2015 Progress Report: Cardiotoxicity Adverse Outcome Pathway: Organotypic Culture Model andinvitro-to-in vivo Extrapolation for High-throughput Hazard,Dose-responseand Variability Assessments

EPA Grant Number: R835802
Center: Organotypic Culture Models For Predictive Toxicology Center
Center Director: Rusyn, Ivan
Title: Cardiotoxicity Adverse Outcome Pathway: Organotypic Culture Model andinvitro-to-in vivo Extrapolation for High-throughput Hazard,Dose-responseand Variability Assessments
Investigators: Rusyn, Ivan , Threadgill, David W. , Wright, Fred A.
Institution: Texas A & M University , North Carolina State University
Current Institution: Texas A & M University , North Carolina State University , The Hamner Institutes
EPA Project Officer: Klieforth, Barbara I
Project Period: June 1, 2015 through May 31, 2019 (Extended to May 31, 2020)
Project Period Covered by this Report: June 1, 2015 through May 31,2016
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 WHO estimates that up to 23% of the global burden of cardiovascular diseases, a leading cause of death, is attributable to environmental chemicals. Methods for assessment of cardiac safety of non-pharmaceutical agents lag behind the traditional health hazards of concern to human health (carcinogenicity, mutagenicity, reproductive toxicity, etc.). The long-term objective of the Center is to advance chemical risk assessment by establishing and validating effective, accurate and fiscally responsible means for identifying/characterizing cardiac chemical hazards.

Recent advances in stem cell research and establishment of robust protocols for culturing, distribution and phenotyping holds promise for development of a functional cardiac OCM for modeling cardiovascular disease and testing for chemical hazards. The central hypotheses of this proposal are that: (i) stem cell-derived cardiomyocyte cultures constitute an effective OCM for predictive toxicity screening of environmental chemicals; (ii) a population-based experimental design utilizing a panel of human iPSCs and mouse Collaborative Cross (CC) can assess variation in toxicity to better characterize uncertainties; and (iii) integration of dosimetry with screening provides an in vivo context to in vitro data and improves human health assessments. Project 1 will conduct population-based concentration-response high-content/-throughput in vitro screening of up to 200 ToxCast chemicals in iPSC-derived cardiomyocytes from 100 humans, and will collect pharmacokinetic data using hepatocytes. Project 2 will conduct mouse population-based in vitro screening of these chemicals in CC-derived cardiomyocytes followed by in vivo validation in the CC strains. Project 3 will conduct dose-response modeling to establish appropriate point of departure, genome-wide association analyses and in vitro-to-in vivo extrapolation modeling.

Progress Summary:

Project 1 work was focused on developing optimal assay multi-plexing for high-content imaging and high-throughput transcriptomic analyses using iCell cardiomyocyte organotypic culture model and other cell types derived from iPS cells. We have also finalized the list of 140 compounds to be used in screening by Projects 1 and 2. Chemical selection was coordinated with FDA, NTP and EPA-NCCT. All compounds have been procured, dilutions prepared, and chemical master plates created for screening. We have acquired from Cellular Dynamics International the first batch of population-wide iCell cardiomyocytes from 30 normal donors (European and African American descent, equal male to female ratio) and have begun screening these cells. Screening for cardiophysiology and cytotoxicity of 140 chemicals in our library on all 30 individual cell lines was completed. Data analysis is underway for this first batch of experiments. Additional 70 cell lines were ordered from CDI, also we have initiated collaboration with Dr. Joseph Wu of Stanford University whose lab is pioneering iPSC cardiomyocyte development and research and we will be procuring additional cell lines from “normal” individuals from his laboratory. In addition, we have conducted a study of chemical-biological grouping using cardiomyocyte organotypic culture and other biological and chemical data for several important classes of compounds: petroleum substances and glycol ethers. This work opens novel possibilities of utilizing this microphysiological system for read-across of mixtures, complex substances, and read-across of closely structurally related chemicals.

