2019 Progress Report: Predictive Toxicology Center for Organotypic Cultures and Assessment ofAOPs for Engineered Nanomaterials

EPA Grant Number: R835738
Center: Center for Air, Climate, and Energy Solutions
Center Director: Robinson, Allen
Title: Predictive Toxicology Center for Organotypic Cultures and Assessment ofAOPs for Engineered Nanomaterials
Investigators: Faustman, Elaine , Griffith, William C. , Kavanagh, Terrance J , Altemeier, William , Kelly, Edward J. , Eaton, David , Gao, Xiaohu
Institution: University of Washington
EPA Project Officer: Callan, Richard
Project Period: December 1, 2014 through November 30, 2019 (Extended to November 30, 2020)
Project Period Covered by this Report: December 1, 2018 through November 30,2019
Project Amount: $6,000,000
RFA: Organotypic Culture Models for Predictive Toxicology Center (2013) RFA Text |  Recipients Lists
Research Category: Chemical Safety for Sustainability

Objective:

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

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 (aka 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 system.

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

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 CdCl2in 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.

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

To develop an organotypic 3-D mpdel of human and rodent liver using a microphysiological device, and to evaluate its suitability for assessing the adverse effects of ENMs and heavy metal.

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

The overall goal of this project is to utilize an organotypicin vitromodel of testicular development to evaluate the male reproductive toxicity of ENMs using an AOP framework. We will use 3-Din vitrotesticular co-cultures that have been shown to capture key processes of male reproductive development to evaluate the potential of ENMs to alter these processes. We will measure the ability of ENMs to alter cellular differentiation and tissue maturation with a focus on the roles of developmental timing and genetics in influencing susceptibility. We will also explore the role of oxidative stress and inflammation pathways in mediating ENM induced perturbation of development. Finally, we will use toxicokinetic and dynamic models to integratein vitrofindings into an AOP framework.

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

The goal of this project is to develop models for integrating organotypic culture responses to ENMs across the lung, liver, kidney, and testis and to predict whole organism response. We will use a systems-based AOP approach linked with toxicokinetic and dynamic models to identify key molecular initiating events and cellular, tissue, and organ responses from each organotypic model. These AOPs will then be integrated with lifestage and genetic susceptibility factors to model ENM toxicity response across organ systems, organisms and populations. This project will also identify critical data gaps and make recommendations for further testing of ENMs.

Progress Summary:

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 increased epithelial barrier dysfunction, oxidative stress, and cytotoxicity in response to AgNP exposure. RNA-seq transcriptomic response for pathway analysis is in process.
  • Dosimetry analysis by ICP-MS was used to identify benchmark dose for endpoints of oxidative stress and cytotoxicity; ROS production was found to be the most sensitive endpoint under both differentiation conditions and will be included in AOP development.
  • 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 oxidative stress and 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:

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 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. We have concluded the toxicity assessment of QDs in our MPS devices.

Cadmium Renal:Liver Toxicity Adverse Outcome Pathway Evaluation

We initially explored the effects of cadmium exposures on PTECs alone then with a kidney MPS device coupled downstream from a liver MPS with human primary hepatocytes to evaluate the toxicological effects of cadmium exposure to hepatocytes and its potential downstream effects on PTECs. We successfully completed four CdCl2(0.5, 1, 5 and 25 μM) exposure experiments plus control with either hepatocytes or PTECs connected together or PTECs alone and collected effluents for biomarker analyses (KIM-1 & FAS ligand), live/dead staining and harvested RNA for RNA transcript analysis. We have demonstrated that cryopreserved human primary hepatocytes are more sensitive to CdCl2(EC50~1 μM) than our human PTECs (EC50~25 μM) and that the impact of flowing CdCl2over hepatocytes cultured in a liver chip on the integrity of kidney chip couple downstream was variable as measured by KIM-1 concentrations in the effluents. Progress on this project was severely hampered in 2019 by the lack of Nortis MPS chips for more than half the year because of Nortis’ halt in chip manufacturing due to financial hardship.

