" /><div class="item-info"> <h2 class="title" itemprop="name headline"><a href="/pages/biblio/1860282-from-qualitative-quantitative-aop-case-study-neurodegeneration" itemprop="url">From Qualitative to Quantitative AOP: A Case Study of Neurodegeneration</a></h2> <div class="metadata"> <small class="text-muted" style="text-transform:uppercase;display:block;line-height:2.5em;">Journal Article</small><span class="authors"> <span class="author">Sinitsyn, Dennis</span> ; <span class="author">Garcia-Reyero, Natàlia</span> ; <span class="author">Watanabe, Karen H.</span> <span class="text-muted pubdata"> - Frontiers in Toxicology</span> </span> </div> <div class="abstract">Adverse outcome pathways (AOPs) include a sequence of events that connect a molecular-level initiating event with an adverse outcome at the cellular level for human health endpoints, or at the population level for ecological endpoints. When there is enough quantitative understanding of the relationships between key events in an AOP, a mathematical model may be developed to connect key events in a quantitative AOP (qAOP). Ideally, a qAOP will reduce the time and resources spent for chemical toxicity testing and risk assessment and enable the extrapolation of data collected at the molecular-level by in vitro assays, for example, to predict<a href='#' onclick='$(this).hide().next().show().next().show();return false;' style='margin-left:10px;'>more »</a><span style='display:none;'> whether an adverse outcome may occur. Here, we review AOPs in the AOPWiki, an AOP repository, to determine best practices that would facilitate conversion from AOP to qAOP. Then, focusing on a particular case study, acetylcholinesterase inhibition leading to neurodegeneration, we describe specific methods and challenges. Examples of challenges include the availability and collection of quantitative data amenable to model development, the lack of studies that measure multiple key events, and model accessibility or transferability across platforms. We conclude with recommendations for improving key event and key event relationship descriptions in the AOPWiki that facilitate the transition of qualitative AOPs to qAOPs.</span><a href='#' onclick='$(this).hide().prev().hide().prev().show();return false;' style='margin-left:10px;display:none;'>« less</a></div><div class="metadata-links small clearfix text-muted" style="margin-top:15px;"> <div class="pure-menu pure-menu-horizontal pull-right" style="width:unset;"> <ul class="pure-menu-list"> <li class="pure-menu-item"><span class="item-info-ftlink"><a class="misc doi-link " href="https://doi.org/10.3389/ftox.2022.838729" target="_blank" rel="noopener" title="Link to document DOI" data-ostiid="1860282" data-product-type="Journal Article" data-product-subtype="PA" >https://doi.org/10.3389/ftox.2022.838729</a></span></li> </ul> </div> </div> </div> <div class="clearfix"></div> </div> </li> <li> <div class="article item document" itemprop="itemListElement" itemscope itemtype="http://schema.org/WebPage"><meta itemprop="position" content="1" /><div class="item-info"> <h2 class="title" itemprop="name headline"><a href="/biblio/1015519-defining-modeling-known-adverse-outcome-pathways-domoic-acid-neuronal-signaling-case-study" itemprop="url">Defining and Modeling Known Adverse Outcome Pathways: Domoic Acid and Neuronal Signaling as a Case Study</a></h2> <div class="metadata"> <small class="text-muted" style="text-transform:uppercase;display:block;line-height:2.5em;">Journal Article</small><span class="authors"> <span class="author">Watanabe, Karen H</span> ; <span class="author">Andersen, Melvin E</span> ; <span class="author">Basu, Nil</span> ; <span class="author">...