Grantee Research Project Results

2018 Progress Report: Airway Epithelium Organotypic Culture as a Platform forAdverseOutcomesPathway Assessment of Engineered Nanomaterials

EPA Grant Number: R835738C001
Subproject: this is subproject number 001 , 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: Center for Air, Climate, and Energy Solutions
Center Director: Robinson, Allen
Title: Airway Epithelium Organotypic Culture as a Platform forAdverseOutcomesPathway Assessment of Engineered Nanomaterials
Investigators: Altemeier, William
Institution: University of Washington
EPA Project Officer: Aja, Hayley
Project Period: December 1, 2014 through November 30, 2018 (Extended to November 30, 2020)
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:

The overall goal of this project is to utilize mouse lung organotypic culture systems to better evaluate for cellular and organ toxicity to relevant engineered nanoparticles. The lungs are a major route of exposure to environmental and occupational compounds, and the airway epithelium is the primary surface for initial contact and management of inhaled exogenous materials. This project focuses on using primary epithelial cells differentiated at an air-liquid system as the basis for modeling. This represents an organotypic model system consisting of a combination of ciliated epithelium and club (Clara) secretory cells. Altering the defined culture medium can skew cell phenotype towards a mucus secretory cell type (i.e. goblet cells) to model chronic airway diseases. This system can be combined with stromal cells in the basal chamber and/or macrophages in the apical chamber to extend relevance of the model system1. Develop AOP in response to data from Experiments #1 and #2 in collaboration with William Boyes.

2. Confirm key findings in human airway organotypic culture.

3. Complete assessment of cadmium exposure to organotypic culture systems differentiated with IL13 and perform RNA-seq and dosimetry studies for AOP planning.

Progress Summary:

• Airway epithelial cells differentiated in the presence of IL13 have modeled a chronic airway disease phenotype with epithelial hyperplasia, increased in mucus secretory cells, and decreased barrier integrity. IL13-skewed epithelial cells have increased epithelial barrier dysfunction, oxidative stress, and cytotoxicity in response to silver nanoparticle (AgNP) exposure. RNA-seq transcriptomic response for pathway analysis is in process.

• Dosimetry analysis by inductively coupled plasma mass spectrometry (ICP-MS) was used to identify benchmark dose (BMD) for endpoints of oxidative stress and cytotoxicity; reactive oxygen species production was found to be the most sensitive endpoint under both differentiation conditions and will be included in adverse outcome pathway (AOP) development.

• Genetic background plays an important role in determining susceptibility to AgNPs in the presence of chronic airway disease. IL13-skewed cells from A/J mice demonstrate heightened susceptibility to AgNP-induced oxidative stress and cytotoxicity as compared with C57BL/6 mice.

• Biological sex has a limited impact on AgNP-induced cytotoxicity. Comparison of an organotypic cell culture model using cells derived from female mice with cells derived from male mice does not reveal significant differences.

Future Activities:

Research

1. Develop AOP in response to data from dose-response and transcriptomic analyses.

2. Confirm key findings in human airway organotypic culture.

3. Complete assessment of cadmium exposure to organotypic culture systems differentiated with IL13 and perform RNA-seq and dosimetry studies for AOP planning.

