Cardiotoxicity Adverse Outcome Pathway: Organotypic Culture Model and in vitro-to-in vivo Extrapolation for High-throughput Hazard, Dose-response and 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 and in vitro-to-in vivo Extrapolation for High-throughput Hazard, Dose-response and Variability Assessments
Investigators: Rusyn, Ivan , Threadgill, David W. , Wright, Fred A.
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
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.

Expected Results:

This project will develop and validate a population-based human and mouse cardiac organotypic culture model (OCM) for characterizing susceptibility and variability in response to chemical hazards.


Journal Articles: 25 Displayed | Download in RIS Format

Other center views: All 94 publications 25 publications in selected types All 25 journal articles
Type Citation Sub Project Document Sources
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)
R835802 (2016)
R835802 (2017)
R835802C003 (2015)
  • Full-text from PubMed
  • Abstract from PubMed
  • Associated PubMed link
  • Full-text: EHP-Full Text PDF
  • Abstract: EHP-Abstract and Full Text HTML
  • 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)
    R835802 (2017)
  • Full-text: Inderscience-Full Text PDF
    Exit
  • Abstract: Inderscience-Abstract
    Exit
  • Other: ResearchGate-Abstract
    Exit
  • 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)
  • Abstract from PubMed
  • Full-text: ScienceDirect-Full Text HTML
    Exit
  • Abstract: ScienceDirect-Abstract
    Exit
  • Other: ScienceDirect-Full Text PDF
    Exit
  • 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)
    R835802 (2017)
    R835166 (2016)
    R835166 (Final)
  • Full-text from PubMed
  • Abstract from PubMed
  • Associated PubMed link
  • Full-text: ALTEX-Full Text PDF
    Exit
  • Abstract: ALTEX-Abstract
    Exit
  • 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)
  • Full-text from PubMed
  • Abstract from PubMed
  • Associated PubMed link
  • Full-text: Rusyn Lab-Full Text PDF
    Exit
  • Abstract: ALTEX-Abstract
    Exit
  • 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)
  • Abstract from PubMed
  • Full-text: Rusyn Lab-Full Text PDF
    Exit
  • Abstract: Springer-Abstract
    Exit
  • 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)
    R835802 (2016)
    R835802 (2017)
    R835802C001 (2015)
    R835166 (Final)
  • Full-text from PubMed
  • Abstract from PubMed
  • Associated PubMed link
  • Full-text: EHP-Full Text PDF
  • Abstract: EHP-Abstract and Full Text HTML
  • 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)
    R835802 (2016)
    R835802 (2017)
    R835802C001 (2015)
  • Full-text from PubMed
  • Abstract from PubMed
  • Associated PubMed link
  • Full-text: Mary Ann Liebert-Full Text HTML
    Exit
  • Abstract: Mary Ann Liebert-Abstract & Full Text HTML
    Exit
  • Other: Mary Ann Liebert-Full Text PDF
    Exit
  • 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)
    R835802 (2016)
    R835802 (2017)
    R835802C001 (2015)
    R835166 (Final)
  • Full-text from PubMed
  • Abstract from PubMed
  • Full-text: Royal Society of Chemistry-Full Text PDF
    Exit
  • Abstract: Royal Society of Chemistry-Abstract
    Exit
  • Other: ResearchGate-Abstract & Full Text PDF
    Exit
  • 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)
    R835802 (2016)
    R835802 (2017)
    R835802C003 (2015)
  • Full-text from PubMed
  • Abstract from PubMed
  • Associated PubMed link
  • Full-text: EHP-Full Text PDF
  • Abstract: EHP-Abstract and Full Text HTML
  • 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)
  • Full-text from PubMed
  • Abstract from PubMed
  • Associated PubMed link
  • Full-text: OUP-Full Text HTML
    Exit
  • Abstract: OUP-Abstract
    Exit
  • Other: OUP-Full Text PDF
    Exit
  • 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)
  • Full-text from PubMed
  • Abstract from PubMed
  • Associated PubMed link
  • Full-text: Frontiers in Genetics-Full Text HTML
    Exit
  • Abstract: Frontiers in Genetics-Abstract
    Exit
  • Other: Frontiers in Genetics-Full Text PDF
