Comparative cardiotoxicity assessment of bisphenol chemicals and estradiol using human induced pluripotent stem cell-derived cardiomyocytes.

Abstract

Bisphenol A (BPA) is commonly used to manufacture consumer and medical-grade plastics. Due to health concerns, BPA substitutes are being incorporated-including bisphenol S (BPS) and bisphenol F (BPF)-without a comprehensive understanding of their toxicological profile. Previous studies suggest that bisphenol chemicals perturb cardiac electrophysiology in a manner that is similar to 17β-estradiol (E2). We aimed to compare the effects of E2 with BPA, BPF, and BPS using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM). Cardiac parameters were evaluated using microelectrode array (MEA) technology and live-cell fluorescent imaging. Cardiac metrics remained relatively stable after exposure to nanomolar concentrations (1-1000 nM) of E2, BPA, BPF, or BPS. At higher micromolar concentrations, chemical exposures decreased the depolarization spike amplitude, and shortened the field potential, action potential duration, and calcium transient duration (E2 ≥ BPA ≥ BPF ≫ BPS). Cardiomyocyte physiology was largely undisturbed by BPS. BPA-induced effects were exaggerated when coadministered with an L-type calcium channel (LTCC) antagonist or E2, and reduced when coadministered with an LTCC agonist or an estrogen receptor alpha antagonist. E2-induced effects were not exaggerated by coadministration with an LTCC antagonist. Although the observed cardiac effects of E2 and BPA were similar, a few distinct differences suggest that these chemicals may act (in part) through different mechanisms. hiPSC-CM are a useful model for screening cardiotoxic chemicals, nevertheless, the described findings should be validated using a more complex ex vivo and/or in vivo model.