2017 Progress Report: 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, 2019 (Extended to May 16, 2020)
Project Period Covered by this Report: December 1, 2016 through November 30,2017
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 the UWA Predictive Toxicology Center (PTC) for Organotypic Cultures is developing more accurate in vitro model, organ-mimicking cell cultures, to test chemicals for their potential risk to humans and to help scientists and regulatory agencies accelerate evaluations of large numbers of chemicals on how these chemicals impact organ and organ-systems. In particular, the PTC’s work will increase the ability to make informed decisions by targeting metals and metal-based engineered nanomaterials (ENMs), which have been challenging to evaluate using other in vitro assessment methods. There are four Projects in the Center that reflect the complexity and function of lung, kidney, liver and testis, aiding to build the framework for a multi-organ Adverse Outcome Pathway (AOP) analysis in Project 5.  

Project 1:  Lung

PI: William Altemeier, MD

The overall goal of this project is to utilize mouse lung organotypic culture systems to better evaluate for cellular and organ toxicity from exposure 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 therefore focuses on using primary epithelial cells differentiated at an air-liquid system as the basis for modeling. This cell system represents an organotypic model system consisting of a combination of ciliated epithelium and club (Clara) secretory cells. Furthermore, altering the defined culture medium can skew the cell phenotype towards a mucus secretory cell type (aka goblet cells) to model chronic airway diseases. The culture system can also be combined with stromal cells in the basal chamber and/or macrophages in the apical chamber to further extend the relevance of the model system.

Project 2: Kidney 

PI: Edward Kelly, PhD

A primary objectives of this Project is to design, implement and test a tissue-engineered human kidney microphysiological system (MPS) and to evaluate the response of exposure to ENMs. They have so far evaluated the toxicological effects of 2 forms of silver nanoparticles (AgNPs) with an organotypic microfluidic device that utilizes the Nortis™ MPS which reflects 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 luminal flow rate.

Project 3: Liver 

PI: Terrance Kavanagh, PhD; Co-Investigator: David Eaton, PhD

For the Liver Project, the Nortis microphysiometer system was populated with rodent and human liver cells as an in vitro test systems that can be used to evaluate uptake, metabolism and elimination of engineered nanomaterials (ENMs). Those ENMs that have practical applications in photonics, optics, solar cells, sensors, imaging, and anti-microbial activity are being focused on. These are quantum dots (QDs) and silver nanoparticles (AgNPs). Importantly, liver models from different inbred strains of mice are used, allowing for prediction of the influence of genetic determinants on differentiation and ENM toxicity.

Project 4: Testis 

PI: Elaine Faustman, PhD

An organotypic in vitro model of testicular development to evaluate the male reproductive toxicity of ENMs using an AOP framework. They are continuing to establish a life stage context for their two organotypic cultures, testes and neurodevelopmental systems. Their focus continues to be evaluation of developmental toxicity as well as the role of genes in response to environmental toxicants. 

Progress Summary:

Please see individual Project Reports for more in-depth information

Project 1: Airway Epithelium Organotypic Culture as a Platform for Adverse Outcomes Pathway Assessment of Engineered Nanomaterials

  • Airway epithelial cells differentiated in the presence of IL13 models a chronic airway disease phenotype with epithelial hyperplasia, increase in mucus secretory cells, and decreased barrier integrity. IL13-skewed epithelial cells have augmented cytotoxicity in response to AgNP exposure. Biospyder transcriptomic response for pathway analysis is in process.

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

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

Project 2: Organotypic Model of Human Kidney as a Platform for Adverse Outcomes Pathway Assessment of Engineered Nanomaterials

Quantum dots (QD) with a CdSe/ZnS core
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, chip effluent biomarker analysis for kidney injury markers- KIM-1, with cadmium dosimetry by inductively coupled plasma mass spectrometry. We observed dose-responsive toxicity, as measured by KIM-1 concentrations, at ≥ 2.5 ng/mL and have submitted RNA from these studies for transcript analyses. ICP-MS analyses of our QD stock solutions have detected free cadmium supporting our detailed evaluation of cadmium renal toxicity.

