Chen Chao, Zheng Yongliang, Li Xue, Zhang Li, Liu Kangyu, Sun Sujie, Zhong Zilin, Hu Hongmei, Liu Fasheng, Xiong Guanghua, Liao Xinjun, Lu Huiqiang, Bi Yanlong, Chen Jianjun, Cao Zigang
Birth Defects Group, Translational Research Institute of Brain and Brain-like Intelligence, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, China.
Department of Ophthalmology, Tongji Hospital, School of Medicine, Tongji University, Shanghai, China.
Front Pharmacol. 2022 Aug 19;13:966710. doi: 10.3389/fphar.2022.966710. eCollection 2022.
Cysteamine is a kind of feed additive commonly used in agricultural production. It is also the only targeted agent for the treatment of cystinosis, and there are some side effects in clinical applications. However, the potential skeletal toxicity remains to be further elucidated. In this study, a zebrafish model was for the first time utilized to synthetically appraise the skeletal developmental defects induced by cysteamine. The embryos were treated with 0.35, 0.70, and 1.05 mM cysteamine from 6 h post fertilization (hpf) to 72 hpf. Substantial skeletal alterations were manifested as shortened body length, chondropenia, and abnormal somite development. The results of spontaneous tail coiling at 24 hpf and locomotion at 120 hpf revealed that cysteamine decreased behavioral abilities. Moreover, the level of oxidative stress in the skeleton ascended after cysteamine exposure. Transcriptional examination showed that cysteamine upregulated the expression of osteoclast-related genes but did not affect osteoblast-related genes expression. Additionally, cysteamine exposure caused the downregulation of the Notch signaling and activating of Notch signaling partially attenuated skeletal defects. Collectively, our study suggests that cysteamine leads to skeletal developmental defects and reduces locomotion activity. This hazard may be associated with cysteamine-mediated inhibition of the Notch signaling and disorganization of notochordal cells due to oxidative stress and apoptosis.
半胱胺是农业生产中常用的一种饲料添加剂。它也是治疗胱氨酸病的唯一靶向药物，在临床应用中存在一些副作用。然而，其潜在的骨骼毒性仍有待进一步阐明。在本研究中，首次利用斑马鱼模型综合评估半胱胺诱导的骨骼发育缺陷。从受精后6小时（hpf）至72小时，用0.35、0.70和1.05 mM半胱胺处理胚胎。显著的骨骼改变表现为体长缩短、软骨减少和体节发育异常。24 hpf时的自发尾部卷曲和120 hpf时的运动结果显示，半胱胺降低了行为能力。此外，半胱胺暴露后骨骼中的氧化应激水平升高。转录检查表明，半胱胺上调了破骨细胞相关基因的表达，但不影响成骨细胞相关基因的表达。此外，半胱胺暴露导致Notch信号下调，激活Notch信号可部分减轻骨骼缺陷。总体而言，我们的研究表明，半胱胺会导致骨骼发育缺陷并降低运动活性。这种危害可能与半胱胺介导的Notch信号抑制以及由于氧化应激和细胞凋亡导致的脊索细胞紊乱有关。
