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
Current Institution: Texas A & M University , North Carolina State University
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: 13 Displayed | Download in RIS Format

Other center views: All 55 publications 13 publications in selected types All 13 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;(1/2/3):261-283. R835802 (2016)
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  • Journal Article Chiu WA, Wright FA, Rusyn I. A tiered, Bayesian approach to estimating of population variability for regulatory decision-making. ALTEX. 2016 Dec 13 [Epub ahead of print] doi:10.14573/altex.1608251. R835802 (2016)
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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 RA, 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 multiyear 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 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 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 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 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)
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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 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 2016;314:109-117. R835802 (2016)
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  • Journal Article Zhou YH, Marron JS, Wright FA. Computation of ancestry scores with mixed families and unrelated individuals. Biometrics 2017 April 27 [Epub ahead of print] doi:10.1111/biom.12708. R835802 (2016)
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  • Supplemental Keywords:

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

    Progress and Final Reports:

    2015 Progress Report
    2016 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