2018 Progress Report: Organotypic Model of Human Kidney as a Platform for Adverse Outcomes Pathway Assessment of Engineered Nanomaterials

EPA Grant Number: R835738C002
Subproject: this is subproject number 002 , established and managed by the Center Director under grant R835738
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).

Center: Predictive Toxicology Center for Organotypic Cultures and Assessment of AOPs for Engineered Nanomaterials
Center Director: Faustman, Elaine
Title: Organotypic Model of Human Kidney as a Platform for Adverse Outcomes Pathway Assessment of Engineered Nanomaterials
Investigators: Kelly, Edward J.
Institution: University of Washington
EPA Project Officer: Klieforth, Barbara I
Project Period: December 1, 2014 through November 30, 2018 (Extended to November 30, 2019)
Project Period Covered by this Report: December 1, 2017 through November 30,2018
RFA: Organotypic Culture Models for Predictive Toxicology Center (2013) RFA Text |  Recipients Lists
Research Category: Safer Chemicals , Health , Human Health

Objective:

One of the primary objectives of our project is to design, implement and test a tissue-engineered human kidney microphysiological system (MPS) and to evaluate the response of exposure to engineered nanomaterials (ENMs). To this end, we evaluated the toxicological effects of quantum dots (QD) with a CdSe/ZnS core and compared its renal toxicity profile with CdCl2 in an organotypic microfluidic device which utilizes the Nortis™ MPS that accurately models human renal physiology with the culturing of primary human proximal tubule epithelial cells (PTEC) in a physiologically-relevant 3-D configuration and an appropriately scaled lumenal flow rate.

Progress Summary:

We exposed PTECs to 0.025, 0.25, 2.5, 12.5 and 25 nM of QD with a CdSe/ZnS core and a net positive charged coating that allows these nanomaterials to remain soluble in our serum-free media which supports toxicity assessment in our MPS devices. Endpoint evaluations included RNA transcript analysis and chip effluent biomarker analysis for kidney injury markers (KIM-1 with cadmium dosimetry by ICP-MS). We observed dose-responsive toxicity, as measured by KIM-1 concentrations, at ≥ 2.5 ng/mL; however, RNA transcript analyses of PTECs at 2.5 µM did not reveal any significant changes in RNA levels relative to controls. At higher QD concentrations, the RNA yields were too low, due to toxicity, to allow for meaningful RNA transcript analysis.

Cadmium Renal:Liver Toxicity Adverse Outcome Pathway Evaluation

Given that cadmium nephrotoxicity is a primary concern for systemic exposures to QD with a Cd/Se core, we first explored the effects of cadmium exposures to PTECs separately. Next, we connected downstream to MPS devices with human hepatocytes to evaluate the toxicological effects of cadmium exposure to hepatocytes and its potential effect on PTECs. We performed numerous dose-response experiments with hepatocytes and PTECs separately; connected liver:kidney chips and collected effluents for biomarker analyses (KIM-1); and harvested RNA for RNA transcript analysis.

Future Activities:

To address whether there are factors released by cadmium-exposed hepatocytes that could influence renal toxicity, we will continue to couple liver MPS devices containing human primary hepatocytes with an MPS PTEC device and place the coupled system under flow. We will be comparing renal toxicity with or without a coupled liver and evaluate mRNA transcripts and biomarkers from the renal MPS to ascertain mechanistic changes. We will evaluate the effluents of cadmium-exposed liver chips to determine what factors may contribute to PTEC toxicity.