</span> <span class="text-muted pubdata"> - Environmental Toxicology and Chemistry, 30(1):9-21</span> </span> </div> <div class="abstract">An adverse outcome pathway (AOP) is a sequence of key events from a molecular-level initiating event and an ensuing cascade of steps to an adverse outcome with population level significance. To implement a predictive strategy for ecotoxicology, the multiscale nature of an AOP requires computational models to link salient processes (e.g., in chemical uptake, toxicokinetics, toxicodynamics, and population dynamics). A case study with domoic acid was used to demonstrate strategies and enable generic recommendations for developing computational models in an effort to move toward a toxicity testing paradigm focused on toxicity pathway perturbations applicable to ecological risk assessment. Domoic acid,<a href='#' onclick='$(this).hide().next().show().next().show();return false;' style='margin-left:10px;'>more »</a><span style='display:none;'> an algal toxin with adverse effects on both wildlife and humans, is a potent agonist for kainate receptors (ionotropic glutamate receptors whose activation leads to the influx of Na+ and Ca2+). Increased Ca2+ concentrations result in neuronal excitotoxicity and cell death primarily in the hippocampus, which produces seizures, impairs learning and memory, and alters behavior in some species. Altered neuronal Ca2+ is a key process in domoic acid toxicity which can be evaluated in vitro. Further, results of these assays would be amenable to mechanistic modeling for identifying domoic acid concentrations and Ca2+ perturbations that are normal, adaptive, or clearly toxic. In vitro assays with outputs amenable to measurement in exposed populations can link in vitro to in vivo conditions, and toxicokinetic information will aid in linking in vitro results to the individual organism. Development of an AOP required an iterative process with three important outcomes: (1) a critically reviewed, stressor-specific AOP; (2) identification of key processes suitable for evaluation with in vitro assays; and (3) strategies for model development.</span><a href='#' onclick='$(this).hide().prev().hide().prev().show();return false;' style='margin-left:10px;display:none;'>« less</a></div><div class="metadata-links small clearfix text-muted" style="margin-top:15px;"> <div class="pure-menu pure-menu-horizontal pull-right" style="width:unset;"> <ul class="pure-menu-list"> <li class="pure-menu-item"><span class="item-info-ftlink"><a class="misc doi-link " href="https://doi.org/10.1002/etc.373" target="_blank" rel="noopener" title="Link to document DOI" data-ostiid="1015519" data-product-type="Journal Article" data-product-subtype="AC" >https://doi.org/10.1002/etc.373</a></span></li> </ul> </div> </div> </div> <div class="clearfix"></div> </div> </li> <li> <div class="article item document" itemprop="itemListElement" itemscope itemtype="http://schema.org/WebPage"><meta itemprop="position" content="2" /><div class="item-info"> <h2 class="title" itemprop="name headline"><a href="/pages/biblio/1976071-connecting-suborganismal-data-bioenergetic-processes-killifish-embryos-exposed-dioxin-like-compound" itemprop="url">Connecting suborganismal data to bioenergetic processes: killifish embryos exposed to a dioxin-like compound</a></h2> <div class="metadata"> <small class="text-muted" style="text-transform:uppercase;display:block;line-height:2.5em;">Journal Article</small><span class="authors"> <span class="author">Stevenson, Louise M.</span> ; <span class="author">Muller, Erik B.</span> ; <span class="author">Nacci, Diane</span> ; <span class="author">...</span> <span class="text-muted pubdata"> - Environmental Toxicology and Chemistry</span> </span> </div> <div class="abstract">A core challenge for ecological risk assessment is to integrate molecular responses into a chain of causality to organismal or population level outcomes. Bioenergetic theory may be a useful approach for integrating suborganismal responses to predict organismal level responses that influence population dynamics. In this work, we describe a novel application of Dynamic Energy Budget (DEB), theory in the context of a toxicity framework (Adverse Outcome Pathways, AOP) to make quantitative predictions of chemical exposures to individuals, starting from suborganismal data. We use early life stage exposure of Fundulus heteroclitus to dioxin-like chemicals (DLCs) and connect AOP Key Events (KEs)<a href='#' onclick='$(this).hide().next().show().next().show();return false;' style='margin-left:10px;'>more »</a><span style='display:none;'> to DEB processes through “damage” that is