Cadmium Renal Toxicity Adverse Outcome Pathway Evaluation

Given that cadmium nephrotoxicity is a primary concern for systemic exposures to QDs with a Cd/Se core we explored AOPs for cadmium exposures to PTECs in order to map out toxicity pathways in our MPS devices to provide a meaningful comparator to the QD toxicity observed in our systems. We performed numerous dose-response MPS experiments with CdCl2 using PTECs from six different kidney donors and evaluated mRNA transcripts from the cells while miRNA and kidney injury biomarkers were evaluated in the MPS effluents. We have determined by RNAseq analyses and Ingenuity Pathway Analysis that the following pathways are involved with a 48-hour Cd exposure: A) Unfolded protein response; B) NRF-2 mediated oxidative stress response and C) Acute phase response with several metallothionein members upregulated.

Project 3: Organotypic Models of Mammalian Liver as a Platform for Adverse Outcomes Pathway Assessment of Engineered Nanomaterials

Primary human and rat hepatocytes were used to populate a dual-chamber Nortis microphysiological system. These devices were then evaluated for cell morphology, viability, functionality (cytochrome P450 activity; HNF4a expression; albumin production). Human and rat hepatocytes were also evaluated for their ability to metabolize Vitamin D and to metabolize and activate the nephrotoxin aristolochic acid (AA) into metabolites that were toxic toward proximal tubule epithelial cells (PTEC) cultured in tandem in another Nortis MPS device. Human hepatocytes were also evaluated for their ability to metabolize the liver hepatotoxicant and carcinogen aflatoxin B1. Results indicate that hepatocytes cultured in the 3D MPS maintain greater viability and hepatic functions for at least 14 days whereas 2D cultures only exhibited these for 5-6 days. Compared to 2D monolayers, hepatocytes in 3D organotypic cultures also exhibit enhanced albumin production, HNF4a expression, cytochrome P450 activity and inducibility (Cyp1A1; Cyp3A4), presence of bile canaliculi, multi-drug resistance protein-2 (MRP2) transporter expression and function, vitamin D hydroxylation, and AA bioactivation (as indicated by a 4 to 10-fold increase in toxicity of AA toward PTEC when AA is passed through the liver prior to PTEC, vs. direct exposure of PTECs to AA). The hepatocytes were also able to metabolize the aflatoxin as indicated by specific adducts on DNA (evaluated with immunofluorescence).

We also evaluated the performance of newer generation Nortis microphysiological chambers. One of these chambers is a wide-bore system that better accommodates primary hepatocyte cultures. Cells were viable in these chambers for up to 28 days

We also evaluated the survival, morphology and differentiated phenotype of human primary hepatocytes seeded into Nortis triple well chamber devices. These newer devices are designed to accommodate hepatocytes such that they can form cord-like structures reminiscent of hepatic sinusoids present in intact liver. The morphology of these structures is cord-like and staining for the hepatocyte differentiation marker HNF4a. These new chambers have provided a convenient model of hepatocyte differentiation and structure that is largely representative of human hepatoctyes in vivo.

We also demonstrated that the Nortis devices can be connected in series to identify important ‘organ-organ interactions in toxicology’. We connected a human liver chip with human kidney (proximal tubule cells, PTECs) and demonstrated that the highly specific kidney toxin, aristolochic acid, is 5 times more toxic to the kidney when first passed through the liver.

Project 4: Organotypic Model of Testis as a Platform for Adverse Outcomes Pathway Assessment of Engineered Nanomaterials

Testicular Co-Culture Model: We have optimized testes markers that are specific markers for each cell type in testes co-culture system to allow us to separate specific cell population in three different cell types. We have developed a systems biology approach for characterization of normal development of our testis organotypic cultures with a life stage context, measuring testosterone production and protein expression at days in vitro (DIV) 2, 3, 6, 7, 15 and 16 (Wilder et al. 2018 in preparation). We are preparing a manuscript on cadmium’s developmental toxicity utilizing our mouse testis organotypic culture systems, evaluating cytotoxicity, cell viability and morphology at 24 hours after cadmium treatment at different developmental stage (DIV 2, 6 and 15).

