Grantee Research Project Results
Final Report: Predictive Toxicology Center for Organotypic Cultures and Assessment ofAOPs for Engineered Nanomaterials
EPA Grant Number: R835738Center: 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 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 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
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
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
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.
Summary/Accomplishments (Outputs/Outcomes):
Project 1: Airway Epithelium Organotypic Culture as a Platform for Adverse Outcomes Pathway Assessment of Engineered Nanomaterials
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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.
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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.
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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.
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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. Results of RNAseq analyses with Advaita Pathway analysis software of RNA transcripts from PTECs treated for 48 hours with 25 μM versus controls revealed that the top five pathways affected by the treatment were: mineral absorption, protein processing in endoplasmic reticulum, ferroptosis, MAPK signaling pathway and Type II diabetes mellitus. All of these pathways had a p value < 6 x 10-4 and an FDR < 0.009. Upregulated genes (LogFc) where dominated by members of the metallothionein and heat shock protein families and markers of oxidative stress including HMOX1.
Project 3: Organotypic Models of Mammalian Liver as a Platform for Adverse Outcomes Pathway Assessment of Engineered Nanomaterials
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 principal site of extramedullary hematopoiesis during vertebrate development, and gives further credence to the idea that our protocol for differentiation of iPSCs is recapitulating in vivo liver differentiation and development. Follow on experiments that are underway for assessing protein expression in these cultures as biomarkers of fetal hepatocytes (Ab (albumin), Rbp4, Ttr) and hematopoiesis (SLC39a8, Car2). 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.
Additional studies are underway to establish immortalized lung epithelial cells from Gclm wild-type (WT), heterozygous (HT) and null (KO) mice. These cultures have been characterized for passaging lifetime and susceptibility to acetaldehyde-induced cytotoxicity.
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 have compared an in vitro and in vivo developmental timeline between rat and mouse systems (Wilder et al. 2021a, in preparation). We are also finalizing 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. 2021b, 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 have analyzed the result and are preparing 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 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. We are finalizing the manuscript reporting our finding for submission (Park et al 2021 in preparation). Furthermore, in our experiment 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 (H14) to be significantly more sensitive than female hNPCs (H9) when exposed to QD ITK. In addition, in order to access sex difference more effectively, we have compared normal development of H9 and H14 and been 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 have published the manuscript based on our observation of strain differences based on exposure conditions and endpoints (Nicholas et al 2020).
Applications of AOPs to in vitro cultures: Our manuscript on AOP for the lung by utilizing our organotypic culture systems is currently in press reporting our AOP development based on the biological changes associated with AgNP exposure in these organotypic cultures, including murine tracheal epithelial cells system (Nicholas et al 2021, in press). We continue 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.
Conclusions:
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 to conduct additional MPS studies with kidney:liver coupled chips to ascertain the impacts of liver toxicity, and the release of hepatic CdCl2-mediated toxicity factors on PTECs that will be coupled “downstream”. Cells from both treated and control livers and kidneys will be evaluated for organ-specific injury markers (e.g., KIM-1 in kidney and LDH in the liver), live-dead staining, and RNAseq analysis. To ensure that the dosimetry of the CdCl2 exposures are characterized, kidney effluents with be analyzed for Cd content. We plan to use the innovative Nortis “hybrid” MPS chip that contains fluid pathways for accommodating both hepatic and PTEC cells. We have evaluated earlier versions of this system and have provided feedback on design features and look forward to resting the next version.
We have worked with Nortis Inc. on a pilot project that evaluated the feasibility of developing animal cell-based kidneys on a chip using primary kidney proximal tubule (KPT) cells from rats and dogs. Chemical-associated acute kidney injury is a potentially life-threatening event and the use of preclinical animals to assess nephrotoxicity risk is a critical component of risk characterization. Replication of the functional human kidney proximal tubule is necessary for accurately modeling in-vivo chemical secretion and kidney injury and we have already demonstrated this with the Nortis KPT-MPS. We leveraged our expertise in human KPTs and have successfully isolated and cultured canine and rat kidney cells and in the case of canine KPTs, have seeded Nortis kidney chips and have maintained more than 14 kidney chips for over a month with viability over 90%. We plan to evaluate CdCl2 toxicity in both canine and rat kidney cells in 2D plates and MPS chips to compare the response with human cells. We plan to use the same markers of toxicity that we have typically used with human cells such as KIM-1 concentrations in effluents and live/dead staining.
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 antibody-based fluorescence detection. Future studies with the immortalized lung epithelial cells established from Gclm WT, HT and KO mice will assess nanoparticle-induced toxicity and stress-response gene expression at cultures grown at the air-liquid interface.