produced at a rate proportional to the internal toxicant concentration. We use transcriptomic data of fish embryos exposed to DLCs to translate molecular indicators of damage into changes in DEB parameters (damage increases somatic maintenance costs) and use DEB models to predict sublethal and lethal effects of young fish. By changing a small subset of model parameters, we predict the evolved tolerance to DLCs in some wild F. heteroclitus populations, a data set not used in model parameterization. The differences in model parameters points to reduced sensitivity and altered damage repair dynamics as contributing to this evolved resistance. Our methodology has potential extrapolation to untested chemicals of ecological concern.</span><a href='#' onclick='$(this).hide().prev().hide().prev().show();return false;' style='margin-left:10px;display:none;'>« less</a></div><div class="metadata-links small clearfix text-muted" style="margin-top:15px;"> <div class="pure-menu pure-menu-horizontal pull-right" style="width:unset;"> <ul class="pure-menu-list"> <li class="pure-menu-item"><span class="item-info-ftlink"><a class="misc doi-link " href="https://doi.org/10.1002/etc.5680" target="_blank" rel="noopener" title="Link to document DOI" data-ostiid="1976071" data-product-type="Journal Article" data-product-subtype="AM" >https://doi.org/10.1002/etc.5680</a></span></li> </ul> </div> </div> </div> <div class="clearfix"></div> </div> </li> <li> <div class="article item document" itemprop="itemListElement" itemscope itemtype="http://schema.org/WebPage"><meta itemprop="position" content="3" /><div class="item-info"> <h2 class="title" itemprop="name headline"><a href="/pages/biblio/1900139-machine-learning-assisted-elucidation-cd81cd44-interactions-promoting-cancer-stemness-extracellular-vesicle-integrity" itemprop="url">Machine learning-assisted elucidation of CD81–CD44 interactions in promoting cancer stemness and extracellular vesicle integrity</a></h2> <div class="metadata"> <small class="text-muted" style="text-transform:uppercase;display:block;line-height:2.5em;">Journal Article</small><span class="authors"> <span class="author">Ramos, Erika K.</span> ; <span class="author">Tsai, Chia-Feng</span> ; <span class="author">Jia, Yuzhi</span> ; <span class="author">...</span> <span class="text-muted pubdata"> - eLife</span> </span> </div> <div class="abstract">Tumor-initiating cells with reprogramming plasticity or stem-progenitor cell properties (stemness) are thought to be essential for cancer development and metastatic regeneration in many cancers; however, elucidation of the underlying molecular network and pathways remains demanding. Combining machine learning and experimental investigation, here we report CD81, a tetraspanin transmembrane protein known to be enriched in extracellular vesicles (EVs), as a newly identified driver of breast cancer stemness and metastasis. Using protein structure modeling and interface prediction-guided mutagenesis, we demonstrate that membrane CD81 interacts with CD44 through their extracellular regions in promoting tumor cell cluster formation and lung metastasis of triple negative<a href='#' onclick='$(this).hide().next().show().next().show();return false;' style='margin-left:10px;'>more »</a><span style='display:none;'> breast cancer (TNBC) in human and mouse models. In-depth global and phosphoproteomic analyses of tumor cells deficient with CD81 or CD44 unveils endocytosis-related pathway alterations, leading to further identification of a quality-keeping role of CD44 and CD81 in EV secretion as well as in EV-associated stemness-promoting function. CD81 is coexpressed along with CD44 in human circulating tumor cells (CTCs) and enriched in clustered CTCs that promote cancer stemness and metastasis, supporting the clinical significance of CD81 in association with patient outcomes. Our study highlights machine learning as a powerful tool in facilitating the molecular understanding of new molecular targets in regulating stemness and metastasis of TNBC.