Project 2 investigators have developed mouse embryonic fibroblast (MEF) cell lines from the entire Collaborative Cross (CC) mouse strain population. These are now being used to generate iPS lines and EBs for chemical treatment studies in vitro. For in vivo experiments in mice, we have acquired (via institution funding sources) advanced cardiac image processing software (VivoStrain) that uses speckle-tracking analysis, a sensitive measure for detecting and quantifying cardiotoxicity in vivo. This will be an enormous benefit for Objective 3. We have already tested the approach and submitted a manuscript documenting our capacity to perform these measurements. We have also explored various relevant developmental defects including early endocardial cushion morphogenesis that results from exposure to dioxin in 16 strains in vivo and will be comparing the response of those same stains in vitro using EBs. 

Project 3 investigators focused their priorities on several computational and statistical approaches. First, considerable methodological advances to pipelining the analyses of high-throughput transcriptomic data (e.g., TempO-Seq technology), including quality controlling the data, filtering of low expressed transcripts, fitting concentration-response functions and pathway analyses, have been made and informed by collaboration with NCATS. Second, we have considerably advanced the options for statistical analyses and grouping/clustering in the ToxPi software. Some of these options are in beta testing, and we expect new software releases next year. ToxPi analysis advances include handling multiple dimensions of prioritization, handling missing data, and quantifying across endpoints with irregular correlation structure. We have expanded the application space for ToxPi to additional datasets and are working to adapt ToxPi to read-across applications using multi-dimensional data. Finally, data integration aimed at leveraging transcriptomic and genetic information has remained an important focus to enable discovery of the linkages between genetics and expression in tissue-specific manner. The first step in this process has been the development of improved methods for genetic stratification. 

Future Activities:

Project 1 will perform data analyses on the first batch of 30 individuals screened against 140 chemicals and appropriate positive and negative controls. We expect to receive the next batch of cells (15-20 donors) from CDI in October-November 2016 and additional batches of 10-15 donors at quarterly intervals thereafter. These cells will be screened and data analyzed. We also plan to conduct several large batches of targeted transcriptomic analyses using S1500+ gene list (~2,700 targets) developed by the National Toxicology Program for TempO-seq high-throughput transcriptomics. We will work with project 3 staff to analyze these data. We will work with project 2 staff to conduct screening of mouse-derived embryoid bodies. Towards the end of year 2 and into subsequent years we will begin conducting experiments for reverse toxicokinetics based on the data for 140 chemicals that are screened.

Project 2 will complete iPS genetics from the CC MEF resource and will perform EB exposure on the first 30 CC lines using the selected 140 chemical panel. As the mouse TempO-seq high-throughout transcriptomics panel is developed, these will also be performed.

Project 3 will finalize the pipeline for dose-response analysis, applicable to both physiological parameters and to expression data (e.g., the TempOSeq technology). We will ensure that the ToxPi software will handle multiple dimensions of prioritization and missing data. We will also finalize our methods for controlling for stratification in genetic association, which will be used in Objective 3 for a limited number of high-priority SNP variants. 


