2018 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, 2017 through November 30,2018
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: Airway Epithelium Organotypic Culture as a Platform for Adverse Outcomes Pathway Assessment of Engineered Nanomaterials

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 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 system.

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

PI: Edward Kelly, PhD

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

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

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

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

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

PI: Elaine Faustman, PhD

The overall goal of this project is to utilize an organotypic in vitro model of testicular development to evaluate the male reproductive toxicity of ENMs using an AOP framework. We will use 3-D in vitro testicular 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 integrate in vitro findings into an AOP framework.

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

Co-PIs: William Griffith, PhD; Xiaohu Gao, PhD

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:

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 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.

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.

Cadmium Renal:Liver Toxicity Adverse Outcome Pathway Evaluation

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

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 Gclm mouse model as a reporter system for a model chemical oxidant (hydroquinone) and AgNP-induced oxidative stress. These cells were established from a Gclm mouse that had exon 1 of the Gclm gene replaced by a b-galactosidase-neomycin phosphotransferase (b-Geo) gene cassette. In this context, b-gal activity reflects the activity of the Gclm gene 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 dose-dependent increase in the amount of b-gal activity in the immortalized Gclm cells, but not in the immortalized Gclm WT cells that lack the b-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 Gclm spheroids show very reliable baseline, oxidative stress, and AgNP-induced increases in b-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. Therefore, further study of iHep differentiation in additional collaborative cross recombinant inbred strains is promising. There is an opportunity to map genes and pathways most important for hepatocyte differentiation and response to toxicant exposures.

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 testic 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. 2019a, 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. 2019b, in preparation).

Mouse midbrain micromass: We have utilized an in vitro 3-D organotypic mouse midbrain micromass culture system to examine adverse effects of AgNPs. We published a manuscript assessing the toxicological effects of various AgNPs, gene, and environmental interactions by comparing AgNP toxicity using two mouse strains' (C57BL/6 and A/J) midbrain micromass cultures (Weldon and Park et al. 2018). Significant dose-response relationships were observed across various AgNPs and particle sizes, coatings, and developmental stages contributed to susceptibility to AgNP exposures. Strain differences were also observed.

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, in preparation), 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 dose-response 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 2019 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.

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

Comparison databases for chemicals in consumer products: Washington State enacted the Children's Safe Product Act (CSPA) in 2009. CSPA requires manufacturers to report chemical use in any product sold or manufactured in Washington, according to the list of 88 chemicals of high concern to children, to the CSPA Manufacturers Database (CSPA-MD). Washington State also maintains a Product Testing Database (PTD) in which children's products are purchased and tested for chemicals of high concern to children. Building upon our previous study that suggested predictive toxicology tools can fill knowledge gaps, this project aimed to compare CSPA-MD and PTD to determine if there are systematic differences in product chemical combinations and if the reported concentrations are different between databases. Comparing records between databases, we merged individual records from CSPA-MD (40,204) and PTD (8,344) to compare averages within each product-family chemical combination for which we had 373 and 365, respectively. Of the product-family chemical combinations detected by the state and reported by manufacturers, the manufactures reported higher concentrations in 69-84% of product-family chemical comparisons. For regulated chemicals, manufacturers reported higher concentrations in 59% of the product-family chemical comparisons. Manufacturers reported higher concentrations because CSPA requires manufacturers to report the highest found concentration. This comparison allows us to hone in on which toxic chemicals are found in consumer products.

Using BMD based dosimetric approaches to interpret in vitro responses: We used 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. In this study, we used particle dosimetry to define physiologically-relevant dose-response relationships. We also used a dosimetrically-adjusted BMD approach to compare the mediating effects of G×E on sensitivity to adverse cellular responses by accounting for differences in the effective dose ranges to induce AgNP toxicity. We observed strain differences based on exposure conditions and endpoints.

Applications of AOPs to in vitro cultures: We are continuing our work on an AOP for the testis and are working 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 3-D testis co-culture and murine tracheal epithelial cells system. 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

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.

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

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

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, QD, 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 iHep studies, we will follow biomarkers of differentiation over time by immunohistochemistry. We will also proceed with single cell RNAseq experiments for a more refined analysis of the trajectory of transcriptomes as the cells differentiate from iPSCs into iHeps.

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 3-D co-culture brain and testis systems by development of organotypic cultures to evaluate reproductive and developmental toxicity. We plan to compare adverse effects of AgNP between species (mouse and human) on developing brains and investigate the effects of cadmium on proliferating and differentiating hNPCs, including the role of gender 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 across the four organogtypic models currently testing metals and ENM toxicity. We will continue to explore the implications of genetic susceptibility factors through characterizing differences in strain 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: 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)
    R835738C003 (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 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:

    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) Exit

    Progress and Final Reports:

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