Mouse midbrain micromass: We have utilized in vitro 3D organotypic mouse midbrain micromass culture system to examine adverse effects of silver nanoparticles (AgNPs). We characterized the development of the micromass cultures over time using embryonic midbrains from two mouse strains (C57BL/6 and A/J) (Park et al. 2017). We observed stage-specific protein expressions of proliferation and differentiation and found that C57BL/6 and A/J in vitro mouse micromass systems had similar developmental trends. This study opened a potential for this model to be used for developmental neurotoxicity testing and gene x environment studies by using different mouse strains. We performed our assessment of the toxicological effects of various AgNPs on C57BL/6 and A/J mouse midbrain micromass cultures (Weldon and Park et al. 2018 in revision). Significant dose-response relationships were observed for various AgNPs, and particle sizes, coatings, and developmental stages contributed to susceptibility to AgNP exposures. Strain differences were also observed.

Human Neuronal Progenitor Cells: We have evaluated AgNP effects on proliferating (day 1) and differentiating (day 1 and 7) human neuronal progenitor cells (hNPCs). Proliferating and differentiating hNPCs at day 1 demonstrated significant dose-response curves after exposures to various AgNPs. Similar to what we have found in the in vitro embryonic midbrain micromass system, the hNPCs study also suggested that particle sizes, coatings, and developmental stages were important contributors to adverse effects of AgNPs.

The following awards were received:

Elijah Weber: School of Pharmacy Leadership Award

Elijah Weber: 2017 Society of Toxicology Annual Meeting Finalist Mechanisms Specialty Section, Renal Toxicology Award

Elijah Weber: 2017 Society of Toxicology Annual Meeting, Emil A. Pfitzer Drug Discovery Study Endowment Award (1st Place)

Brittany Weldon: 2016 Society of Toxicology Regulatory and Safety Evaluation Specialty Section Travel Award

Brittany Weldon: 2016 International Society for Regulatory Toxicology and Pharmacology Award

Brittany Weldon: 2016 Society of Toxicology Perry J. Gehring Best Graduate Student Abstract Award

Brittany Weldon:  2015 PANWAT Best Poster Presentation

Rachel Shaffer: 2017 Society of Toxicology Regulatory and Safety Evaluation Specialty Section Travel Award

Rachel Shaffer: 2017 Angelo Furgiele Young Investigator Technology Award

Rachel Shaffer: Biostatistics, Epidemiologic and Bioinformatic Training in Environmental Health (BEBTEH) training grant

Tyler Nicholas: Environmental Pathology/Toxicology Training Program Award, 2017 (EP/T).

In addition, the PTC contributed MPS-related technology to the Northwest Kidney Gala Annual Auction (which raised $1750 to support kidney research) and it was featured as a story in the School of Pharmacy newsletter.

Future Activities:

Project 1

  • Complete AgNP dosimetry studies for use in AOP development

  • Confirm select target genes used in AOP development in primary human airway epithelial cells

  • Complete and publish AOP for silver nanoparticles

  • Evaluate response of IL13-skewed epithelial cells to cadmium

Project 2

To address whether there are factors released by cadmium-exposed hepatocytes that could influence renal toxicity, we have started to couple liver MPS devices containing human primary hepatocytes with an MPS PTEC device and placed 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 continue to evaluate QD renal toxicity with comparisons to cadmium renal toxicity as a reference.

Project 3

We continue to characterize hepatocyte function in the 3D MPS system and assess the polarized phenotype (presence of bile canaliculi; xenobiotic transporter expression and localization). We will evaluate the effects of silver nanoparticles (AgNPs), quantum dot nanoparticles, silver and cadmium ions and other heavy metals in hepatocytes cultured in 2D monolayers vs. 3D MPS. These will include quantitative measures of viability, function, the induction of glutathione pathway genes and proteins, metallothionein (MT) expression, and oxidative stress biomarker expression. In a manner similar to that we have described for tandem organ on a chip evaluation of AA toxicity, we will examine the ability of hepatocyte expression of MT to deliver Cd and Ag to PTECS and determine if such delivery influences kidney cell viability and function. We also have developed lentiviral vectors that report on cellular redox status, and these will be applied to this system as well as other systems in the UW PTC.