Journal Articles: 35 Displayed | Download in RIS Format

Other center views: All 192 publications 35 publications in selected types All 35 journal articles
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Journal Article Auerbach S, Filer D, Reif D, Walker V, Holloway AC, Schlezinger J, Srinivasan S, Svoboda D, Judson R, Bucher JR, Thayer KA. Prioritizing environmental chemicals for obesity and diabetes outcomes research: a screening approach using ToxCastTM high-throughput data. Environmental Health Perspectives 2016;124(8):1141-1154. R835802 (2015)
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  • Journal Article Barton-Maclaren TS, Westphal M, Sarwar E, Mattison D, Chiu WA, Dix D, Kavlock R, Krewski D. Challenges and opportunities in the risk assessment of existing substances in Canada: lessons learned from the international community. International Journal of Risk Assessment and Management 2017;20;(1-3):261-283. R835802 (2016)
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  • Journal Article Blanchette AD, Grimm FA, Dalaijamts C, Hsieh NH, Ferguson K, Luo YS, Anson B, Rusyn I, Chiu WA. Thorough QT/QTc in a dish:An in vitro human model that accurately predicts clinical concentration-QTc relationships. Clinical Pharmacology and Therapeutics 2019;105:1175-1186. R835802 (2018)
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  • Journal Article Bokkers BGH, Mengelers MJ, Bakker MI, Chiu WA, Slob W. APROBA-Plus: a probabilistic tool to evaluate and express uncertainty in hazard characterization and exposure assessment of substances. Food and Chemical Toxicology. 2017;110:408-417. R835802 (2017)
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  • Journal Article Chiu WA, Wright FA, Rusyn I. A tiered, Bayesian approach to estimating population variability for regulatory decision-making. ALTEX 2017;34(3):377-388. R835802 (2016)
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  • Journal Article Chiu WA, Axelrad DA, Dalaijamts C, Dockins C, Shao K, Shapiro AJ, Paoli G. Beyond the RfD:Broad application of a probabilistic approach to improve chemical dose-response assessments for noncancer effects. Environmental Health Perspective 2018;126(6):067009. R835802 (2018)
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  • Journal Article Chiu WA, Guyton KZ, Martin MT, Reif DM, Rusyn I. Use of high-throughput in vitro toxicity screening data in cancer hazard evaluations by IARC Monograph Working Groups. ALTEX 2018;35(1):51-64. R835802 (2017)
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  • Journal Article Chiu WA, Rusyn I. Advancing chemical risk assessment decision-making with population variability data: challenges and opportunities. Mammalian Genome 2018;29(1-2):182-189. R835802 (2017)
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  • Journal Article Cote I, Andersen ME, Ankley GT, Barone S, Birnbaum LS, Boekelheide K, Bois FY, Burgoon LD, Chiu WA, Crawford-Brown D, Crofton KM, DeVito M, Devlin RB, Edwards SW, Guyton KZ, Hattis D, Judson RS, Knight D, Krewski D, Lambert J, Maull EA, Mendrick D, Paoli GM, Patel CJ, Perkins EJ, Poje G, Portier CJ, Rusyn I, Schulte PA, Simeonov A, Smith MT, Thayer KA, Thomas RS, Thomas R, Tice RR, Vandenberg JJ, Villeneuve DL, Wesselkamper S, Whelan M, Whittaker C, White R, Xia M, Yauk C, Zeise L, Zhao J, DeWoskin RS. The next generation of risk assessment multi-year study--highlights of findings, applications to risk assessment, and future directions. Environmental Health Perspectives 2016;124(11):1671-1682. R835802 (2015)
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  • Journal Article Fantke P, Aylward L, Bare J, Chiu WA, Dodson R, Dwyer R, Ernstoff A, Howard B, Jantunen M, Jolliet O, Judson R, Kirchhübel N, Li D, Miller A, Paoli G, Price P, Rhomberg L, Shen B, Shin HM, Teeguarden J, Vallero D, Wambaugh J, Wetmore BA, Zaleski R, McKone TE. Advancements in life cycle human exposure and toxicity characterization. Environmetnal Health Perspective 2018;126:125001. R835802 (2018)
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  • Journal Article Garbutt TA, Konneker TI, Konganti K, Hillhouse AE, Swift-Haire F, Jones A, Phelps D, Aylor DL, Threadgill D. Permissiveness to form pluripotent stem cells may be an evolutionarily derived characteristic in Mus musculus. Scientific Reports 2018;8:14706. R835802 (2018)
