Cooper Blake L, Salameh Shatha, Posnack Nikki Gillum
bioRxiv. 2023 Sep 15:2023.09.13.557564. doi: 10.1101/2023.09.13.557564.
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 at baseline and in response to chemical exposure (0.001-100 μM).
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 co-administration with an L-type calcium channel antagonist.
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 findings should be validated using a more complex and/or model.
双酚A（BPA）常用于制造消费级和医疗级塑料。出于对健康的担忧，双酚A替代品正在被采用，包括双酚S（BPS）和双酚F（BPF），但人们对它们的毒理学特征缺乏全面了解。
先前的研究表明，双酚类化学物质以类似于17β-雌二醇（E2）的方式扰乱心脏电生理。我们旨在使用人诱导多能干细胞衍生的心肌细胞（hiPSC-CM）比较E2与BPA、BPF和BPS的作用。
在基线时以及化学物质暴露（0.001 - 100 μM）后，使用微电极阵列（MEA）技术和活细胞荧光成像评估心脏参数。
暴露于纳摩尔浓度（1 - 1000 nM）的E2、BPA、BPF或BPS后，心脏指标保持相对稳定。在更高的微摩尔浓度下，化学物质暴露导致去极化尖峰幅度降低、场电位和动作电位持续时间缩短、钙瞬变持续时间缩短以及hiPSC-CM收缩性降低（E2 > BPA > BPF >> BPS）。BPS暴露对心肌细胞生理的影响较小。当与L型钙通道拮抗剂（维拉帕米）或E2共同给药时，BPA诱导的效应会增强；而当与L型钙通道激动剂（Bay K8644）或雌激素受体α拮抗剂（MPP）共同给药时，BPA诱导的效应会减弱。E2诱导的效应通常与BPA相似，但与L型钙通道拮抗剂共同给药时不会增强。
综合多个心脏终点来看，E2是hiPSC-CM功能最有效的破坏者，而BPS是最无效的。尽管观察到的E2和BPA对心脏的影响相似，但一些明显的差异表明这些化学物质可能（部分）通过不同的机制起作用。hiPSC-CM是筛选心脏毒性化学物质的有用模型，然而，所描述的结果应使用更复杂的模型进行验证。