Project 4

We continue to focus on expanding the applications of our testis co-culture system to answer this project’s research questions through development of organotypic cultures to evaluate reproductive and developmental toxicity, modification of our previous co-culture system for immature mouse testes, characterization of normal testes development, and evaluation of perturbed conditions using various chemicals including cadmium. We will finalize our characterization of life-stage specific AOPs for reproductive and developmental toxicity (Welder, et al., 2018 in progress). We plan to continue to assess the toxic effects of AgNP on the developing brain using mouse and human cells. We will investigate the effects of cadmium on proliferating and differentiating hNPCs.

Project 5: Integrating Liver, Kidney and Testis Nanomaterial Toxicity Using the Adverse Outcome Pathway Approach

Predictive Toxicology for Alternatives Analyses: Children’s consumer products represent an important exposure source for many toxicants due to their intended uses, which lead to direct contact with children. Alternatives assessments are used to identify safer chemical alternatives, however, many times these assessments are limited by lack of toxicity data. This project examines how predictive toxicology tools fill gaps in alternatives assessments for chemicals found in children’s consumer products. Formal national and international lists, such as the European Chemical Agency’s (ECHA) Endocrine Disruptor Substances of Concern classification were compared with the toxicological prioritization index (ToxPi) score. We used ExpoCast and CPCat to assess exposure. Alternative chemicals were rarely classified as endocrine disruptors by the ECHA, yet the in vitro ToxPi scores for alterative chemicals were similar to the conventional chemicals. ExpoCast scores for conventional chemicals were higher than alternative chemicals. Our results suggest that predictive toxicology tools can fill gaps when existing classifications are incomplete.

Using Benchmark Dose-based Dosimetric Approaches to Interpret In Vitro Responses: We have built a translational framework for interpreting our in vitro results in the context of current regulatory and risk assessment needs. We developed frameworks to compare relationships between previously published in vitro and in vivo toxicity assessments of cadmium-selenium containing quantum dots (QDs) using benchmark dose (BMD) and dosimetric assessment methods (Weldon, et al., 2018). This approach was useful for identifying sensitive assays and strains. We found consistent responses in common endpoints between in vitro and in vivo studies. Dosimetric adjustments identified similar sensitivity among cell types. BMD analysis can be used as an effective tool to compare the sensitivity of different strains, cell types, and assays to QDs. These methods allow in vitro assays to be used to predict in vivo responses, improve the efficiency of in vivo studies, and allow for prioritization of nanomaterial assessments.

Applications of AOPs to In Vitro Cultures: We are continuing to work on an adverse outcome pathway for the testis that is able to not only relate molecular markers to tissue effects but also can account for the dynamic developmental changes observed in our in vitro system. This AOP development is based on the biological changes associated with phthalate exposure in our 3-dimensional testis co-culture system. We expect that some of these same pathways (e.g., inflammation and reactive oxygen species) may be perturbed following metal and ENM exposure. As we generate more data from ENM exposure in the four 3D organotypic models, AOPs specific to the pathways perturbed by ENMs will be developed and linked across all organ systems to better characterize the organ response.

Project 5

The core will continue to utilize the BMD and AOP approaches exemplified in the progress summary to develop and link adverse outcome pathways across the four organotypic models currently testing metals and ENM toxicity. We will explore the implications of genetic susceptibility factors through characterizing differences in strain responses. The results will allow us to identify unique toxicity profiles of ENMs and develop prioritization and translational frameworks to inform risk.

In addition, the core plans to perform in vitro in vivo comparison on our nanotoxicity studies as well as comparison across species (i.e., rat vs. mouse, human vs. rodent). The core also will continue to develop case studies and frameworks to encourage the incorporation of in vitro data in translational models and decision frameworks.