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

We utilized specialized 6-well plates to form hepatocyte spheroids (both human and mouse). We have continued to evaluate the utility of glutathione deficient immortalized mouse hepatocytes derived from a Gclmnull mouse model as a reporter system for a model chemical oxidant (hydroquinone) and AgNP-induced oxidative stress. These cells were established from a Gclmnull mouse that had exon 1 of the Gclmgene replaced by a β−galactosidase-neomycin phosphotransferase (β−Geo) gene cassette. In this context, β−gal activity reflects the activity of theGclmgene promoter, which is known to be a target of the Nrf2 and AP1 transcription factors. When exposed to the model oxidant hydroquinone or to AgNPs, there was a dosedependent increase in the amount of β−gal activity in the immortalizedGclmnull cells, but not in the immortalized GclmWT cells that lack the β−Geo cassette and therefore serve as a negative control for the assay. This was accomplished in both 2-D sandwich cultures in standard tissue culture plates and in 3-D spheroids suspended in Matrigel in Nortis chips. These Gclmnull spheroids show very reliable baseline, oxidative stress, and AgNP-induced increases in β−gal activity.

We worked together with colleagues at Texas A&M University to differentiate induced pluripotent stem cells (iPSCs) derived from three collaborative cross recombinant inbred (CCRI) mouse strains into induced hepatocyte-like (iHep) cells. CCRI iHep cell lines have variable amounts of differentiation as shown by various biomarkers of stem cells, definitive endoderm, hepatoblasts and fetal hepatocytes (e.g. albumin production; cytochrome P450 expression; HNF4 expression). Immunohistochemistry studies indicated “islands” of hepatocyte-like cells within the culture, but these were relatively rare. Whole culture RNAseq showed a number of similarities in differentiated iHep cells to the mouse liver transcriptome, although at lower levels. A number of candidate hepatocyte-specific biomarker genes were up-regulated in iHep cultures after 21 days of differentiation in vitro. We also identified several transcripts that were present at high levels in iPSCs, but low in mouse liver. These will be used to follow CCRI strain-specific variation in iPSC to iHep differentiation. We determined the two most important parameters influencing variance in iHeps using principal components analysis: differentiation time in culture and cell strain. Moreover, by employing published cellular/tissue deconvolution algorithms on these RNAseq data, we have discovered that there is upregulation of genes associated with hematopoiesis during the differentiation of these iPSCs, and this is also variable among the 3 different CCRI cell strains. This is important because the fetal liver is recognized as a principle site of extramedullary hematopoiesis during vertebrate development, and gives further credence

to the idea that our protocol for differentiation of iPSCs is recapitulatingin vivo liver differentiation and development. Follow on experiments that are underway for assessing protein expression in these cultures as biomarkers of fetal hepatocytes (albumin, retinol binding protein 4, transthyretin) and hematopoiesis (solute-like carrier 39a8, carbonic anhydrase 2). Further study of iPSC liver differentiation in additional collaborative cross recombinant inbred strains is therefore warranted, and provides for an opportunity to map genes and pathways most important for hepatocyte and blood cell differentiation, and the adverse effects of toxicant exposures on these developmental programs.

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

Toxic effects on the testes: We optimized testis-specific markers for each cell type in our 3D organotypic testicular culture (3D-OTC). We measured testosterone production and protein expression at days in vitro (DIV) 2, 3, 6, 7, 15 and 16. We are finalizing a publication that reports our baseline characterization of normal development with a life stage context and are comparing an in vitro and in vivo developmental timeline between rat and mouse systems (Wilder et al. 2020a, in preparation). We are also preparing a manuscript on cadmium’s developmental toxicity by utilizing our 3D-OTC and evaluating mechanisms of cytotoxicity, dose-dependent cell viability, and morphology at 24 hours after cadmium treatment at different developmental stages (DIV 2, 6 and 15) (Wilder et al. 2020b, in preparation). In addition, we have completed cytotoxicity analysis of three AgNP particles (Ag Citrate 20nm, Ag Citrate 110nm and Ag PVP 110 nm) on mouse testis. We plan to complete the data analysis of the result and prepare for publication.

