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Toxicol Appl Pharmacol. 2019 Oct 15;381:114711. doi: 10.1016/j.taap.2019.114711. Epub 2019 Aug 16.

Population-based toxicity screening in human induced pluripotent stem cell-derived cardiomyocytes.

Author information

1
Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, TX 77843-4458, USA. Electronic address: sburnett@cvm.tamu.edu.
2
Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, TX 77843-4458, USA. Electronic address: ablanchette@cvm.tamu.edu.
3
Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, TX 77843-4458, USA. Electronic address: fgrimm@cvm.tamu.edu.
4
Bioinformatics Research Center, North Carolina State University, Raleigh, NC 27695, USA. Electronic address: jshouse@ncsu.edu.
5
Department of Biological Sciences, North Carolina State University, Raleigh, NC 27695, USA; Department of Statistics, North Carolina State University, Raleigh, NC 27695, USA.
6
Department of Biological Sciences, North Carolina State University, Raleigh, NC 27695, USA; Department of Statistics, North Carolina State University, Raleigh, NC 27695, USA. Electronic address: fred_wright@ncsu.edu.
7
Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, TX 77843-4458, USA. Electronic address: wchiu@cvm.tamu.edu.
8
Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, TX 77843-4458, USA. Electronic address: irusyn@cvm.tamu.edu.

Abstract

The potential for cardiotoxicity is carefully evaluated for pharmaceuticals, as it is a major safety liability. However, environmental chemicals are seldom tested for their cardiotoxic potential. Moreover, there is a large variability in both baseline and drug-induced cardiovascular risk in humans, but data are lacking on the degree to which susceptibility to chemically-induced cardiotoxicity may also vary. Human induced pluripotent stem cell (iPSC)-derived cardiomyocytes have become an important in vitro model for drug screening. Thus, we hypothesized that a population-based model of iPSC-derived cardiomyocytes from a diverse set of individuals can be used to assess potential hazard and inter-individual variability in chemical effects on these cells. We conducted concentration-response screening of 134 chemicals (pharmaceuticals, industrial and environmental chemicals and food constituents) in iPSC-derived cardiomyocytes from 43 individuals, comprising both sexes and diverse ancestry. We measured kinetic calcium flux and conducted high-content imaging following chemical exposure, and utilized a panel of functional and cytotoxicity parameters in concentration-response for each chemical and donor. We show reproducible inter-individual variability in both baseline and chemical-induced effects on iPSC-derived cardiomyocytes. Further, chemical-specific variability in potency and degree of population variability were quantified. This study shows the feasibility of using an organotypic population-based human in vitro model to quantitatively assess chemicals for which little cardiotoxicity information is available. Ultimately, these results advance in vitro toxicity testing methodologies by providing an innovative tool for population-based cardiotoxicity screening, contributing to the paradigm shift from traditional animal models of toxicity to in vitro toxicity testing methods.

KEYWORDS:

Alternative methods; Cardiotoxicity; Environmental chemicals; High-content screening; In vitro; iPSC

PMID:
31425687
DOI:
10.1016/j.taap.2019.114711

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