Grantee Research Project Results

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: Aja, Hayley
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: Chemical Safety for Sustainability

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

Publications Views
Other subproject views:	All 64 publications	17 publications in selected types	All 16 journal articles
Other center views:	All 159 publications	56 publications in selected types	All 55 journal articles

Publications
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.	R835738 (Final) R835738C001 (2018) R835738C002 (2018)	Abstract from PubMed Full-text: ASPET - Full Text HTML and PDF Exit
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) R835738 (Final) R835738C002 (2017) R835738C002 (2018)	Full-text from PubMed Abstract from PubMed Associated PubMed link Full-text: JCI Insight-Full Text PDF Exit Abstract: JCI Insight-Abstract & Full Text HTML Exit Other: JCI-Full Text PDF Exit
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.	R835738 (Final) R835738C001 (2018) R835738C002 (2018)	Abstract from PubMed Abstract: Journal of the American Society of Nephrology - Abstract Exit
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	R835738 (Final) R835738C001 (2018) R835738C002 (2018)	Full-text from PubMed Abstract from PubMed Full-text: Scientific Reports - Full Text HTML and PDF Exit
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) R835738 (Final) R835738C001 (2018) R835738C002 (2017) R835738C002 (2018) R835738C004 (2018) R835738C005 (2017)	Abstract from PubMed Abstract: Wiley-Abstract Exit
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) R835738 (Final) R835738C002 (2017) R835738C002 (2018)	Full-text from PubMed Abstract from PubMed Associated PubMed link Abstract: ScienceDirect-Abstract Exit
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.	R835738 (Final) R835738C002 (2018)	not available
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.	R835738 (Final) R835738C002 (2018)	Full-text from PubMed Abstract from PubMed Full-text: JCI Insight - Full Text HTML

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:

Predictive Toxicology Center Exit

Progress and Final Reports:

Original Abstract

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

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The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.