Human Neuronal Progenitor Cells: Building upon our baseline characterization of in vitro human neural progenitor cell (hNPC) culture development (Wegner and Park et al. 2019), we are preparing a manuscript evaluating AgNP effects on proliferating (day 1) and differentiating (day 1 and 7) hNPCs. Proliferating and differentiating hNPCs at day 1 demonstrated significant doseresponse curves after exposures to various AgNPs. Consistent with previous findings, we found that particle sizes, coatings, and developmental stages were important contributors to adverse effects of AgNPs. Based on the benchmark dose (BMD) and found the early differentiation phase is more sensitive than the proliferation phase (Park et al 2020 in preparation). Furthermore, we have exposed hNPCs derived from male (H14) and female (H9) to evaluate the role of gender in neurodevelopmental toxicity of QD, AgNP and cadmium. We have observed a significant dose response at Day 1 proliferation and observed male hNPCs to be significantly more sensitive than female hNPCs when exposed to QD ITK. In addition, in order to access sex difference more effectively, we are comparing normal development of H9 and H14 and preparing manuscript.

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

Using BMD based dosimetric approaches to interpret in vitro responses: Building upon our use of BMD and dosimetric assessment methods used in Weldon et al. 2018 as our translational framework for interpreting in vitro results in the context of current regulatory and risk assessment needs, we compared sensitivity to AgNP toxicity in organotypic cultures of murine tracheal epithelial cells from two mouse strains, C57BL/6 and AJ. We are finalizing the manuscript based on our observation of strain differences based on exposure conditions and endpoints (Nicholas et al 2020, revision).

Applications of AOPs to in vitro cultures: We are finalizing a manuscript on AOP for the lung by utilizing our organotypic culture systems. Our AOP development is based on the biological changes associated with AgNP exposure in these organotypic cultures, including murine tracheal epithelial cells system. We are also continuing our work on AOP for testis, utilizing our 3D testis co-culture systems. We expect that some of these same pathways (e.g. inflammation and reactive oxygen species) may be perturbed following both metal and ENM exposure. As our body of results from ENM exposure in the four 3-D organotypic models grows, we will develop and link AOPs specific to the pathways perturbed by ENMs across all organ systems under investigation to better characterize the organ response.

Future Activities:

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

N/A

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

We plan on working with Nortis Inc. on a pilot project that will evaluate the feasibility of developing animal cell-based kidneys on a chip using primary kidney proximal tubule (KPT) cells from rats and dogs. Drug-associated acute kidney injury is a potentially life-threatening event and the use of preclinical animals to assess nephrotoxicity risk in drug development is a critical component in the drug approval pathway. Replication of the functional human kidney proximal tubule is necessary for accurately modeling in-vivo drug secretion and kidney injury and we have already demonstrated this with the Nortis KPT-MPS. We would like to leverage our expertise in human KPTs and expand to other species with the ultimate goal of eventually replacing test animals with rat/canine KPT-MPS

The project will be completed in two phases: feasibility studies followed by nephrotoxic compound testing Phase I: we will establish the feasibility of a commercializable animal-based KPT-MPS with rat and canine PTECs using existing Nortis hardware and established protocols used for human cells. We will demonstrate viability and structural integrity of rat and/or canine KPT models generated in the Nortis platform and demonstrate injury response in the KPT-MPS using an in-vivo relevant toxicant. KPT cells from rat/dog will be cultured to form viable and structurally complete tubules, and assessed for physiologic stress responses when exposed to compounds with established in vivo toxicity.

