Department of Veterinary Physiology and Pharmacology, TAMU 4466, Texas A&M University, College Station, TX, 77843-4466, USA.
Department of Biological Sciences and Statistics, North Carolina State University, Raleigh, NC, 27695, USA.
Hum Genomics. 2024 Sep 2;18(1):92. doi: 10.1186/s40246-024-00665-x.
Per- and poly-fluoroalkyl substances (PFAS) are emerging contaminants of concern because of their wide use, persistence, and potential to be hazardous to both humans and the environment. Several PFAS have been designated as substances of concern; however, most PFAS in commerce lack toxicology and exposure data to evaluate their potential hazards and risks. Cardiotoxicity has been identified as a likely human health concern, and cell-based assays are the most sensible approach for screening and prioritization of PFAS. Human-induced pluripotent stem cell (iPSC)-derived cardiomyocytes are a widely used method to test for cardiotoxicity, and recent studies showed that many PFAS affect these cells. Because iPSC-derived cardiomyocytes are available from different donors, they also can be used to quantify human variability in responses to PFAS. The primary objective of this study was to characterize potential human cardiotoxic hazard, risk, and inter-individual variability in responses to PFAS. A total of 56 PFAS from different subclasses were tested in concentration-response using human iPSC-derived cardiomyocytes from 16 donors without known heart disease. Kinetic calcium flux and high-content imaging were used to evaluate biologically-relevant phenotypes such as beat frequency, repolarization, and cytotoxicity. Of the tested PFAS, 46 showed concentration-response effects in at least one phenotype and donor; however, a wide range of sensitivities were observed across donors. Inter-individual variability in the effects could be quantified for 19 PFAS, and risk characterization could be performed for 20 PFAS based on available exposure information. For most tested PFAS, toxicodynamic variability was within a factor of 10 and the margins of exposure were above 100. This study identified PFAS that may pose cardiotoxicity risk and have high inter-individual variability. It also demonstrated the feasibility of using a population-based human in vitro method to quantify population variability and identify cardiotoxicity risks of emerging contaminants.
全氟和多氟烷基物质（PFAS）因其广泛的用途、持久性以及对人类和环境造成危害的潜力而成为令人关注的新兴污染物。一些 PFAS 已被指定为关注物质；然而，商业上大多数 PFAS 缺乏毒理学和暴露数据，无法评估其潜在危害和风险。心脏毒性已被确定为一个可能的人类健康关注点，基于细胞的检测方法是筛选和优先考虑 PFAS 的最合理方法。人诱导多能干细胞（iPSC）衍生的心肌细胞是一种广泛用于测试心脏毒性的方法，最近的研究表明，许多 PFAS 会影响这些细胞。由于 iPSC 衍生的心肌细胞可来自不同的供体，因此它们也可用于量化人类对 PFAS 反应的个体差异。本研究的主要目的是描述对 PFAS 反应的潜在人类心脏毒性危害、风险和个体间变异性。使用来自 16 名无已知心脏病的供体的人类 iPSC 衍生的心肌细胞，在浓度反应中测试了来自不同子类的 56 种 PFAS。动力学钙通量和高内涵成像用于评估生物学相关表型，如搏动频率、复极化和细胞毒性。在所测试的 PFAS 中，有 46 种在至少一种表型和供体中表现出浓度反应效应；然而，在供体之间观察到广泛的敏感性差异。19 种 PFAS 的效应可以量化个体间的变异性，并且可以根据可用的暴露信息对 20 种 PFAS 进行风险特征描述。对于大多数测试的 PFAS，毒代动力学变异性在 10 倍以内，暴露边际大于 100。本研究确定了可能具有心脏毒性风险和个体间高度变异性的 PFAS。它还证明了使用基于人群的体外方法来量化人群变异性和识别新兴污染物心脏毒性风险的可行性。