Journal Articles on this Report : 8 Displayed | Download in RIS Format

Other subproject views: All 64 publications 17 publications in selected types All 16 journal articles
Other center views: All 147 publications 47 publications in selected types All 46 journal articles
Type Citation Sub Project Document Sources
Journal Article Bajaj, P., Chowdhury SK, Yucha R, Kelly EJ and Xiao G. Emerging Kidney Models to Investigate Metabolism, Transport, and Toxicity of Drugs and Xenobiotics. Drug Metabolism and Disposition 2018: 46(11);1692-1702. R835738C001 (2018)
R835738C002 (2018)
  • Abstract from PubMed
  • Full-text: ASPET - Full Text HTML and PDF
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  • Journal Article Chang S-Y, Weber EJ, Sidorenko VS, Chapron A, Yeung CK, Gao C, Mao Q, Shen D, Wang J, Rosenquist TA, Dickman KG, Neumann T, Grollman AP, Kelly EJ, Himmelfarb J, Eaton DL. Human liver-kidney model elucidates the mechanisms of aristolochic acid nephrotoxicity. JCI Insight 2017;2(22):95978 (15 pp.). R835738 (2017)
    R835738C002 (2017)
    R835738C002 (2018)
  • Full-text from PubMed
  • Abstract from PubMed
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  • Full-text: JCI Insight-Full Text PDF
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  • Abstract: JCI Insight-Abstract & Full Text HTML
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  • Other: JCI-Full Text PDF
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  • Journal Article Monteiro, M. B., Ramm S, Chandrasekaran V, Boswell SA, Weber EJ, Lidberg KA, Kelly EJ, Vaidya VS. A High-Throughput Screen Identifies DYRK1A Inhibitor ID-8 that Stimulates Human Kidney Tubular Epithelial Cell Proliferation. Journal of the American Society of Nephrology 2018:29(12);2820-2833. R835738C001 (2018)
    R835738C002 (2018)
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  • Abstract: Journal of the American Society of Nephrology - Abstract
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  • Journal Article Sakolish, C., Weber EJ, Kelly EJ, Himmelfarb J, Mouneimne R, Grimm FA, House JS, Wade T, Han A, Chiu WA, Rusyn I. Technology Transfer of the Microphysiological Systems: A Case Study of the Human Proximal Tubule Tissue Chip. Scientific Reports 2018: 8(1);14882 R835738C001 (2018)
    R835738C002 (2018)
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  • Abstract from PubMed
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  • Journal Article Van Ness KP, Chang SY, Weber EJ, Zumpano D, Eaton DL, Kelly EJ. Microphysiological systems to assess nonclinical toxicity. Current Protocols in Toxicology 2017;73(1):14.18.1-14.18.28. R835738 (2017)
    R835738C001 (2018)
    R835738C002 (2017)
    R835738C002 (2018)
    R835738C004 (2018)
    R835738C005 (2017)
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  • Journal Article Weber EJ, Himmelfarb J, Kelly EJ. Concise review: current and emerging biomarkers of nephrotoxicity. Current Opinion in Toxicology 2017;4:16-21. R835738 (2017)
    R835738C002 (2017)
    R835738C002 (2018)
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  • Abstract: ScienceDirect-Abstract
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  • Journal Article Van Ness, K, & Kelly, E. Excretory Processes in Toxicology:Drug Transporters in Drug Development. In:McQueen, C. A., Comprehensive Toxicology, (2018) Third Edition. Vol. 1, pp. 143–164. Oxford:Elsevier Ltd. R835738C002 (2018)
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    Journal Article Weber EJ, Lidberg KA, Wang L, Bammler TK, MacDonald JW, Li MJ, Redhair M, Atkins WM, Tran C, Hines KM, Herron J, Xu L, Monteiro MB, Ramm S, Vaidya V, Vaara M, Vaara T, Himmelfarb J, Kelly EJ. “Human Kidney on a Chip Assessment of Polymyxin Antibiotic Nephrotoxicity” JCI Insight:3(24) e123673. R835738C002 (2018)
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    Supplemental Keywords:

    airway, lung, engineered nanomaterials, asthma, chronic obstructive lung disease, kidney, quantum dots, cadmium, kidney injury, KIM-I (Kidney Injury Molecule), 3-D organotypic cultures, microphysiological systems, hepatocytes, mouse, human, nanoparticles, aristolochic acid, silver, cytotoxicity, redox status, cellular stress response, Nrf2 reporter assay, induced pluripotent stem cells, genetics, reproductive and developmental toxicity, chemical screening, testicular development, in vitro model, gender comparison, adverse outcome pathway, AOP, chemical prioritization, dose-response modeling, benchmark dose

    Relevant Websites:

    Progress and Final Reports:

    Original Abstract
  • 2015 Progress Report
  • 2016 Progress Report
  • 2017 Progress Report
  • Final

  • Main Center Abstract and Reports:

    R835738    Predictive Toxicology Center for Organotypic Cultures and Assessment of AOPs for Engineered Nanomaterials

    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 forAdverseOutcomesPathway 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