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  • Journal Article Grimm FA, Iwata Y, Sirenko O, Bittner M, Rusyn I. High-content assay multiplexing for toxicity screening in induced pluripotent stem cell-derived cardiomyocytes and hepatocytes. Assay and Drug Development Technologies 2015;13(9):529-546. R835802 (2015)
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  • Journal Article Grimm FA, Iwata Y, Sirenko O, Chappell GA, Wright FA, Reif DM, Braisted J, Gerhold DL, Yeakley JM, Shepard P, Seligmann B, Roy T, Boogaard PJ, Ketelslegers HB, Rohde AM, Rusyn I. A chemical-biological similarity-based grouping of complex substances as a prototype approach for evaluating chemical alternatives. Green Chemistry 2016;18(16):4407-4419. R835802 (2015)
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  • Journal Article Grimm FA, Blanchette A, House JS, Ferguson K, Hsieh NH, Dalaijamts C, Wright AA, Anson B, Wright FA, Chiu WA, Rusyn I. A human population-based organotypic in vitro model for cardiotoxicity screening. ALTEX 2018;35:441-452. R835802 (2018)
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  • Journal Article Grimm FA, House JS, Wilson MR, Sirenko O, Iwata Y, Wright FA, Ball N, Rusyn I. Multi-Dimensional in Vitro Bioactivity Profiling for Grouping of Glycol Ethers. Regulatory Toxicology and Pharmacology 2019;101:91-102. R835802 (2018)
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  • Journal Article Grondin CJ, Davis AP, Wiegers TC, King BL, Wiegers JA, Reif DM, Hoppin JA, Mattingly CJ. Advancing exposure science through chemical data curation and integration in the Comparative Toxicogenomics Database. Environmental Health Perspectives 2016;124(10):1592-1599. R835802 (2015)
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  • Journal Article Guyton KZ, Rusyn I, Chiu WA, Corpet DE, van den Berg M, Ross MK, Christiani DC, Beland FA, Smith MT. Application of the key characteristics of carcinogens in cancer hazard identification. Carcinogenesis 2018;39(4):614-622. R835802 (2017)
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  • Journal Article House JS, Grimm FA, Jima DD, Zhou Y-H, Rusyn I, Wright FA. A pipeline for high-throughput concentration response modeling of gene expression for toxicogenomics. Frontiers in Genetics 2017;8:168 (11 pp.). R835802 (2017)
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  • Journal Article Iwata Y, Klaren WD, Lebakken CS, Grimm FA, Rusyn I. High-content assay multiplexing for vascular toxicity screening in induced pluripotent stem cell-derived endothelial cells and human umbilical vein endothelial cells. Assay and Drug Development Technologies 2017;15(6):267-279. R835802 (2017)
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  • Journal Article Judson R, Houck K, Martin M, Richard AM, Knudsen TB, Shah I, Little S, Wambaugh J, Woodrow Setzer R, Kothya P, Phuong J, Filer D, Smith D, Reif D, Rotroff D, Kleinstreuer N, Sipes N, Xia M, Huang R, Crofton K, Thomas RS. Editor's highlight: Analysis of the effects of cell stress and cytotoxicity on in vitro assay activity across a diverse chemical and assay space. Toxicological Sciences 2016;152(2):323-339. R835802 (2015)
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  • Journal Article Konganti K, Ehrlich A, Rusyn I, Threadgill DW. gQTL:a web application for QTL analysis using the collaborative cross mouse genetic reference population. G3:Genes, Genomes, Genetics 2018;8(8):2559-2562 R835802 (2017)
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  • Journal Article Li G, Shabalin AA, Rusyn I, Wright FA, Nobel AB. An empirical Bayes approach for multiple tissue eQTL analysis. Biostatistics 2018;19(3):391-406. R835802 (2017)
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  • Journal Article Marvel SW, To K, Grimm FA, Wright FA, Rusyn I, Reif DM. ToxPi Graphical User Interface 2.0: dynamic exploration, visualization, and sharing of integrated data models. BMC Bioinformatics 2018;19(1):80 (7 pp.). R835802 (2017)