</span><a href='#' onclick='$(this).hide().prev().hide().prev().show();return false;' style='margin-left:10px;display:none;'>« less</a></div><div class="metadata-links small clearfix text-muted" style="margin-top:15px;"> <div class="pure-menu pure-menu-horizontal pull-right" style="width:unset;"> <ul class="pure-menu-list"> <li class="pure-menu-item"><span class="item-info-ftlink"><a class="misc doi-link " href="https://doi.org/10.7554/elife.82669" target="_blank" rel="noopener" title="Link to document DOI" data-ostiid="1900139" data-product-type="Journal Article" data-product-subtype="AM" >https://doi.org/10.7554/elife.82669</a></span></li> <li class="pure-menu-item"><span class="item-info-ftlink"><a class="misc fulltext-link " href="/pages/servlets/purl/1900139" title="Link to document media" target="_blank" rel="noopener" data-ostiid="1900139" data-product-type="Journal Article" data-product-subtype="AM" >Full Text Available</a></span></li> </ul> </div> </div> </div> <div class="clearfix"></div> </div> </li> <li> <div class="article item document" itemprop="itemListElement" itemscope itemtype="http://schema.org/WebPage"><meta itemprop="position" content="4" /><div class="item-info"> <h2 class="title" itemprop="name headline"><a href="/pages/biblio/1660491-gene-expression-thresholds-derived-from-short-term-exposures-identify-rat-liver-tumorigens" itemprop="url">Gene Expression Thresholds Derived From Short-term Exposures Identify Rat Liver Tumorigens</a></h2> <div class="metadata"> <small class="text-muted" style="text-transform:uppercase;display:block;line-height:2.5em;">Journal Article</small><span class="authors"> <span class="author">Hill, III,, Thomas</span> ; <span class="author">Rooney, John</span> ; <span class="author">Abedini, Jaleh</span> ; <span class="author">...</span> <span class="text-muted pubdata"> - Toxicological Sciences</span> </span> </div> <div class="abstract">Abstract Traditional methods for cancer risk assessment are resource-intensive, retrospective, and not feasible for the vast majority of environmental chemicals. In this study, we investigated whether quantitative genomic data from short-term studies may be used to set protective thresholds for potential tumorigenic effects. We hypothesized that gene expression biomarkers measuring activation of the key early events in established pathways for rodent liver cancer exhibit cross-chemical thresholds for tumorigenesis predictive for liver cancer risk. We defined biomarker thresholds for 6 major liver cancer pathways using training sets of chemicals with short-term genomic data (3–29 days of exposure) from the TG-GATES (n = 77 chemicals)<a href='#' onclick='$(this).hide().next().show().next().show();return false;' style='margin-left:10px;'>more »</a><span style='display:none;'> and DrugMatrix (n = 86 chemicals) databases and then tested these thresholds within and between datasets. The 6 pathway biomarkers represented genotoxicity, cytotoxicity, and activation of xenobiotic, steroid, and lipid receptors (aryl hydrocarbon receptor, constitutive activated receptor, estrogen receptor, and peroxisome proliferator-activated receptor α). Thresholds were calculated as the maximum values derived from exposures without detectable liver tumor outcomes. We identified clear response values that were consistent across training and test sets. Thresholds derived from the TG-GATES training set were highly predictive (97%) in a test set of independent chemicals, whereas thresholds derived from the DrugMatrix study were 96%–97% predictive for the TG-GATES study. Threshold values derived from an abridged gene list (2/biomarker) also exhibited high predictive accuracy (91%–94%). These findings support the idea that early genomic changes can be used to establish threshold estimates or “molecular tipping points” that are predictive of later-life health outcomes.