Department of Biology, William Jewell College, Liberty, Missouri 64068, USA.
Toxicol Sci. 2021 Apr 12;180(2):342-355. doi: 10.1093/toxsci/kfaa193.
Tributyltin (TBT) remains a global health concern. The primary route of human exposure to TBT is either through ingestion or skin absorption, but TBT's effects on the peripheral nervous system have still not been investigated. Therefore, we exposed in vitro sensory dorsal root ganglion (DRG) neurons to TBT at a concentration of 50-200 nM, which is similar to the observed concentrations of TBT in human blood samples. We observed that TBT causes extensive axon degeneration and neuronal death in the DRG neurons. Furthermore, we discovered that TBT causes an increase in both cytosolic and mitochondrial calcium levels, disrupts mitochondrial dynamics, decreases neuronal ATP levels, and leads to the activation of calpains. Additional experiments demonstrated that inhibition of calpain activation prevented TBT-induced fragmentation of neuronal cytoskeletal proteins and neuronal cell death. Thus, we conclude that calpain activation is the key executioner of TBT-induced peripheral neurodegeneration.
三丁基锡（TBT）仍然是一个全球性的健康问题。人类接触 TBT 的主要途径是摄入或皮肤吸收，但 TBT 对周围神经系统的影响尚未得到研究。因此，我们将体外感觉背根神经节（DRG）神经元暴露于浓度为 50-200 nM 的 TBT 中，这与在人类血液样本中观察到的 TBT 浓度相似。我们观察到 TBT 导致 DRG 神经元中的广泛轴突退化和神经元死亡。此外，我们发现 TBT 导致细胞溶质和线粒体钙水平升高，破坏线粒体动力学，降低神经元 ATP 水平，并导致钙蛋白酶的激活。进一步的实验表明，抑制钙蛋白酶的激活可防止 TBT 诱导的神经元细胞骨架蛋白碎裂和神经元细胞死亡。因此，我们得出结论，钙蛋白酶的激活是 TBT 诱导的周围神经退行性变的关键执行者。