For Phase II: We will optimize KPT-MPS culture protocols using animal cells and assay parameters for chemical toxicity screening. We will characterize species-specific toxicity in KPTMPS and correlate to in vivo outcomes. Panels of five known KPT toxic compounds will be introduced into the rat and/or dog KPT-MPS after hepatocyte incubation and assessed for nephrotoxicity by measuring KIM-1 concentrations in the MPS effluents The concentration required to cause 4-fold increase in KIM-1 will be determined and compared with published in vivo data for rat, dog, and human Finally, kidney chips pre-seeded with rat and dog PTECs will be assessed for assay performance after shipment to assure robustness

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

We will continue to characterize hepatocyte spheroids in the 3-D MPS system and assess their functional phenotypes. We will continue to evaluate the effects of AgNPs, QDs, silver and cadmium ions, and other heavy metals in hepatocytes cultured in 2-D monolayers vs. spheroids in the 3-D 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 We will examine the ability of hepatocyte spheroid expression of MT to deliver Cd and Ag to PTECS and determine if such delivery influences kidney cell viability and function. We will also continue to develop and assess the utility of the mouse IM Gclm hepatocytes grown in 2-D and 3-D spheroids as a model for comparison to the human hepatocyte cultures, especially to evaluate Nrf2 responsiveness in each system. Regarding CCRI iPSC studies, we will follow liver and hematopoietic biomarkers of differentiation over time by immunohistochemistry using QD-adapter/antibody based fluorescence detection.

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

We continue to focus on expanding the applications of our 3D co-culture brain and testis systems by development of organotypic cultures to evaluate reproductive and developmental toxicity. We plan to evaluate effects of nanoparticles in transcriptomics using our 3D testicular co culture and hNPC culture systems. We also plan to compare adverse effects of AgNP between species (mouse and human) on developing brains. We will complete manuscripts reporting our findings in investigating the effects of cadmium on proliferating and differentiating hNPCs, including the role of sex in neuronal development

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

Moving forward, the core will continue to utilize the BMD and AOP approaches exemplified in the progress summary to develop and link adverse outcome pathways (AOP) across the four organogtypic model systems (lung, liver, kidney and testis) currently testing metals and ENM toxicity. We will continue to explore the implications of genetic susceptibility factors through characterizing differences in strain and sex responses. The utility of the results will allow us to identify unique toxicity profiles of ENMs and develop prioritization and translational frameworks to inform risk


