Bisphenol S and Bisphenol F Are Less Disruptive to Cardiac Electrophysiology, as Compared With Bisphenol A

Tomas M Prudencio; Luther M Swift; Devon Guerrelli; Blake Cooper; Marissa Reilly; Nina Ciccarelli; Jiansong Sheng; Rafael Jaimes; Nikki Gillum Posnack

doi:10.1093/toxsci/kfab083

Bisphenol S and Bisphenol F Are Less Disruptive to Cardiac Electrophysiology, as Compared With Bisphenol A

Toxicol Sci. 2021 Aug 30;183(1):214-226. doi: 10.1093/toxsci/kfab083.

Authors

Tomas M Prudencio^{1

2}, Luther M Swift^{1

2}, Devon Guerrelli^{1

2

3}, Blake Cooper^{1

2

4}, Marissa Reilly^{1

2}, Nina Ciccarelli^{1

2}, Jiansong Sheng⁵, Rafael Jaimes^{1

2}, Nikki Gillum Posnack^{1

2

4

6}

Affiliations

¹ Sheikh Zayed Institute for Pediatric Surgical Innovation, Children's National Hospital, Washington, District of Columbia 20010, USA.
² Children's National Heart Institute, Children's National Hospital, Washington, District of Columbia 20010, USA.
³ Department of Biomedical Engineering, The George Washington University, Washington, District of Columbia 20037, USA.
⁴ Department of Pharmacology & Physiology, The George Washington University, Washington, District of Columbia 20037, USA.
⁵ CiPA Lab, Rockville, Maryland 20852, USA.
⁶ Department of Pediatrics, The George Washington University, Washington, District of Columbia 20037, USA.

Abstract

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.

Keywords: bisphenol; cardiac electrophysiology; comprehensive in vitro proarrhythmia assay (CiPA); plastics.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Benzhydryl Compounds* / toxicity
Electrophysiologic Techniques, Cardiac*
Humans
Phenols
Rats
Sulfones

Substances

Benzhydryl Compounds
Phenols
Sulfones
bisphenol F
bis(4-hydroxyphenyl)sulfone
bisphenol A

Grants and funding

R01 HL139472/HL/NHLBI NIH HHS/United States