In-depth mechanistic analysis including high-throughput RNA sequencing in the prediction of functional and structural cardiotoxicants using hiPSC cardiomyocytes

Rosell-Hidalgo, Alicia; Bruhn, Christopher; Shardlow, Emma; Barton, Ryan; Ryder, Stephanie; Samatov, Timur; Hackmann, Alexandra; Aquino, Gerald Ryan; Fernandes Dos Reis, Micael; Galatenko, Vladimir; Fritsch, Ruediger; Dohrmann, Cord; Walker, Paul A

doi:10.1080/17425255.2023.2273378

Cited by 1 publication

(3 citation statements)

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“…First, gene expression can be used for qualitative and quantitative potency ranking of drugs. For example, it was shown that drugs that elicit both structural and functional cardiotoxicity had greater transcriptomic effects (i.e., larger number of transcripts perturbed) than drugs known for either structural or functional toxicity alone, or noncardiotoxic compounds . In our study, pharmaceuticals known to have functional effects on the iPSC-derived cardiomyocytes, such as nifedipine, bepridil, and diltiazem, also affected a greater number of transcripts, compared to other pharmaceuticals and environmental chemicals.…”

Section: Discussionmentioning

confidence: 52%

“…For example, it was shown that drugs that elicit both structural and functional cardiotoxicity had greater transcriptomic effects (i.e., larger number of transcripts perturbed) than drugs known for either structural or functional toxicity alone, or noncardiotoxic compounds. 81 In our study, pharmaceuticals known to have functional effects on the iPSC-derived cardiomyocytes, such as nifedipine, bepridil, and diltiazem, also affected a greater number of transcripts, compared to other pharmaceuticals and environmental chemicals. While drug "potency" in terms of potential toxicity could be deduced from the magnitude of the transcriptional changes, 91 it is not a quantitative evaluation that would be necessary for formal risk assessment.…”

Section: ■ Discussionmentioning

confidence: 53%

“…Transcriptomic effects of various drugs on iPSC-derived cardiomyocytes have been explored by several groups. ,,,− These studies identified molecular mechanisms underlying adverse effects of both individual cardiotoxic compounds and entire drug classes. − In addition, some studies integrated transcriptomics with disease-associated genetic variants and mechanistic models to generate experimentally testable hypotheses of adverse event risk. , Collectively, these studies demonstrate that transcriptional profiles in human cardiomyocytes can be used to derive mechanism-based drug signatures, information that could be useful to predict the cardiotoxic potential of existing and new chemicals. Our study provides additional information in terms of the number and diversity of chemicals.…”

Section: Discussionmentioning

confidence: 99%

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Informing Hazard Identification and Risk Characterization of Environmental Chemicals by Combining Transcriptomic and Functional Data from Human-Induced Pluripotent Stem-Cell-Derived Cardiomyocytes

Tsai,

Ford,

Burnett

et al. 2024

Chem. Res. Toxicol.

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Environmental chemicals may contribute to the global burden of cardiovascular disease, but experimental data are lacking to determine which substances pose the greatest risk. Human-induced pluripotent stem cell (iPSC)-derived cardiomyocytes are a high-throughput cardiotoxicity model that is widely used to test drugs and chemicals; however, most studies focus on exploring electro-physiological readouts. Gene expression data may provide additional molecular insights to be used for both mechanistic interpretation and dose−response analyses. Therefore, we hypothesized that both transcriptomic and functional data in human iPSC-derived cardiomyocytes may be used as a comprehensive screening tool to identify potential cardiotoxicity hazards and risks of the chemicals. To test this hypothesis, we performed concentration−response analysis of 464 chemicals from 12 classes, including both pharmaceuticals and nonpharmaceutical substances. Functional effects (beat frequency, QT prolongation, and asystole), cytotoxicity, and whole transcriptome response were evaluated. Points of departure were derived from phenotypic and transcriptomic data, and risk characterization was performed. Overall, 244 (53%) substances were active in at least one phenotype; as expected, pharmaceuticals with known cardiac liabilities were the most active. Positive chronotropy was the functional phenotype activated by the largest number of tested chemicals. No chemical class was particularly prone to pose a potential hazard to cardiomyocytes; a varying proportion (10−44%) of substances in each class had effects on cardiomyocytes. Transcriptomic data showed that 69 (15%) substances elicited significant gene expression changes; most perturbed pathways were highly relevant to known key characteristics of human cardiotoxicants. The bioactivity-to-exposure ratios showed that phenotypic-and transcriptomicbased POD led to similar results for risk characterization. Overall, our findings demonstrate how the integrative use of in vitro transcriptomic and phenotypic data from iPSC-derived cardiomyocytes not only offers a complementary approach for hazard and risk prioritization, but also enables mechanistic interpretation of the in vitro test results to increase confidence in decision-making.

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Section: Discussionmentioning

confidence: 52%

Section: ■ Discussionmentioning

confidence: 53%