Journal Articles: 60 Displayed | Download in RIS Format

Other center views: All 159 publications 56 publications in selected types All 55 journal articles
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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)
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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):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.). R835738 (Final)
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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.). R835738 (Final)
    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 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 R835738 (Final)
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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. R835738 (Final)
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  • 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. R835738 (Final)
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  • Journal Article Nicholas T, Haik A, Bammler T, Workman T, Kavanaugh T, Faustman E, Gharib S, Altemeier W. The effects of genotype x phenotype interactions on transcriptional response to silver nanoparticle Toxicity in organotypic cultures of marine tracheal epithelial cells. Toxicological Sciences 2020;173(1):131-143. R835738 (2018)
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  • Journal Article Nocholas T, Haick A, Workman T, Griffith W, Nolin J, Kanahagh T, Faustman E, ALtemeir W. The effects of genotype x phenotype interactions on silver nanoparticle toxicity in organotypic cultures of murine tracheal epithelial cells. Nanotoxicology 2020;14(7):908-928 R835738 (2019)
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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 (Final)
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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 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 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)
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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 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. R835738 (Final)
    R835738C001 (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. TOXICOLOGY AND APPLIED PHARMACOLOGY 2019:368;55-62 R835738 (Final)
    R835738C001 (2018)
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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 M, Hubal E, Faustman E. A Case study on the utility of predictive toxicology tools in alternatives assessments for hazardous chemicals in children's consumer products. JOURNAL OF EXPOSURE SCIENCE AND ENVIRONMENTAL EPIDEMIOLOGY 2020;30(1):160-170. R835738 (2018)
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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 (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 (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. 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. 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 Wegner S, Park J, Workman T, Workman T, Hermsan S, Wallace J, Stanaway I, Kim H, Griffith W, Hong S, Faustman E. Anchoring a dynamic in vitro model of human neuronal differentiation to key processes of early brain development in vivo. Reproductive Toxicology 2020;91:116-130. R835738 (2018)
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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 2018:354;215-224 R835738 (2017)
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  • Journal Article ZImaoka T, Yang J, Wang L, McDonald M, Afsharinejad Z, Bammler T, Van Ness K, Yeung C, Rettie A, Himmelfarb J. Microphysiological system modeling of ochratoxin A-associated nephrotoxicity. Toxicology 2020;444. R835738 (2019)
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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 (Final)
    R835738C004 (2018)
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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 Carlson LM, Champagne FA, Cory-Slechta DA, Dishaw L, Faustman E, Mundy W, Segal D, Sobin C, Starkey C, Taylor M, Makris SL. Potential frameworks to support evaluation of mechanistic data for developmental neurotoxicity outcomes:A symposium report. Neurotoxicology and Teratology 2020;78:106865. R835738 (Final)
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  • Journal Article Nicholas TP, Haick AK, Bammler TK, Workman TW, Kavanagh TJ, Faustman EM, Gharib SA, Altemeier WA. The Effects of Genotype× Phenotype Interactions on Transcriptional Response to Silver Nanoparticle Toxicity in Organotypic Cultures of Murine Tracheal Epithelial Cells. Toxicological Sciences 2020;173(1):131-43. R835738 (Final)
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  • Journal Article Knudsen TB, Fitzpatrick SC, De Abrew KN, Birnbaum LS, Chappelle A, Daston GP, Dolinoy DC, Elder A, Euling S, Faustman EM, Fedinick KP. FutureTox IV Workshop Summary:Predictive Toxicology for Healthy Children. Toxicological Sciences 2021;180(2):198-211. R835738 (Final)
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  • Journal Article Knudsen TB, Spielmann M, Megason SG, Faustman EM. Single‐cell profiling for advancing birth defects research and prevention. Birth Defects Research 2021 ;113(7):546-59. R835738 (Final)
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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. R835738 (Final)
    R835738C002 (2018)
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    Journal Article Jo MS, Kim JK, Kim Y, Kim HP, Kim HS, Ahn K, Lee JH, Faustman EM, Gulumian M, Kelman B, Yu IJ. Mode of silver clearance following 28-day inhalation exposure to silver nanoparticles determined from lung burden assessment including post-exposure observation periods. Archives of toxicology 2020:1-2. R835738 (Final)
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  • Journal Article Nicholas TP, Boyes WK, Scoville DK, Workman TW, Kavanagh TJ, Altemeier WA, Faustman EM. The effects of gene× environment interactions on silver nanoparticle toxicity in the respiratory system:An adverse outcome pathway. Wiley Interdisciplinary Reviews:Nanomedicine and Nanobiotechnology. 2021:e1708. R835738 (Final)
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  • Journal Article Nicholas TP, Haick AK, Workman T, Griffith WC, Nolin JD, Kavanagh TJ, Faustman EM, Altemeier WA. The mediating effects of genetic strain and differentiation condition on sensitivity to silver nanoparticle toxicity in organotypic cultures of murine tracheal epithelial cells. Nanotoxicology 2020 14(7) 908-928. R835738 (Final)
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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. R835738 (Final)
    R835738C002 (2018)
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  • Supplemental Keywords:

    Airway, Lung, Engineered Nanomaterials, Asthma, Chronic Obstructive Lung Disease, Kidney, Engineered nanomaterials, Quantum Dots, Cadmium, Kidney Injury, KIM-I (Kidney Injury Molecule), Preclinical, in vitro toxicology, 3-D organotypic cultures, microphysiological systems, hepatocytes, mouse, human, nanoparticles, quantum dots, aristolochic acid, cadmium, silver, cytotoxicity, redox status, cellular stress response, Nrf2 reporter assay, induced pluripotent stem cells, RNAseq, deconvolution algorithms, liver, hematopoiesis, genetics, Reproductive and Developmental Toxicity, Chemical Screening, testicular development, in vitro model, gender comparison, Adverse Outcome Pathway, Chemical prioritization, Dose-response modeling, Benchmark dose.

    Relevant Websites:

    UW Predictive Toxicology Center Exit

    Progress and Final Reports:

    Original Abstract
  • 2015 Progress Report
  • 2016 Progress Report
  • 2017 Progress Report
  • 2018 Progress Report
  • Final 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 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