Journal Articles on this Report : 13 Displayed | Download in RIS Format

Publications Views
Other subproject views:	All 34 publications	16 publications in selected types	All 15 journal articles
Other center views:	All 150 publications	50 publications in selected types	All 49 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.	R835738C001 (2018) R835738C002 (2018)	Abstract from PubMed Full-text: ASPET - Full Text HTML and PDF Exit
Journal Article	Kim YH, Jo MS, Kim JK, Shin JH, Baek JE, Park HS, An HJ, Lee JS, Kim BW, Kim HP, Ahn KH, Jeon KS, Oh SM, Lee JH, Workman T, Faustman EM, Yu IJ. Short-term inhalation study of graphene oxide nanoplates. Nanotoxicology 2018;12(3):224-238.	R835738 (2017) R835738C001 (2018) R835738C004 (2018) R835738C005 (2018)	Full-text from PubMed Abstract from PubMed Full-text: Nanotoxicology - Full Text HTML and PDF Exit Abstract: Taylor and Francis-Abstract Exit
Journal Article	Melnikov F, Botta D, White CC, Schmuck SC, Schaupp CM, Gallagher EP, Brooks BW, Williams ES, Coish P, Anastas PT, Voutchkova-Kostal A, Kostal J and Kavanagh TJ. Kinetics of Glutathione Depletion and Antioxidant Gene Expression as Indicators of Chemical Modes of Action Assessed in vitro in Mouse Hepatocytes with Enhanced Glutathione Synthesis. Chemical Research in Toxicology2019:32(3);421-436	R835738C001 (2018) R835738C003 (2018) R835738C004 (2018)	Abstract from PubMed Abstract: ACS Publications - Abstract HTML 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.	R835738C001 (2018) R835738C002 (2018)	Abstract from PubMed Abstract: Journal of the American Society of Nephrology - Abstract Exit
Journal Article	Nicholas TP, Kavanaugh T, Faustman EM, Altermeier WA. The Effects of Gene × Environment Interactions on Silver Nanoparticle Toxicity in the Respiratory System. Chemical Research in Toxicology 2019:32(6); 952-968.	R835738C001 (2018) R835642 (Final)	Abstract from PubMed Abstract: ACS Publications - Abstract HTML Exit
Journal Article	Nolin JD, Lai Y, Ogden HL, Manicone AM, Murphy RC, An D, Frevert CW, Ghomashchi F, Naika GS, Gelb MH, Gauvreau GM, Piliponsky AM, Altemeier WA, Hallstrand TS. Secreted PLA2 group X orchestrates innate and adaptive immune responses to inhaled allergen. JCI Insight 2017;2(21):e94929 (18 pp.).	R835738 (2017) R835738C001 (2018) R835738C002 (2017)	Full-text from PubMed Abstract from PubMed Associated PubMed link Full-text: JCI Insight-Full Text HTML Exit Abstract: JCI Insight-Abstract Exit Other: JCI Insight-Full Text PDF Exit
Journal Article	Park JJ, Weldon BA, Hong S, Workman T, Griffith WC, Park JH, Faustman EM. Characterization of 3D embryonic C57BL/6 and A/J mouse midbrain micromass in vitro culture systems for developmental neurotoxicity testing. Toxicology In Vitro 2018;48:33-44.	R835738 (2017) R835738C001 (2018) R835738C004 (2018) R835738C005 (2018)	Abstract from PubMed Full-text: ScienceDirect-Full Text HTML Exit Abstract: ScienceDirect-Abstract Exit Other: ScienceDirect-Full Text PDF 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	R835738C001 (2018) R835738C002 (2018)	Full-text from PubMed Abstract from PubMed Full-text: Scientific Reports - Full Text HTML and PDF Exit
Journal Article	Scoville DK, Botta D, Galdanes K, Schmuck SC, White CC, Stapleton PL, Bammler TK, MacDonald JW, Altemeier WA, Hernandez M, Kleeberger SR, Chen LC, Gordon T, Kavanagh TJ. Genetic determinants of susceptibility to silver nanoparticle-induced acute lung inflammation in mice. FASEB Journal 2017;31(10):4600-4611.	R835738 (2017) R835738C001 (2017) R835738C001 (2018) R835738C002 (2017)	Abstract from PubMed Abstract: FASEB Journal-Abstract Exit
Journal Article	Scoville DK, White CC, Botta D, An D, Afsharinejad Z, Bammler TK, Gao X, Altemeier WA, Kavanagh TJ. Quantum dot induced acute changes in lung mechanics are mouse strain dependent. Inhalation Toxicology 2018; 30(9-10):397-403.	R835738C001 (2018)	Abstract from PubMed Full-text: Taylor & Francis Online - Full Text HTML and PDF Exit
Journal Article	Scoville DK, Nolin JD, Ogden HL, An D, Afsharinejad Z, Johnson BW, Bammler TK, Gao X, Frevert CW, Altemeier WA, Hallstrand TS, Kavanagh TJ. Quantum dots and mouse strain influence house dust mite-induced allergic airway disease. TOXICOLOGY AND APPLIED PHARMACOLOGY 2019:368;55-62	R835738C001 (2018)	Abstract from PubMed Full-text: ScienceDirect - 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) R835738C001 (2018) R835738C002 (2017) R835738C002 (2018) R835738C004 (2018) R835738C005 (2017)	Abstract from PubMed Abstract: Wiley-Abstract Exit
Journal Article	Weldon BA, Griffith WC, Workman T, Scoville DK, Kavanagh TJ, Faustman EM. 2018. In vitro to in vivo benchmark dose comparisons to inform risk assessment of quantum dot nanomaterials. Wiley Interdisciplinary Reviews. Nanomedicine and Nanobiotechnology 2018;10(4):e1507.	R835738 (2017) R835738C001 (2018) R835738C004 (2017) R835738C004 (2018) R835738C005 (2017) R835738C005 (2018)	Full-text from PubMed Abstract from PubMed Abstract: Wiley-Abstract Exit

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:

The Predictive Toxicology Center (PTC) for Organotypic Cultures Exit

Progress and Final Reports:

Original Abstract

Main Center Abstract and Reports:

R835738 Center for Air, Climate, and Energy Solutions

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.