References:

1. Kavlock, R.J., Allen, B.C., Faustman, E.M., and Kimmel, C.A. Dose-response assessments for developmental toxicity. IV. Benchmark doses for fetal weight changes. Fundam. Appl. Toxicol. 1995;26:211-222.

2. The National Academy Press, A Framework to Guide Selection of Chemical Alternatives. https://www.nap.edu/catalog/18872/a-framework-to-guide-selection-of-chemical-alternatives, 2014.

3. Rozman, K.K. and C.D. Klaassen. Casarett and Doull’s Toxicology: The Basic Science of Poisons. New York, NY: McGraw-Hill, 2007.

4. Smith, M.N., Grice, J., Cullen, A., and Faustman E.M. A toxicological framework for the prioritization of Children's Safe Product Act data. Int J Environ Res Public Health 2016;13(4):431.

5. Wambaugh, J.F., et al. High-throughput models for exposure-based chemical prioritization in the ExpoCast project. Environ Sci Technol 2013;47(15):8479-8488.

6. Dionisio, K.L., et al. Exploring consumer exposure pathways and patterns of use for chemicals in the environment. Toxicol Rep 2015;2:228-237.


Journal Articles: 40 Displayed | Download in RIS Format

Other center views: All 134 publications 39 publications in selected types All 38 journal articles
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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)
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  • Journal Article Chang S-Y, 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)
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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):e95978 (15 pp.). R835738C003 (2017)
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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)
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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):e95978 (15 pp.). R835738C003 (2017)
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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)
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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)
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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)
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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)
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  • 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)
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  • Journal Article Kimmel DW, Rogers LM, Aronoff DM, Cliffel DE. Prostaglandin E2 regulation of macrophage innate immunity. Chemical Research in Toxicology 2016;29(1):19-25. R835738 (2017)
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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 Lee JH, Han JH, Kim JH, Kim B, Bello D, Kim JK, Lee GH, Sohn EK, Lee K, Ahn K, Faustman EM, Yu IJ. Exposure monitoring of graphene nanoplatelets manufacturing workplaces. Inhalation Toxicology 2016;28(6):281-291. R835738 (2016)
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  • Journal Article Lee JH, Sung JH, Ryu HR, Song KS, Song NW, Park HM, Shin BS, Ahn K, Gulumian M, Faustman EM, Yu IJ. Tissue distribution of gold and silver after subacute intravenous injection of co-administered gold and silver nanoparticles of similar sizes. Archives of Toxicology 2018;92(4):1393-1405. R835738 (2017)
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  • 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)
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  • 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):94929 (18 pp.). R835738 (2018)
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  • 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)
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  • Journal Article Ramaiahgari SC, Waidyanatha S, Dixon D, DeVito MJ, Paules RS, Ferguson SS. From the cover: three-dimensional (3D) hepaRG spheroid model with physiologically relevant xenobiotic metabolism competence and hepatocyte functionality for liver toxicity screening. Toxicological Sciences 2017;159(1):124-136. R835738 (2017)
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  • Journal Article Rountree A, Karkamkar A, Khalil G, Folch A, Cook DL, Sweet IR. BaroFuse, a novel pressure-driven, adjustable-throughput perfusion system for tissue maintenance and assessment. Heliyon 2016;2(12):e00210 (18 pp.). R835738 (2017)
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  • 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)
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  • Journal Article Shaffer R, Smith MN, Faustman EM. Developing the regulatory utility of the exposome: mapping exposures for risk assessment through Lifestage Exposome Snapshots (LEnS). Environmental Health Perspectives 2017;123(8):085003 (8 pp.). R835738 (2017)
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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)
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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)
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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 (2018)
