Carbonic anhydrase inhibitor induces otic hair cell apoptosis via an intrinsic pathway and ER stress in zebrafish larvae.
Carbonic anhydrase inhibitor induces otic hair cell apoptosis via an intrinsic pathway and ER stress in zebrafish larvae.
复制标题
DOI：
10.1016/j.toxrep.2021.11.018
复制
发表时间：
2021
影响因子：
--
通讯作者：
Tsuzuki M
中科院分区：
文献类型：
--
作者：
Matsumoto H;Miyagi H;Nakamura N;Shiga Y;Ohta T;Fujiwara S;Tsuzuki M
CA抑制剂EZA导致斑马鱼幼鱼侧线器官死亡。神经肥大毛细胞在胚胎发育过程中对EZA尤为敏感。EZA通过内源性途径和内质网应激诱导耳毛细胞凋亡。碳酸酐酶（CA）催化CO2可逆水合成HCO3−，介导pH和离子稳态。据报道，一些化学污染物对鱼类CA具有抑制作用。在本研究中，我们研究了CA抑制剂乙氧基唑胺（EZA）对斑马鱼胚胎发生过程中神经突发育的影响，因为水生生物的胚胎发生对水污染特别敏感。EZA引起幼虫体内pH、钙浓度的改变和活性氧（ROS）的产生，诱导体表CA2分布的毛细胞尤其是耳神经肥大细胞凋亡。EZA可提高毛细胞凋亡基因mRNA水平和caspase活性，而抗氧化剂和凋亡抑制剂Bax、NF-κB和p53抑制剂可显著缓解毛细胞死亡的诱导。此外，EZA上调了内质网应激诱导的Bip和CHOP mRNA水平，表明EZA通过线粒体内在途径和内质网应激诱导耳毛细胞凋亡。我们的研究结果表明，CA通过维持离子转运和pH值在神经肥大发育中起重要作用，并且直接暴露于环境水中的CA对EZA表现出明显的敏感性。
CA inhibitor EZA causes lateral line organ death in zebrafish larvae. Neuromast hair cells are especially sensitive to EZA during embryo development. EZA induces apoptosis in otic hair cells via an intrinsic pathway and ER stress. Carbonic anhydrase (CA) catalyzes reversible hydration of CO2 to HCO3− to mediate pH and ion homeostasis. Some chemical pollutants have been reported to have inhibitory effects on fish CA. In this study, we investigated effects of a CA inhibitor ethoxyzolamide (EZA) on neuromasts development during zebrafish embryogenesis, since embryogenesis in aquatic organisms can be particularly sensitive to water pollution. EZA caused alteration of pH and calcium concentration and production of reactive oxygen species (ROS) in larvae, and induced apoptosis in hair cells especially in the otic neuromast, in which CA2 was distributed on the body surface. mRNA levels of apoptotic genes and caspase activities were increased by EZA, whereas anti-oxidants and apoptotic inhibitors, Bax, NF-κB, and p53 inhibitors significantly relieved the induction of hair cell death. Also, mRNA levels of Bip and CHOP, which are induced in response to ER stress, were upregulated by EZA, suggesting that EZA induces otic hair cell apoptosis via the intrinsic mitochondrial pathway and ER stress. Our results demonstrated an essential role of CA in neuromast development via maintenance of ion transport and pH, and that the CA, which is directly exposed to the ambient water, shows marked sensitivity to EZA.