Xu Hai-Yang, Wang Pan, Sun Ying-Jian, Jiang Lu, Xu Ming-Yuan, Wu Yi-Jun
Laboratory of Molecular Toxicology, State Key Laboratory of Integrated Management of Pest Insects and Rodents, Institute of Zoology, Chinese Academy of Sciences, Beijing, People's Republic of China.
Department of Veterinary Medicine and Animal Science, Beijing University of Agriculture, Beijing, People's Republic of China.
J Neuropathol Exp Neurol. 2017 Jan 1;76(1):52-60. doi: 10.1093/jnen/nlw108.
The widely used organophosphorus compound tri-o-cresyl phosphate (TOCP) elicits delayed neurotoxicity characterized by progressive axonal degeneration in the spinal cord and peripheral nerves. However, the precise mechanisms of TOCP-induced delayed neurotoxicity are not clear. Because autophagy has been linked to the pathogenesis of neurodegenerative diseases, we aimed to characterize autophagy in the progression of TOCP-induced delayed neurotoxicity. In vivo experiments using the adult hen animal model showed that autophagy in spinal cord axons and in sciatic nerves was markedly induced at the early preclinical stage of TOCP-induced delayed neurotoxicity; it was decreased as the delayed neurotoxicity progressed to the overt neuropathy stage. In cultured human neuroblastoma SH-SY5Y cells, TOCP reduced cell growth, and induced prominent autophagy. The autophagy inhibitor 3-methyladenine could attenuate TOCP-induced cytotoxicity, indicating that the autophagy is accountable for TOCP-induced neurotoxicity. In addition, we found that TOCP-induced Parkin translocation to mitochondria in SH-SY5Y cells, suggesting that autophagy may function to degrade mitochondria after TOCP exposure. These results suggest that autophagy may play an important role in the initiation and progression of axonal damage during TOCP-induced neurotoxicity.
广泛使用的有机磷化合物三邻甲苯基磷酸酯（TOCP）会引发迟发性神经毒性，其特征是脊髓和周围神经中出现进行性轴突退化。然而，TOCP诱导迟发性神经毒性的确切机制尚不清楚。由于自噬与神经退行性疾病的发病机制有关，我们旨在描述自噬在TOCP诱导迟发性神经毒性进展中的特征。使用成年母鸡动物模型进行的体内实验表明，在TOCP诱导迟发性神经毒性的临床前早期阶段，脊髓轴突和坐骨神经中的自噬明显被诱导；随着迟发性神经毒性发展到明显的神经病变阶段，自噬减少。在培养的人神经母细胞瘤SH-SY5Y细胞中，TOCP降低细胞生长，并诱导显著的自噬。自噬抑制剂3-甲基腺嘌呤可以减弱TOCP诱导的细胞毒性，表明自噬是TOCP诱导神经毒性的原因。此外，我们发现TOCP诱导SH-SY5Y细胞中Parkin转位至线粒体，提示自噬可能在TOCP暴露后发挥降解线粒体的作用。这些结果表明，自噬可能在TOCP诱导神经毒性期间轴突损伤的起始和进展中起重要作用。