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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 (15 pp.). R835738 (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. 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 (2017)
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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 (15 pp.). R835738 (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)
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  • Journal Article Wallace JC, Port JA, Smith MN, Faustman EM. FARME DB:a functional antibiotic resistance element database. Database 2017;2017(1):1-7. R835738 (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)
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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)
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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)
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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)
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  • Journal Article Weldon BA, Park JJ, Hong S, Workman T, Dills R, Lee JH, Griffith WC, Kavanagh TJ, Faustman EM. Using primary organotypic mouse midbrain cultures to examine developmental neurotoxicity of silver nanoparticles across two genetic strains. Toxicology and Applied Pharmacology 2018 (April 17), 10 pp. [epub ahead of print]. R835738 (2017)
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  • 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)
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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. Feb 8;7:42296. doi:10.1038/srep42296. Erratum in:Sci Rep. 2017 Mar 16;7:44517. R835738 (2018)
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    Journal Article Van Ness, K, & Kelly, E (2018) 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. Bajaj, P., Chowdhury SK, Yucha R, Kelly EJ and Xiao G. (2018). "Emerging Kidney Models to Investigate Metabolism, Transport, and Toxicity of Drugs and Xenobiotics." Drug Metab Dispos 46(11): 1692-1702. Monteiro, M. B., Ramm S, Chandrasekaran V, Boswell SA, Weber EJ, Lidberg KA, Kelly EJ and Vaidya VS. (2018). "A High-Throughput Screen Identifies DYRK1A Inhibitor ID-8 that Stimulates Human Kidney Tubular Epithelial Cell Proliferation." J Am Soc Nephrol 29(12): 2820-2833. Sakolish, C., Weber EJ, Kelly EJ, Himmelfarb J, Mouneimne R, Grimm FA, House JS, Wade T, Han A, Chiu WA and Rusyn I. (2018). "Technology Transfer of the Microphysiological Systems:A Case Study of the Human Proximal Tubule Tissue Chip." Scientific Reports 8(1):14882. (published) 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. (2018). “Human Kidney on a Chip Assessment of Polymyxin Antibiotic Nephrotoxicity” JCI Insight:3(24) e123673. R835738 (2018)
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    Journal Article Van Ness, K, & Kelly, E (2018) 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. Bajaj, P., Chowdhury SK, Yucha R, Kelly EJ and Xiao G. (2018). "Emerging Kidney Models to Investigate Metabolism, Transport, and Toxicity of Drugs and Xenobiotics." Drug Metab Dispos 46(11): 1692-1702. Monteiro, M. B., Ramm S, Chandrasekaran V, Boswell SA, Weber EJ, Lidberg KA, Kelly EJ and Vaidya VS. (2018). "A High-Throughput Screen Identifies DYRK1A Inhibitor ID-8 that Stimulates Human Kidney Tubular Epithelial Cell Proliferation." J Am Soc Nephrol 29(12): 2820-2833. Sakolish, C., Weber EJ, Kelly EJ, Himmelfarb J, Mouneimne R, Grimm FA, House JS, Wade T, Han A, Chiu WA and Rusyn I. (2018). "Technology Transfer of the Microphysiological Systems:A Case Study of the Human Proximal Tubule Tissue Chip." Scientific Reports 8(1):14882. (published) 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. (2018). “Human Kidney on a Chip Assessment of Polymyxin Antibiotic Nephrotoxicity” JCI Insight:3(24) e123673. R835738 (2018)
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    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 (2018). 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. Chem Res Tox. doi:10.1021/acs.chemrestox.8b00259. PMID:30547568. R835738 (2018)
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    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. Toxicol Appl Pharmacol 2019 Jan 22. pii: S0041-008X(19)30026-2. doi:10.1016/j.taap.2019.01.018. 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. Inhal Toxicol 2018; 30(9-10):397-403. R835738 (2018)
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    Supplemental Keywords:

    3D organotypic cultures, microphysiological systems, reproductive and developmental toxicity, chemical screening, adverse outcome pathway, AOP, chemical prioritization, dose-response modeling, benchmark dose, testicular development, in vitro model, hepatocytes, mouse, human, rat, nanoparticles, quantum dots, aristolochic acid, cadmium, silver, cytotoxicity, redox status, cellular stress response

    Relevant Websites:

    http://deohs.washington.edu/ptc

    Progress and Final Reports:

    Original Abstract
  • 2015 Progress Report
  • 2016 Progress Report
  • 2018 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