三甲基锡的神经毒性和耳毒性

摘要

Environmental pollution of organotin compounds (OTCs) are very harmful to people. Trimethyltin (TMT) is one of the most toxic agents of OTCs. The clinical symptoms of neurotoxicity and ototoxicity include disorientation, amnesia, hearing loss, muscle spasms, epilepsy, ataxia, and etc. The major mechanisms of TMT-induced cell damage have been identi-fied relating to an excessive release of excitatory neurotransmitters, oxidative stress, intracellular high calcium concentration, mitochondrial lesions, and inflammatory response. In the neurotoxic effects, the excitatory amino acid release is significantly in-creased, and also associated with high inhibition to the inhibitory amino acid by TMT treatment that causes an imbalanced ex-citation/inhibition in nervous system. TMT treatment increases the production of free radicals and reactive oxygen species, and also causes a decline in activity of enzymic and non enzymic antioxidants which can lead to apoptosis. TMT treatment can also elevate intracellular calcium in sensitive cells due to efflux of calcium from intracellular reserves and/or influx of extracellular calcium . High intracellular calcium activates multiple degenerative pathways. However, the greatest threat to cells is by acti-vation of calpains, a calcium activated proteinase, which breaks down proteins, kinases, phosphatases and transcription fac-tors, and eventually leads to cell apoptosis or necrosis. Stannin a mitochondrial membrane protein, being sensitive to TMT, was undermined by irreversible alternation of its stereochemistry on binding with TMT. Therefore, neurons and cells rich in mitochondria are breakthrough points of TMT to exert its toxic effects. As the damage progresses, cytochrome C was released from damaged mitochondrial membrane into cytoplasm, which eventually activates caspases and leads to cell apoptosis. TMT-induced damage to the peripheral auditory system precedes neural injury in the central nervous system with rapid high-frequency hearing loss. The earliest influence to hearing function by TMT treatment is the threshold elevation of cochlear action potential followed by amplitude reduction of cochlear microphonic potentials. This suggests that the initial toxicity of TMT is localized to the synapse between the inner hair cells and type I spiral ganglion neurons, whereas the outer hair cells will be affected afterwards. TMT-induced hearing loss and demyelinating damage to auditory nerve fibers simulates auditory neuropathy with characteristic features of demyelination. Thus, the neurotoxic effects and ototoxic effects of TMT might be a suitable model to investigate auditory neuropathy and also an ideal model to study the mechanisms underlying the multi-facto-rial hearing impairment.%有机锡化合物环境污染对人类健康造成很大的危害。众多有机锡化合物中三甲基锡（TMT）对人体有较强的神经毒性和耳毒性。TMT神经毒性可选择性破坏大脑边缘结构尤其是海马神经元以及听神经系统的神经元。TMT之所以选择性损害某些敏感神经元，其原因是因为这些神经元富含一种被称为Stannin的蛋白质，而Stannin蛋白正是TMT攻击的特异性靶目标。由于这种蛋白同样存在于线粒体，因此富含线粒体的细胞比线粒体贫乏的细胞更容易遭受有机锡化合物的攻击。TMT与Stannin产生不可逆性结合之后进而破坏线粒体的结构和功能，最终导致线粒体损害，细胞色素C释放，从而启动细胞凋亡程序。TMT耳毒性主要表现在用药后迅速发生的高频听力损失，其最早期功能改变表现为听神经动作电位的反应阈升高，随后逐渐出现耳蜗微音器电位振幅的降低。因此，TMT对听觉系统的急性损伤部位很可能最早是发生在从内毛细胞到I型螺旋神经节的听神经末梢及其神经纤维，随着用药后时间的延长才会逐渐累及外毛细胞。TMT对周边听觉系统的损害作用包括兴奋性氨基酸毒性，氧化应激，细胞内钙超载，线粒体破坏，神经纤维脱髓鞘病变等多重损害机制，因此TMT模型可能有助于模拟和研究听神经病的多重损害模式。