Interdisciplinary Faculty of Toxicology, Texas A&M University, College Station, Texas 77843, United States.
Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas 77843, United States.
Chem Res Toxicol. 2024 Aug 19;37(8):1428-1444. doi: 10.1021/acs.chemrestox.4c00193. Epub 2024 Jul 24.
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 transcriptomic-based 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.
环境化学物质可能导致全球心血管疾病负担增加，但缺乏实验数据来确定哪些物质构成最大风险。人类诱导多能干细胞（iPSC）衍生的心肌细胞是一种高通量的心肌毒性模型，广泛用于测试药物和化学物质；然而，大多数研究集中在探索电生理读数。基因表达数据可能提供额外的分子见解，用于机制解释和剂量反应分析。因此，我们假设人类 iPSC 衍生心肌细胞中的转录组和功能数据可作为一种综合筛选工具，以识别潜在的心脏毒性危害和化学物质的风险。为了验证这一假设，我们对来自 12 类的 464 种化学物质进行了浓度反应分析，包括药物和非药物物质。评估了功能效应（搏动频率、QT 延长和停搏）、细胞毒性和全转录组反应。从表型和转录组数据中得出了起始点，并进行了风险特征描述。总的来说，244 种（53%）物质在至少一种表型中具有活性；如预期的那样，具有已知心脏毒性的药物是最活跃的。正性变时性是被测试的化学物质中激活最多的功能表型。没有特定的化学物质类别特别容易对心肌细胞构成潜在危害；每个类别的物质中有不同比例（10-44%）对心肌细胞有影响。转录组数据显示，69 种（15%）物质引起了显著的基因表达变化；大多数受干扰的途径与已知的人类心脏毒性物质的关键特征高度相关。生物活性-暴露比表明，基于表型和转录组的 POD 导致了相似的风险特征描述结果。总的来说，我们的研究结果表明，整合使用源自 iPSC 衍生心肌细胞的体外转录组和表型数据不仅提供了一种用于危害和风险优先级排序的补充方法，还能够对体外测试结果进行机制解释，从而提高决策的信心。
