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Informing Hazard Identification and Risk Characterization of Environmental Chemicals by Combining Transcriptomic and

Han-Hsuan D Tsai1,2, Lucie C Ford1,2, Sarah D Burnett1,2

  • 1Interdisciplinary Faculty of Toxicology, Texas A&M University, College Station, Texas 77843, United States.

Chemical Research in Toxicology
|July 24, 2024
PubMed
Summary

Human stem cell-derived heart cells combined with gene expression analysis effectively screen environmental chemicals for heart risks. This integrated approach aids in identifying cardiotoxicity hazards and understanding mechanisms.

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Area of Science:

  • Toxicology
  • Cardiovascular Research
  • Stem Cell Biology

Background:

  • Environmental chemicals contribute to cardiovascular disease burden.
  • Existing cardiotoxicity models often lack comprehensive molecular insights.
  • Human induced pluripotent stem cell (iPSC)-derived cardiomyocytes offer a high-throughput screening platform.

Purpose of the Study:

  • To evaluate the combined use of transcriptomic and functional data from iPSC-derived cardiomyocytes for chemical cardiotoxicity screening.
  • To identify potential cardiotoxicity hazards and risks associated with environmental chemicals.
  • To enable mechanistic interpretation of cardiotoxicity.

Main Methods:

  • Concentration-response analysis of 464 chemicals (pharmaceuticals and non-pharmaceuticals).
  • Evaluation of functional effects (beat frequency, QT prolongation, asystole), cytotoxicity, and whole transcriptome response.
  • Derivation of points of departure (POD) from phenotypic and transcriptomic data for risk characterization.

Main Results:

  • 244 (53%) chemicals showed activity in at least one phenotype; pharmaceuticals with known cardiac liabilities were most active.
  • Positive chronotropy was the most frequently activated functional phenotype.
  • 69 (15%) chemicals induced significant gene expression changes, with perturbed pathways relevant to known cardiotoxicants.
  • Phenotypic and transcriptomic data yielded similar risk characterization outcomes.

Conclusions:

  • Integrative analysis of in vitro transcriptomic and phenotypic data from iPSC-derived cardiomyocytes provides a robust method for cardiotoxicity hazard and risk assessment.
  • This approach enhances mechanistic understanding and decision-making confidence in chemical safety evaluations.
  • The study highlights the utility of iPSC-derived cardiomyocytes as a comprehensive screening tool for environmental chemical cardiotoxicity.