Neurotoxicity and Ototoxicity of Trimethyltin

Jintao Yu; Dalian Ding; Hong Sun; Shankai Yin; Richard Salvi

doi:10.3969/j.issn.1672-2922.2013.04.030

Abstract：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.