Predictive Toxicology Center for Organotypic Cultures and Assessment of AOPs for Engineered Nanomaterials

EPA Grant Number: R835738
Center: Predictive Toxicology Center for Organotypic Cultures and Assessment of AOPs for Engineered Nanomaterials
Center Director: Faustman, Elaine
Title: Predictive Toxicology Center for Organotypic Cultures and Assessment of AOPs for Engineered Nanomaterials
Investigators: Faustman, Elaine , Altemeier, William , Eaton, David , Gao, Xiaohu , Griffith, William C. , Kavanagh, Terrance J , Kelly, Edward J.
Institution: University of Washington
EPA Project Officer: Klieforth, Barbara I
Project Period: December 1, 2014 through November 30, 2018
Project Amount: $6,000,000
RFA: Organotypic Culture Models for Predictive Toxicology Center (2013) RFA Text |  Recipients Lists
Research Category: Human Health , Health , Safer Chemicals

Objective:

The overall goal of this Center is to develop innovative organotypic culture systems to better evaluate the potential for cellular and organ toxicity following exposure to Engineered Nanomaterials (ENMs) within an adverse outcomes pathway (AOP) model. We have designed four organotypic culture projects that reflect complexity and function of lung, kidney, liver and testis. Our center will provide an academic research setting to further develop 3-D organotypic culture systems. We will accomplish this by integrating the extensive research currently occurring at the University of Washington on this topic with this new and exciting initiative from the EPA.

Approach:

We will illustrate the importance of organotypic culture application and our integrating models to assess our observations across species, organs, and lifestages. These models will help scientists and regulatory agencies answer the need for better, more informative and faster testing of emerging environmental contaminants in the context of the organ and organ systems. Our work will greatly increase the EPA’s ability to make informed regulatory decisions by targeting metals and metal based ENMs.

Rationale:

We will design 3D organotypic culture models for the Lung, Kidney, Liver and Testis using initial technologies from UW funded projects (Nanotoxicology Center, Center for Nanotechnology and our UH2 grant from NIH for microphysiological systems). Two of our systems will build off established microfluidic culture approaches (kidney and liver). For lung we have designed an air-liquid interface culture system using differentiated primary tracheal epithelial cells. For testis we have designed a co-culture system that has been proven to mimic testicular morphogenesis and function in vitro for over two weeks. Our Center will include technological innovations such as cell specific tagging (Ribotag) of transcriptomic responses and microfluidic applications that will be developed in one organotypic culture and then transferred to our other organ systems as validation and lessons learned evolve. Our cultures will use common markers of response at multiple levels of biological evaluation (molecular to cell and tissue level) to facilitate comparisons of responses to ENMs across organs and to inform our AOP models. Our project 5 will design a systems based approach for evaluating and testing AOP based hypotheses across Center organotypic culture, dose type of metal based ENM. Our AOP hypotheses includes evaluation of oxidative and inflammatory pathways, windows of susceptibility, and genetic evaluations of ENM responses after both acute as well as 14 day exposures within a toxicokinetic and dynamic driven risk assessment framework.


