Sheikh Zayed Institute for Pediatric Surgical Innovation, Children's National Hospital, Washington, District of Columbia 20010, USA.
Children's National Heart Institute, Children's National Hospital, Washington, District of Columbia 20010, USA.
Toxicol Sci. 2021 Aug 30;183(1):214-226. doi: 10.1093/toxsci/kfab083.
Bisphenol A (BPA) is a high-production volume chemical used to manufacture consumer and medical-grade plastic products. Due to its ubiquity, the general population can incur daily environmental exposure to BPA, whereas heightened exposure has been reported in intensive care patients and industrial workers. Due to health concerns, structural analogs are being explored as replacements for BPA. This study aimed to examine the direct effects of BPA on cardiac electrophysiology compared with recently developed alternatives, including BPS (bisphenol S) and BPF (bisphenol F). Whole-cell voltage-clamp recordings were performed on cell lines transfected to express the voltage-gated sodium channel (Nav1.5), L-type voltage-gated calcium channel (Cav1.2), or the rapidly activating delayed rectifier potassium channel (hERG). Cardiac electrophysiology parameters were measured using human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) and intact, whole rat heart preparations. BPA was the most potent inhibitor of fast/peak (INa-P) and late (INa-L) sodium channel (IC50 = 55.3, 23.6 µM, respectively), L-type calcium channel (IC50 = 30.8 µM), and hERG channel current (IC50 = 127 µM). Inhibitory effects on L-type calcium channels were supported by microelectrode array recordings, which revealed a shortening of the extracellular field potential (akin to QT interval). BPA and BPF exposures slowed atrioventricular (AV) conduction and increased AV node refractoriness in isolated rat heart preparations, in a dose-dependent manner (BPA: +9.2% 0.001 µM, +95.7% 100 µM; BPF: +20.7% 100 µM). BPS did not alter any of the cardiac electrophysiology parameters tested. Results of this study demonstrate that BPA and BPF exert an immediate inhibitory effect on cardiac ion channels, whereas BPS is markedly less potent. Additional studies are necessary to fully elucidate the safety profile of bisphenol analogs on the heart.
双酚 A (BPA) 是一种高产量的化学物质，用于制造消费类和医疗级塑料产品。由于其无处不在，普通人群可能会每天接触到环境中的 BPA，而在重症监护患者和工业工人中则报告了更高的接触水平。由于健康问题，正在探索结构类似物来替代 BPA。本研究旨在比较 BPA 与最近开发的替代品（包括双酚 S (BPS) 和双酚 F (BPF)) 对心脏电生理学的直接影响。通过转染表达电压门控钠离子通道 (Nav1.5)、L 型电压门控钙通道 (Cav1.2) 或快速激活延迟整流钾通道 (hERG) 的细胞系进行全细胞电压钳记录。使用人诱导多能干细胞衍生的心肌细胞 (hiPSC-CM) 和完整的大鼠心脏制剂测量心脏电生理学参数。BPA 是最有效的快/峰 (INa-P) 和晚期 (INa-L) 钠离子通道 (IC50 = 55.3、23.6 µM)、L 型钙通道 (IC50 = 30.8 µM) 和 hERG 通道电流 (IC50 = 127 µM) 抑制剂。L 型钙通道的抑制作用得到微电极阵列记录的支持，该记录显示细胞外场电位缩短（类似于 QT 间期）。BPA 和 BPF 暴露以剂量依赖性方式减缓了分离大鼠心脏制剂中的房室 (AV) 传导，并增加了 AV 结不应性 (BPA: +9.2% 0.001 µM，+95.7% 100 µM；BPF: +20.7% 100 µM)。BPS 没有改变测试的任何心脏电生理学参数。本研究结果表明，BPA 和 BPF 对心脏离子通道立即产生抑制作用，而 BPS 的作用明显较弱。需要进一步研究以充分阐明双酚类似物对心脏的安全性概况。
