Characterizing PFAS hazards and risks: a human population-based in vitro cardiotoxicity assessment strategy.

IF 3.8 3区 医学 Q2 GENETICS & HEREDITY
Lucie C Ford, Hsing-Chieh Lin, Yi-Hui Zhou, Fred A Wright, Vijay K Gombar, Alexander Sedykh, Ruchir R Shah, Weihsueh A Chiu, Ivan Rusyn
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引用次数: 0

Abstract

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.

表征全氟辛烷磺酸的危害和风险:基于人群的体外心脏毒性评估战略。
全氟烷基和多氟烷基物质(PFAS)因其广泛使用、持久性以及对人类和环境的潜在危害而成为新出现的污染物。有几种全氟辛烷磺酸已被指定为关注物质;然而,商业中的大多数全氟辛烷磺酸都缺乏毒理学和暴露数据来评估其潜在危害和风险。心脏毒性已被确定为可能对人类健康造成危害的一种物质,而基于细胞的检测方法是筛选全氟辛烷磺酸并确定其优先次序的最合理方法。人类诱导多能干细胞(iPSC)衍生的心肌细胞是一种广泛用于检测心脏毒性的方法,最近的研究表明,许多 PFAS 会影响这些细胞。由于 iPSC 衍生的心肌细胞来自不同的供体,因此也可用于量化人类对 PFAS 反应的差异性。本研究的主要目的是描述人类对 PFAS 的潜在心脏毒性危害、风险和个体间反应的差异性。研究人员使用来自 16 名无已知心脏病的供体的人类 iPSC 衍生心肌细胞,对不同亚类的共 56 种 PFAS 进行了浓度反应测试。采用动力学钙通量和高含量成像技术来评估生物相关表型,如搏动频率、再极化和细胞毒性。在接受测试的全氟辛烷磺酸中,有 46 种至少在一种表型和供体中显示出浓度反应效应;不过,在不同供体中观察到的敏感性差异很大。可以对 19 种 PFAS 的个体间效应差异进行量化,并根据现有的暴露信息对 20 种 PFAS 进行风险定性。对于大多数受测的全氟辛烷磺酸来说,毒效学变异性在 10 倍以内,而暴露的边际值在 100 以上。这项研究确定了可能具有心脏毒性风险且个体间差异较大的 PFAS。它还证明了使用基于人群的人体体外方法来量化人群变异性和确定新出现污染物的心脏毒性风险的可行性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Human Genomics
Human Genomics GENETICS & HEREDITY-
CiteScore
6.00
自引率
2.20%
发文量
55
审稿时长
11 weeks
期刊介绍: Human Genomics is a peer-reviewed, open access, online journal that focuses on the application of genomic analysis in all aspects of human health and disease, as well as genomic analysis of drug efficacy and safety, and comparative genomics. Topics covered by the journal include, but are not limited to: pharmacogenomics, genome-wide association studies, genome-wide sequencing, exome sequencing, next-generation deep-sequencing, functional genomics, epigenomics, translational genomics, expression profiling, proteomics, bioinformatics, animal models, statistical genetics, genetic epidemiology, human population genetics and comparative genomics.
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