</span><a href='#' onclick='$(this).hide().prev().hide().prev().show();return false;' style='margin-left:10px;display:none;'>« less</a></div><div class="metadata-links small clearfix text-muted" style="margin-top:15px;"> <div class="pure-menu pure-menu-horizontal pull-right" style="width:unset;"> <ul class="pure-menu-list"> <li class="pure-menu-item"><span class="item-info-ftlink"><a class="misc doi-link " href="https://doi.org/10.1093/toxsci/kfaa102" target="_blank" rel="noopener" title="Link to document DOI" data-ostiid="1660491" data-product-type="Journal Article" data-product-subtype="PA" >https://doi.org/10.1093/toxsci/kfaa102</a></span></li> </ul> </div> </div> </div> <div class="clearfix"></div> </div> </li> </ul> </aside> </div> </section> </div> <div class="col-sm-3 order-sm-3"> <ul class="nav nav-stacked"> <li class="active"><a class="tab-nav disabled" data-tab="related" style="color: #636c72 !important; opacity: 1;"><span class="fa fa-angle-right"></span> Similar Records</a></li> </ul> </div> </div> </section> </div></div> </div> </div> </section> <footer class="" style="background-color:#f9f9f9;"> <div class="footer-minor"> <div class="container"> <hr class="footer-separator"/> <br/> <div class="col text-center mt-3"> <div class="pure-menu pure-menu-horizontal"> <ul class="pure-menu-list" id="footer-org-menu"> <li class="pure-menu-item"> <a href="https://energy.gov" target="_blank" rel="noopener noreferrer"> <img src="data:image/gif;base64,R0lGODlhAQABAIAAAP///wAAACH5BAEAAAAALAAAAAABAAEAAAICRAEAOw==" class="sprite sprite-footer-us-doe-min" alt="U.S. Department of Energy" /> </a> </li> <li class="pure-menu-item"> <a href="https://www.energy.gov/science/office-science" target="_blank" rel="noopener noreferrer"> <img src="data:image/gif;base64,R0lGODlhAQABAIAAAP///wAAACH5BAEAAAAALAAAAAABAAEAAAICRAEAOw==" class="sprite sprite-footer-office-of-science-min" alt="Office of Science" /> </a> </li> <li class="pure-menu-item"> <a href="https://www.osti.gov" target="_blank" rel="noopener noreferrer"> <img src="data:image/gif;base64,R0lGODlhAQABAIAAAP///wAAACH5BAEAAAAALAAAAAABAAEAAAICRAEAOw==" class="sprite sprite-footer-osti-min" alt="Office of Scientific and Technical Information" /> </a> </li> </ul> </div> </div> <div class="col text-center small" style="margin-top: 0.5em;margin-bottom:2.0rem;"> <div class="row justify-content-center" style="color:white"> <div class="pure-menu pure-menu-horizontal" style='white-space:normal'> <ul class="pure-menu-list"> <li class="pure-menu-item"><a href="https://www.osti.gov/disclaim" class="pure-menu-link" target="_blank" ref="noopener noreferrer"><span class="fa fa-institution"></span> Website Policies <span class="d-none d-sm-inline d-print-none" style="color:#737373;">/ Important Links</span></a></li> <li class="pure-menu-item" style='float:none;'><a href="/pages/contact" class="pure-menu-link"><span class="fa fa-comments-o"></span>Contact Us</a></li> <li class="d-block d-md-none mb-1"></li> <li class="pure-menu-item" style='float:none;'><a target="_blank" title="Vulnerability Disclosure Program" class="pure-menu-link" href="https://doe.responsibledisclosure.com/hc/en-us" rel="noopener noreferrer">Vulnerability Disclosure Program</a></li> <li class="d-block d-lg-none mb-1"></li> <li class="pure-menu-item" style="float:none;"><a href="https://www.facebook.com/ostigov" target="_blank" class="pure-menu-link social ext fa fa-facebook" rel="noopener noreferrer"><span class="sr-only" style="background-color: #fff; color: #333;">Facebook</span></a></li> <li class="pure-menu-item" style="float:none;"><a href="https://twitter.com/OSTIgov" target="_blank" class="pure-menu-link social ext fa fa-twitter" rel="noopener noreferrer"><span class="sr-only" style="background-color: #fff; color: #333;">Twitter</span></a></li> <li class="pure-menu-item" style="float:none;"><a href="https://www.youtube.com/user/ostigov" target="_blank" class="pure-menu-link social ext fa fa-youtube-play" rel="noopener noreferrer"><span class="sr-only" style="background-color: #fff; color: #333;">Youtube</span></a></li> </ul> </div> </div> </div> </div> </div> </footer> <link href="/pages/css/pages.fonts.240327.0205.css" rel="stylesheet"> <script src="/pages/js/pages.240327.0205.js"></script><noscript></noscript> <script defer src="/pages/js/pages.biblio.240327.0205.js"></script><noscript></noscript> <script defer src="/pages/js/lity.js"></script><noscript></noscript> <script async type="text/javascript" src="/pages/js/Universal-Federated-Analytics-Min.js?agency=DOE" id="_fed_an_ua_tag"></script><noscript></noscript> </body>  </html>