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  • Journal Article Rusyn I, Greene N. The impact of novel assessment methodologies in toxicology on green chemistry and chemical alternatives. Toxicological Sciences 2018;161(2):276-284. R835802 (2017)
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  • Journal Article Shah I, Setzer RW, Jack J, Houck KA, Judson RS, Knudsen TB, Liu J, Martin MT, Reif DM, Richard AM, Thomas RS, Crofton KM, Dix DJ, Kavlock RJ. Using ToxCast™ data to reconstruct dynamic cell state trajectories and estimate toxicological points of departure. Environmental Health Perspectives 2016;124(7):910-919. R835802 (2015)
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  • Journal Article Sirenko O, Grimm FA, Ryan KR, Iwata Y, Chiu WA, Parham F, Wignall JA, Anson B, Cromwell EF, Behl M, Rusyn I, Tice RR. In vitro cardiotoxicity assessment of environmental chemicals using an organotypic human induced pluripotent stem cell-derived model. Toxicology and Applied Pharmacology 2017;322:60-74. R835802 (2016)
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  • Journal Article Tilley SK, Reif DM, Fry RC. Incorporating ToxCast and Tox21 datasets to rank biological activity of chemicals at Superfund sites in North Carolina. Environment International 2017;101:19-26. R835802 (2017)
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  • Journal Article Wignall JA, Muratov E, Sedykh A, Guyton KZ, Tropsha A, Rusyn I, Chiu WA. Conditional Toxicity Value (CTV) predictor: an in silico approach for generating quantitative risk estimates for chemicals. Environmental Health Perspectives 2018;126(5):057008 (13 pp.). R835802 (2017)
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  • Journal Article Zhang G, Marvel S, Truong L, Tanguay RL, Reif DM. Aggregate entropy scoring for quantifying activity across endpoints with irregular correlation structure. Reproductive Toxicology 2016;62:92-99. R835802 (2015)
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  • Journal Article Zhang G, Roell KR, Truong L, Tanguay RL, Reif DM. A data-driven weighting scheme for multivariate phenotypic endpoints recapitulates zebrafish developmental cascades. Toxicology and Applied Pharmacology 2017;314:109-117. R835802 (2016)
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  • Journal Article Zhou Y-H, Marron JS, Wright FA. Computation of ancestry scores with mixed families and unrelated individuals. Biometrics 2018;74(1):155-164. R835802 (2016)
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  • Journal Article Li G, Jima D, Wright FA, Nobel AB. HT-eQTL:integrative expression quantitative trait loci analysis in a large number of human tissues. BMC Bioinformatics 2018;19:95. R835802 (2018)
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  • Journal Article Kosnik MB, Reif DM. Determination of chemical-disease risk values to prioritize connections between environmental factors, genetic variants, and human diseases. Toxicology and Applied Pharmacology2019;379:114674. R835802C003 (2018)
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  • Journal Article Kosnik MB, Planchart A, Marvel SW, Reif DM, Mattingly CJ. Integration of curated and high-throughput screening data to elucidate environmental influences on disease pathways. Computational Toxicology2019;12:100094. R835802C003 (2018)
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  • Journal Article Hsieh NH, Reisfeld, B, Bois FY, Chiu WA. Applying a global sensitivity analysis workflow to improve the computational efficiencies in physiologically-based pharmacokinetic modeling. Frontiers in Pharmacology 2018 9:588. R835802 (2018)
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  • Progress and Final Reports:

    Original Abstract
  • 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).
    R835802C001 High-throughput Hazard,Dose-responseandPopulationVariabilityAssessmentof Cardiotoxicity in aHumanInducedPluripotentStem Cell(iPSC)-derivedin vitro Culture Model
    R835802C002 Linking in vitro-to-in vivoToxicity Testing Using Genetically-matchedOrganoids and Mice from a Novel Genetic Reference Population
    R835802C003 A Pipeline for in vitro-to-in vivo Extrapolation, Population Modeling, & Prioritization