    Exit
  • 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)
    R835166 (Final)
  • Abstract from PubMed
  • Full-text: Rusyn Lab-Full Text PDF
    Exit
  • Abstract: Liebert Publishers-Abstract
    Exit
  • 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)
    R835802 (2016)
    R835802 (2017)
    R835802C003 (2015)
  • Abstract from PubMed
  • Full-text: Oxford Journals-Full Text HTML
    Exit
  • Abstract: Oxford Journals-Abstract
    Exit
  • Other: Oxford Journals-Full Text PDF
    Exit
  • 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:g3-200230.2018. R835802 (2017)
  • Abstract from PubMed
  • Full-text: G3-Full Text PDF
    Exit
  • Abstract: G3-Abstract
    Exit
  • 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)
  • Abstract from PubMed
  • Full-text: Rusyn Lab-Full Text PDF
    Exit
  • Abstract: Oxford Academic-Abstract
    Exit
  • 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)
  • Full-text from PubMed
  • Abstract from PubMed
  • Associated PubMed link
  • Full-text: BMC Bioinformatics-Full Text HTML
    Exit
  • Abstract: BMC Bioinformatics-Abstract
    Exit
  • Other: BMC Bioinformatics-Full Text PDF
    Exit
  • 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)
  • Abstract from PubMed
  • Full-text: Rusyn Lab-Full Text PDF
    Exit
  • Abstract: OUP-Abstract
    Exit
  • 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 ToxCastâ„¢ data to reconstruct dynamic cell state trajectories and estimate toxicological points of departure. Environmental Health Perspectives 2016;124(7):910-919. R835802 (2015)
    R835802 (2016)
    R835802 (2017)
  • Full-text from PubMed
  • Abstract from PubMed
  • Associated PubMed link
  • Full-text: EHP-Full Text PDF
  • Abstract: EHP-Abstract and Full Text HTML
  • 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)
    R835802 (2017)
    R835166 (Final)
  • Full-text from PubMed
  • Abstract from PubMed
  • Associated PubMed link
  • Full-text: ScienceDirect-Full Text HTML
    Exit
  • Abstract: ScienceDirect-Abstract
    Exit
  • Other: ScienceDirect-Full Text PDF
    Exit
  • 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)
  • Full-text from PubMed
  • Abstract from PubMed
  • Associated PubMed link
  • Full-text: ScienceDirect-Full Text HTML
    Exit
  • Abstract: ScienceDirect-Abstract
    Exit
  • Other: ScienceDirect-Full Text PDF
    Exit
  • 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)
  • Abstract from PubMed
  • Full-text: EHP-Full Text PDF
  • Abstract: EHP-Abstract and Full Text HTML
  • 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)
    R835802 (2016)
    R835802 (2017)
    R835802C003 (2015)
    R835168 (Final)
    R835796 (2017)
  • Full-text from PubMed
  • Abstract from PubMed
  • Associated PubMed link
  • Full-text: ScienceDirect-Full Text HTML
    Exit
  • Abstract: ScienceDirect-Abstract
    Exit
  • Other: ScienceDirect-Full Text PDF
    Exit
  • 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)
    R835802 (2017)
    R835168 (Final)
    R835796 (2017)
  • Full-text from PubMed
  • Abstract from PubMed
  • Associated PubMed link
  • Full-text: ScienceDirect-Full Text HTML
    Exit
  • Abstract: ScienceDirect-Abstract
    Exit
  • Other: ScienceDirect-Full Text PDF
    Exit
  • 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)
    R835802 (2017)
  • Full-text: Wiley-Full Text HTML
    Exit
  • Abstract: Wiley-Abstract
    Exit
  • Other: Wiley-Full Text PDF
    Exit
  • Supplemental Keywords:

    cardiovascular, stem cells, toxicity pathway, tissue mimetics, variability, pharmacokinetic model

    Progress and Final Reports:

  • 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).
    R835802C001 High-throughput Hazard, Dose-response and Population Variability Assessment of Cardiotoxicity in a Human Induced Pluripotent Stem Cell (iPSC)-derived in vitro Culture Model
    R835802C002 Linking in vitro-to-in vivoToxicity Testing Using Genetically-matched Organoids and Mice from a Novel Genetic Reference Population
    R835802C003 A Pipeline for in vitro-to-in vivo Extrapolation, Population Modeling, & Prioritization