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

Abstract

Citation Formats

CYP2F2-generated metabolites, not styrene oxide, are a key event mediating the mode of action of styrene-induced mouse lung tumors journal, February 2012

The role of cytochromes P-450 in styrene induced pulmonary toxicity and carcinogenicity journal, December 2001

Achaete-Scute Homologue-1 Tapers Neuroendocrine Cell Differentiation in Lungs after Exposure to Naphthalene journal, June 2010

The Human Relevance of Information on Carcinogenic Modes of Action: Overview journal, January 2003

Studies of styrene, styrene oxide and 4-hydroxystyrene toxicity in CYP2F2 knockout and CYP2F1 humanized mice support lack of human relevance for mouse lung tumors journal, June 2013

Repair of naphthalene-injured microdissected airways in vitro. journal, July 1996

Immunohistochemical analysis of Clara cell secretory protein expression in a transgenic model of mouse lung carcinogenesis journal, May 2003

Clinical Aspects of Clara Cell 10-kDa Protein / Uteroglobin (Secretoglobin 1A1) journal, May 2003

New developments in the evolution and application of the WHO/IPCS framework on mode of action/species concordance analysis: WHO/IPCS framework on mode of action/species concordance analysis journal, October 2013

Comparison of the depletion of glutathione in mouse liver and lung following administration of styrene and its metabolites styrene oxide and 4-vinylphenol journal, January 2005

Applying the Bradford Hill criteria in the 21st century: how data integration has changed causal inference in molecular epidemiology journal, September 2015

Relationship of Metabolism and Cell Proliferation to the Mode of Action of Fluensulfone-Induced Mouse Lung Tumors. II: Additional Mechanistic Studies journal, September 2016

Long-Term Chemical Carcinogenesis Bioassays Predict Human Cancer Hazards: Issues, Controversies, and Uncertainties journal, December 1999

Mouse Strain Modulates the Role of the Ciliated Cell in Acute Tracheobronchial Airway Injury-Distal Airways journal, January 2002

Metabolism of Styrene to Styrene Oxide and Vinylphenols in Cytochrome P450 2F2- and P450 2E1-Knockout Mouse Liver and Lung Microsomes journal, December 2013

Identification of cytochrome P450 2D6 and 2C9 substrates and inhibitors by QSAR analysis journal, March 2012

Inflammatory and Epithelial Responses in Mouse Strains That Differ in Sensitivity to Hyperoxic Injury journal, January 1998

Pharmacophore, QSAR, and Binding Mode Studies of Substrates of Human Cytochrome P450 2D6 (CYP2D6) Using Molecular Docking and Virtual Mutations and an Application to Chinese Herbal Medicine Screening journal, June 2012

A close family resemblance: the importance of structure in understanding cytochromes P450 journal, September 1998

Relationship of Metabolism and Cell Proliferation to the Mode of Action of Fluensulfone-Induced Mouse Lung Tumors: Analysis of Their Human Relevance Using the IPCS Framework journal, April 2012

Scientific and Regulatory Policy Committee (SRPC) Review*: Interpretation and Use of Cell Proliferation Data in Cancer Risk Assessment journal, March 2015

CC10 mRNA and protein expression in Clara cells of CD-1 mice following exposure to styrene or its metabolites styrene oxide or 4-vinylphenol journal, December 2008

Applying Adverse Outcome Pathways (AOPs) to support Integrated Approaches to Testing and Assessment (IATA) journal, December 2014

Pulmonary Tumours in Mice induced by Oral Isoniazid and its Metabolites journal, May 1962

Adverse Outcome Pathways for Regulatory Applications: Examination of Four Case Studies With Different Degrees of Completeness and Scientific Confidence journal, October 2015

Styrene Metabolism by cDNA-Expressed Human Hepatic and Pulmonary Cytochromes P450 journal, November 1994

Chronic toxicity/oncogenicity study of styrene in cd-1 mice by inhalation exposure for 104 weeks journal, January 2001

K-ras activation generates an inflammatory response in lung tumors journal, November 2005

Prediction of Non-Genotoxic Carcinogenicity Based on Genetic Profiles of Short Term Exposure Assays journal, October 2016

The effects of styrene on lung cells in female mice and rats journal, October 2004

Adverse outcome pathways: A conceptual framework to support ecotoxicology research and risk assessment journal, March 2010

Review of Styrene and Styrene Oxide Long-Term Animal Studies journal, January 1994

Styrene: Toxicity Studies — What Do They Show? journal, January 1994

Conformational selectivity in cytochrome P450 redox partner interactions journal, July 2016

Mechanism of Ethylbenzene-Induced Mouse-Specific Lung Tumor: Metabolism of Ethylbenzene by Rat, Mouse, and Human Liver and Lung Microsomes journal, December 2008

Effects of styrene and its metabolites on different lung compartments of the mouse—cell proliferation and histomorphology journal, June 2005

CYP2F2-generated metabolites, not styrene oxide, are a key event mediating the mode of action of styrene-induced mouse lung tumors
journal, February 2012

The role of cytochromes P-450 in styrene induced pulmonary toxicity and carcinogenicity
journal, December 2001

Achaete-Scute Homologue-1 Tapers Neuroendocrine Cell Differentiation in Lungs after Exposure to Naphthalene
journal, June 2010

The Human Relevance of Information on Carcinogenic Modes of Action: Overview
journal, January 2003

Studies of styrene, styrene oxide and 4-hydroxystyrene toxicity in CYP2F2 knockout and CYP2F1 humanized mice support lack of human relevance for mouse lung tumors
journal, June 2013