Journal Articles: 13 Displayed | Download in RIS Format

Other center views: All 74 publications 13 publications in selected types All 13 journal articles
Type Citation Sub Project Document Sources
Journal Article Cartwright MM, Schmuck SC, Corredor C, Wang B, Scoville DK, Chisholm CR, Wilkerson HW, Afsharinejad Z, Bammler TK, Posner JD, Shutthanandan V, Baer DR, Mitra S, Altemeier WA, Kavanagh TJ. The pulmonary inflammatory response to multiwalled carbon nanotubes is influenced by gender and glutathione synthesis. Redox Biology 2016;9:264-275. R835738 (2016)
R835738C001 (2016)
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  • Journal Article Chang SY, Weber EJ, Van Ness KP, Eaton DL, Kelly EJ. Liver and kidney on chips: microphysiological models to understand transporter function. Clinical Pharmacology & Therapeutics 2016;100(5):464-478. R835738 (2016)
    R835738C002 (2016)
    R835738C003 (2016)
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  • Journal Article Chang S-Y, Voellinger JL, Van Ness KP, Chapron B, Shaffer RM, Neumann T, White CC, Kavanagh TJ, Kelly EJ, Eaton DL. Characterization of rat or human hepatocytes cultured in microphysiological systems (MPS) to identify hepatotoxicity. Toxicology In Vitro 2017;40:170-183. R835738 (2016)
    R835738C002 (2016)
    R835738C003 (2016)
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  • Journal Article Harris S, Hermsen SA, Yu X, Hong SW, Faustman EM. Comparison of toxicogenomic responses to phthalate ester exposure in an organotypic testis co-culture model and responses observed in vivo. Reproductive Toxicology 2015;58:149-159. R835738 (2016)
    R835738C004 (2015)
    R834514 (Final)
    R834514C003 (2015)
    R834514C003 (Final)
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  • Journal Article Harris S, Wegner S, Hong SW, Faustman EM. Phthalate metabolism and kinetics in an in vitro model of testis development. Toxicology in Vitro 2016;32:123-131. R835738 (2016)
    R835738C004 (2015)
    R835738C004 (2016)
    R834514 (Final)
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  • Journal Article Harris S, Shubin SP, Wegner S, Van Ness K, Green F, Hong SW, Faustman EM. The presence of macrophages and inflammatory responses in an in vitro testicular co-culture model of male reproductive development enhance relevance to in vivo conditions. Toxicology In Vitro 2016;36:210-215. R835738 (2016)
    R835738C004 (2016)
    R834514 (Final)
    R834514C003 (Final)
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  • Journal Article Knudsen TB, Keller DA, Sander M, Carney EW, Doerrer NG, Eaton DL, Fitzpatrick SC, Hastings KL, Mendrick DL, Tice RR, Watkins PB, Whelan M. FutureTox II:in vitro data and in silico models for predictive toxicology. Toxicological Sciences 2015;143(2):256-267. R835738 (2016)
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  • Journal Article Smith MN, Grice J, Cullen A, Faustman EM. A toxicological framework for the prioritization of Children’s Safe Product Act data. International Journal of Environmental Research and Public Health 2016;13(4):431 (24 pp.). R835738 (2016)
    R835738C005 (2015)
    R835738C005 (2016)
    R834514 (Final)
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  • Journal Article Vernetti L, Gough A, Baetz N, Blutt S, Broughman JR, Brown JA, Foulke-Abel J, Hasan N, In J, Kelly E, Kovbasnjuk O, Repper J, Senutovitch N, Stabb J, Yeung C, Zachos NC, Donowitz M, Estes M, Himmelfarb J, Truskey G, Wikswo JP, Taylor DL. Functional coupling of human microphysiology systems: intestine, liver, kidney proximal tubule, blood-brain barrier and skeletal muscle.Scientific Reports 2017; 7:42296 (14 pp.). R835738 (2016)
    R835738C002 (2016)
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  • Journal Article Vernetti L, Gough A, Baetz N, Blutt S, Broughman JR, Brown JA, Foulke-Abel J, Hasan N, In J, Kelly E, Kovbasnjuk O, Repper J, Senutovitch N, Stabb J, Yeung C, Zachos NC, Donowitz M Estes M, Himmelfarb J, Truskey G, Wikswo JP, Taylor DL. Corrigendum: Functional coupling of human microphysiology systems: intestine, liver, kidney proximal tubule, blood-brain barrier and skeletal muscle. Scientific Reports 2017;7:44517. R835738 (2016)
    R835738C002 (2016)
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  • Journal Article Weber EJ, Chapron A, Chapron BD, Voellinger JL, Lidberg KA, Yeung CK, Wang Z, Yamaura Y, Hailey DW, Neumann T, Shen DD, Thummel KE, Muczynski KA, Himmelfarb J, Kelly EJ. Development of a microphysiological model of human kidney proximal tubule function. Kidney International 2016;90(3):627-637. R835738 (2016)
    R835738C002 (2016)
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  • Journal Article Wegner SH, Yu X, Pacheco Shubin S, Griffith WC, Faustman EM. Stage-specific signaling pathways during murine testis development and spermatogenesis: a pathway-based analysis to quantify developmental dynamics. Reproductive Toxicology 2015;51:31-39. R835738 (2016)
    R835738C004 (2015)
    R834514 (2015)
    R834514 (Final)
    R834514C003 (2015)
    R834514C003 (Final)
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  • Journal Article Weldon BA, Faustman EM, Oberdorster G, Workman T, Griffith WC, Kneuer C, Yu IJ. Occupational exposure limit for silver nanoparticles: considerations on the derivation of a general health-based value. Nanotoxicology 2016;10(7):945-956. R835738 (2015)
    R835738 (2016)
    R835738C005 (2015)
    R835738C005 (2016)
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  • Supplemental Keywords:

    organotypic models, decision-making, engineered nanomaterials, adverse outcome pathway

    Progress and Final Reports:

    2015 Progress Report
    2016 Progress Report

    Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
    R835738C001 Airway Epithelium Organotypic Culture as a Platform for Adverse Outcomes Pathway Assessment of Engineered Nanomaterials
    R835738C002 Organotypic Model of Human Kidney as a Platform for Adverse Outcomes Pathway Assessment of Engineered Nanomaterials
    R835738C003 Organotypic Models of Mammalian Liver as a Platform for Adverse Outcomes Pathway Assessment of Engineered Nanomaterials
    R835738C004 Organotypic Model of Testis as a Platform for Adverse Outcomes Pathway Assessment of Engineered Nanomaterials
    R835738C005 Integrating Liver, Kidney and Testis Nanomaterial Toxicity using the Adverse Outcome Pathway Approach