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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Bajaj, P., Chowdhury SK, Yucha R, Kelly EJ and Xiao G. Emerging Kidney Models to Investigate Metabolism, Transport, and Toxicity of Drugs and Xenobiotics. Drug Metabolism and Disposition 2018: 46(11);1692-1702. |
R835738 (Final) R835738C001 (2018) R835738C002 (2018) |
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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. |
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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. |
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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.). |
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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) R835738C005 (2017) |
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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.). |
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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) R835738C005 (2017) |
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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. |
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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. |
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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. |
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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. |
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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. |
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Kimmel DW, Rogers LM, Aronoff DM, Cliffel DE. Prostaglandin E2 regulation of macrophage innate immunity. Chemical Research in Toxicology 2016;29(1):19-25. |
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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. |
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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. |
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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. |
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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) R835738C001 (2018) R835738C003 (2018) R835738C004 (2018) |
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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. |
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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. |
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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. |
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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 |
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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.). |
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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) R835738C001 (2017) |
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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.). |
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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. |
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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. |
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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.). |
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Sakolish, C., Weber EJ, Kelly EJ, Himmelfarb J, Mouneimne R, Grimm FA, House JS, Wade T, Han A, Chiu WA, Rusyn I. Technology Transfer of the Microphysiological Systems: A Case Study of the Human Proximal Tubule Tissue Chip. Scientific Reports 2018: 8(1);14882 |
R835738 (Final) R835738C001 (2018) R835738C002 (2018) |
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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. |
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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. |
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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 |
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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) R835738 (Final) R835738C004 (2018) R835738C005 (2017) |
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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) R835738 (2017) R835738 (Final) R835738C005 (2015) R835738C005 (2016) R835738C005 (2017) R834514 (Final) |
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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) R835738 (Final) |
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Van Ness KP, Chang SY, Weber EJ, Zumpano D, Eaton DL, Kelly EJ. Microphysiological systems to assess nonclinical toxicity. Current Protocols in Toxicology 2017;73(1):14.18.1-14.18.28. |
R835738 (2017) R835738 (Final) R835738C001 (2018) R835738C002 (2017) R835738C002 (2018) R835738C004 (2018) R835738C005 (2017) |
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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) R835738C002 (2017) R835738C005 (2017) R835736 (2017) R835736C004 (2018) |
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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) R835738 (Final) R835738C003 (2017) R835738C005 (2017) R835736 (2015) R835736 (2016) R835736C004 (2016) R835736C005 (2016) |
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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) R835738 (Final) R835738C002 (2016) R835736C004 (2017) |
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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) R835738 (Final) R835738C003 (2017) R835738C005 (2017) R835736 (2015) R835736 (2016) R835736C004 (2016) R835736C005 (2016) |
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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) R835738 (Final) R835738C002 (2016) R835736C004 (2017) |
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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) R835738 (2017) R835738 (Final) R835738C002 (2016) R835738C002 (2017) R835738C005 (2017) |
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Wallace JC, Port JA, Smith MN, Faustman EM. FARME DB:a functional antibiotic resistance element database. Database 2017;2017(1):1-7. |
R835738 (2016) R835738 (Final) |
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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) R835738 (2017) R835738 (Final) R835738C002 (2016) R835738C002 (2017) |
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Weber EJ, Himmelfarb J, Kelly EJ. Concise review: current and emerging biomarkers of nephrotoxicity. Current Opinion in Toxicology 2017;4:16-21. |
R835738 (2017) R835738 (Final) R835738C002 (2017) R835738C002 (2018) |
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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) R835738 (2017) R835738 (Final) R835738C004 (2015) R835738C004 (2017) R834514 (2015) R834514 (Final) R834514C003 (2015) R834514C003 (Final) |
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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) R835738 (Final) R834514 (Final) |
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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) R835738 (2016) R835738 (2017) R835738 (Final) R835738C005 (2015) R835738C005 (2016) R835738C005 (2017) |
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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) R835738 (Final) R835738C004 (2017) R835738C004 (2018) R835738C005 (2017) R835738C005 (2018) |
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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) R835738 (Final) |
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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) R835738C005 (2018) |
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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) R835738 (Final) R835738C001 (2018) R835738C004 (2017) R835738C004 (2018) R835738C005 (2017) R835738C005 (2018) |
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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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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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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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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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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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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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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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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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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:
Project 1: Airway Epithelium Organotypic Culture as a Platform for Adverse Outcomes Pathway Assessment of Engineered Nanomaterials Airway, Lung, Engineered Nanomaterials, Asthma, Chronic Obstructive Lung Disease Project 2: Organotypic Model of Human Kidney as a Platform for Adverse Outcomes Pathway Assessment of Engineered Nanomaterials Kidney, Engineered nanomaterials, Quantum Dots, Cadmium, Kidney Injury, KIM-I (Kidney Injury Molecule), Preclinical, in vitro toxicology Project 3: Organotypic Models of Mammalian Liver as a Platform for Adverse Outcomes Pathway Assessment of Engineered Nanomaterials 3-D organotypic cultures, microphysiological systems, hepatocytes, mouse, human, nanoparticles, quantum dots, cadmium, silver, cytotoxicity, redox status, cellular stress response, Nrf2 reporter assay, induced pluripotent stem cells, RNAseq, deconvolution algorithms, liver, hematopoiesis, lung, glutathione, genetics. Project 4: Organotypic Model of Testis as a Platform for Adverse Outcomes Pathway Assessment of Engineered Nanomaterials Reproductive and Developmental Toxicity, Chemical Screening, testicular development, in vitro model, gender comparison Project 5: Integrating Liver, Kidney and Testis Nanomaterial Toxicity using the Adverse Outcome Pathway Approach Adverse Outcome Pathway, Chemical prioritization, Dose-response modeling, Benchmark doseRelevant Websites:
Predictive Toxicology Center Exit
Progress and Final Reports:
Original Abstract 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
The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.
Project Research Results
- 2019 Progress Report
- 2018 Progress Report
- 2017 Progress Report
- 2016 Progress Report
- 2015 Progress Report
- Original Abstract
55 journal articles for this center