Repair of naphthalene-injured microdissected airways in vitro.
journal, July 1996

Immunohistochemical analysis of Clara cell secretory protein expression in a transgenic model of mouse lung carcinogenesis
journal, May 2003

Clinical Aspects of Clara Cell 10-kDa Protein / Uteroglobin (Secretoglobin 1A1)
journal, May 2003

New developments in the evolution and application of the WHO/IPCS framework on mode of action/species concordance analysis: WHO/IPCS framework on mode of action/species concordance analysis
journal, October 2013

Comparison of the depletion of glutathione in mouse liver and lung following administration of styrene and its metabolites styrene oxide and 4-vinylphenol
journal, January 2005

Applying the Bradford Hill criteria in the 21st century: how data integration has changed causal inference in molecular epidemiology
journal, September 2015

Relationship of Metabolism and Cell Proliferation to the Mode of Action of Fluensulfone-Induced Mouse Lung Tumors. II: Additional Mechanistic Studies
journal, September 2016

Long-Term Chemical Carcinogenesis Bioassays Predict Human Cancer Hazards: Issues, Controversies, and Uncertainties
journal, December 1999

Mouse Strain Modulates the Role of the Ciliated Cell in Acute Tracheobronchial Airway Injury-Distal Airways
journal, January 2002

Metabolism of Styrene to Styrene Oxide and Vinylphenols in Cytochrome P450 2F2- and P450 2E1-Knockout Mouse Liver and Lung Microsomes
journal, December 2013

Identification of cytochrome P450 2D6 and 2C9 substrates and inhibitors by QSAR analysis
journal, March 2012

Inflammatory and Epithelial Responses in Mouse Strains That Differ in Sensitivity to Hyperoxic Injury
journal, January 1998

Pharmacophore, QSAR, and Binding Mode Studies of Substrates of Human Cytochrome P450 2D6 (CYP2D6) Using Molecular Docking and Virtual Mutations and an Application to Chinese Herbal Medicine Screening
journal, June 2012

A close family resemblance: the importance of structure in understanding cytochromes P450
journal, September 1998

Relationship of Metabolism and Cell Proliferation to the Mode of Action of Fluensulfone-Induced Mouse Lung Tumors: Analysis of Their Human Relevance Using the IPCS Framework
journal, April 2012

Scientific and Regulatory Policy Committee (SRPC) Review*: Interpretation and Use of Cell Proliferation Data in Cancer Risk Assessment
journal, March 2015

CC10 mRNA and protein expression in Clara cells of CD-1 mice following exposure to styrene or its metabolites styrene oxide or 4-vinylphenol
journal, December 2008

Applying Adverse Outcome Pathways (AOPs) to support Integrated Approaches to Testing and Assessment (IATA)
journal, December 2014

Pulmonary Tumours in Mice induced by Oral Isoniazid and its Metabolites
journal, May 1962

Adverse Outcome Pathways for Regulatory Applications: Examination of Four Case Studies With Different Degrees of Completeness and Scientific Confidence
journal, October 2015

Styrene Metabolism by cDNA-Expressed Human Hepatic and Pulmonary Cytochromes P450
journal, November 1994

Chronic toxicity/oncogenicity study of styrene in cd-1 mice by inhalation exposure for 104 weeks
journal, January 2001

K-ras activation generates an inflammatory response in lung tumors
journal, November 2005

Prediction of Non-Genotoxic Carcinogenicity Based on Genetic Profiles of Short Term Exposure Assays
journal, October 2016

The effects of styrene on lung cells in female mice and rats
journal, October 2004

Adverse outcome pathways: A conceptual framework to support ecotoxicology research and risk assessment
journal, March 2010

Review of Styrene and Styrene Oxide Long-Term Animal Studies
journal, January 1994

Styrene: Toxicity Studies — What Do They Show?
journal, January 1994

Conformational selectivity in cytochrome P450 redox partner interactions
journal, July 2016

Mechanism of Ethylbenzene-Induced Mouse-Specific Lung Tumor: Metabolism of Ethylbenzene by Rat, Mouse, and Human Liver and Lung Microsomes
journal, December 2008

Effects of styrene and its metabolites on different lung compartments of the mouse—cell proliferation and histomorphology
journal, June 2005