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

Abstract

Background: 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. Objective: Previous studies suggest that bisphenol chemicals perturb cardiac electrophysiology in a manner that is similar to beta 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). Methods: Cardiac parameters were evaluated using microelectrode array (MEA) technology and live cell fluorescent imaging at baseline and in response to chemical exposure (0.001-100 uM). Results: Cardiac metrics remained relatively stable after exposure to nanomolar concentrations (1-1,000 nM) of E2, BPA, BPF, or BPS. At higher micromolar concentrations, chemical exposures resulted in a decrease in the depolarizing spike amplitude, shorter field potential and action potential duration, shorter calcium transient duration, and decrease in hiPSC-CM contractility (E2 > BPA > BPF >> BPS). Cardiomyocyte physiology was largely undisturbed by BPS exposure. BPA induced effects were exaggerated when co-administered with an L-type calcium channel antagonist (verapamil) or E2, and reduced when co-administered with an L type calcium channel agonist (Bay K8644) or an estrogen receptor alpha antagonist (MPP). E2 induced effects generally mirrored those of BPA, but were not exaggerated by coadministration with an L-type calcium channel antagonist. Discussion: Collectively across multiple cardiac endpoints, E2 was the most potent and BPS was the least potent disruptor of hiPSC-CM function. 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 in vitro findings should be validated using a more complex ex vivo and/or in vivo model.

Impact of 17β-Estradiol on the Shape, Survival, Osteogenic Transformation, and mRNA Expression of Gingiva-Derived Stem Cell Spheroids

“…A kind of estrogen called 17β-estradiol is known to affect several types of cells, including stem cells [19]. Estrogen can help stem cells survive under challenging circumstances, like oxidative stress, when it comes to stem cell treatment applications [20].…”