Bisphenol A (BPA) is widely used in plastic and paper products, and its exposure can occur through skin contact or oral ingestion. The hazardous effects of BPA absorbed through the skin may be more severe; however, few studies have investigated the skin toxicity of BPA. This study investigated the effects of BPA on human epidermal keratinocyte cell lines, which is relevant for skin exposure. BPA treatment reduced cell viability in a time‐ and concentration‐dependent manner and elevated oxidative and endoplasmic reticulum (ER) stress. N‐acetylcysteine (NAC), an oxidative stress inhibitor, reduced BPA‐induced reactive oxygen species (ROS) levels. However, only 10% of the decreased cell viability was restored at the highest NAC concentration. Treatment with tauroursodeoxycholic acid (TUDCA), which is an ER stress inhibitor, effectively countered the increase in ER stress‐related proteins induced by BPA. Moreover, TUDCA treatment led to a reduction in oxidative stress, as demonstrated by the decrease in ROS levels, maintenance of mitochondrial membrane potential, and modulation of stress signaling proteins. Consequently, TUDCA significantly improved BPA‐induced cytotoxicity in a concentration‐dependent manner. Notably, combined treatment using TUDCA and NAC further reduced the BPA‐induced ROS levels; however, no significant difference in cell viability was observed compared with that for TUDCA treatment alone. These findings indicated that the oxidative stress observed following BPA exposure was exacerbated by ER stress. Moreover, the principal factor driving BPA‐induced cytotoxicity was indeed ER stress, which has potential implications for developing therapeutic strategies for diseases associated with similar stress responses.

中文翻译：

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内质网应激对双酚 A 诱导的人角质形成细胞 HaCaT 细胞毒性的关键作用

双酚A (BPA) 广泛用于塑料和纸制品中，其暴露可通过皮肤接触或口腔摄入发生。通过皮肤吸收的 BPA 的危害可能更为严重；然而，很少有研究调查 BPA 的皮肤毒性。本研究调查了 BPA 对人表皮角质形成细胞系的影响，这与皮肤暴露有关。 BPA 处理以时间和浓度依赖性方式降低细胞活力，并升高氧化应激和内质网 (ER) 应激。 N-乙酰半胱氨酸 (NAC) 是一种氧化应激抑制剂，可降低 BPA 诱导的活性氧 (ROS) 水平。然而，在最高 NAC 浓度下，仅恢复了 10% 下降的细胞活力。使用牛磺熊去氧胆酸 (TUDCA)（一种 ER 应激抑制剂）进行治疗，可有效对抗 BPA 诱导的 ER 应激相关蛋白的增加。此外，TUDCA 治疗导致氧化应激减少，ROS 水平降低、线粒体膜电位维持和应激信号蛋白调节证明了这一点。因此，TUDCA 以浓度依赖性方式显着改善 BPA 诱导的细胞毒性。值得注意的是，使用 TUDCA 和 NAC 联合治疗进一步降低了 BPA 诱导的 ROS 水平；然而，与单独使用 TUDCA 处理相比，没有观察到细胞活力的显着差异。这些发现表明，内质网应激加剧了 BPA 暴露后观察到的氧化应激。此外，驱动 BPA 诱导的细胞毒性的主要因素确实是 ER 应激，这对于制定与类似应激反应相关的疾病的治疗策略具有潜在的意义。