Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH 45267 USA.
Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH 45267 USA.
Chemosphere. 2024 Apr;353:141567. doi: 10.1016/j.chemosphere.2024.141567. Epub 2024 Feb 26.
Bisphenol A (BPA) and its analogs are common environmental chemicals with various adverse health impacts, including cardiac toxicity. In this study, we examined the long term effect of low dose BPA and three common BPA analogs, bisphenol S (BPS), bisphenol F (BPF), and bisphenol AF (BPAF), in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) based models. HiPSC-CMs and human cardiac organoids were exposed to these chemicals for 4-5 or 20 days. 1 nM BPA, BPS, and BPAF, but not BPF, resulted in suppressed myocyte contractility, retarded contraction kinetics, and aberrant Ca transients in hiPSC-CMs. In cardiac organoids, BPAF and BPA, but not the other bisphenols, resulted in suppressed contraction and Ca transients, and aberrant contraction kinetics. The order of toxicities was BPAF > BPA>∼BPS > BPF and the toxicities of BPAF and BPA were more pronounced under longer exposure. The impact of BPAF on myocyte contraction and Ca handling was mediated by reduction of sarcoplasmic reticulum Ca load and inhibition of L-type Ca channel involving alternation of Ca handling proteins. Impaired myocyte Ca handling plays a key role in cardiac pathophysiology and is a characteristic of cardiac hypertrophy; therefore we examined the potential pro-hypertrophic cardiotoxicity of these bisphenols. Four to five day exposure to BPAF did not cause hypertrophy in normal hiPSC-CMs, but significantly exacerbated the hypertrophic phenotype in myocytes with existing hypertrophy induced by endothelin-1, characterized by increased cell size and elevated expression of the hypertrophic marker proBNP. This pro-hypertrophic cardiotoxicity was also occurred in cardiac organoids, with BPAF having the strongest toxicity, followed by BPA. Our findings demonstrate that long term exposures to BPA and some of its analogs cause contractile dysfunction and abnormal Ca handling, and have potential pro-hypertrophic cardiotoxicity in human heart cells/tissues, and suggest that some bisphenol chemicals may be a risk factor for cardiac hypertrophy in human hearts.
双酚 A（BPA）及其类似物是常见的环境化学物质，具有多种不良健康影响，包括心脏毒性。在这项研究中，我们在基于人诱导多能干细胞衍生的心肌细胞（hiPSC-CMs）的模型中研究了低剂量 BPA 和三种常见 BPA 类似物，双酚 S（BPS）、双酚 F（BPF）和双酚 AF（BPAF）的长期影响。将 hiPSC-CMs 和人心肌类器官暴露于这些化学物质 4-5 或 20 天。1 nM BPA、BPS 和 BPAF，但不是 BPF，导致 hiPSC-CMs 中的心肌收缩力受抑制、收缩动力学减慢和 Ca 瞬变异常。在心脏类器官中，BPAF 和 BPA 导致收缩和 Ca 瞬变受抑制，收缩动力学异常，但其他双酚则不然。毒性顺序为 BPAF>BPA>∼BPS>BPF，且在较长暴露时间下，BPAF 和 BPA 的毒性更为明显。BPAF 对心肌收缩和 Ca 处理的影响是通过减少肌浆网 Ca 负荷和抑制涉及 Ca 处理蛋白改变的 L 型 Ca 通道来介导的。心肌细胞 Ca 处理受损在心脏病理生理学中起关键作用，是心脏肥大的特征；因此，我们检查了这些双酚类化合物潜在的促心肌毒性。4-5 天的 BPAF 暴露不会导致正常 hiPSC-CMs 肥大，但会显著加剧内皮素-1诱导的已有肥大心肌细胞的肥大表型，表现为细胞大小增加和肥厚标志物 proBNP 的表达升高。这种促心肌毒性也发生在心脏类器官中，其中 BPAF 的毒性最强，其次是 BPA。我们的研究结果表明，长期暴露于 BPA 和其一些类似物会导致收缩功能障碍和 Ca 处理异常，并在人心细胞/组织中具有潜在的促心肌毒性，提示某些双酚类化学物质可能是人类心脏肥大的一个危险因素。
