THE NEUROTOXICOLOGY OF CARBON DISULFIDE & 2,5-HEXANEDION

在过去的20年里，人们越来越关注 工业中使用的某些有机溶剂的神经毒性。 比如说， 二硫化碳（CD）、2，5-己二酮（2，5-HD）和丙烯酰胺已被 与暴露工人多发性神经病的爆发有关。 在这些 人类疾病，暴露于毒素导致远端变性 轴突与神经丝的积累在远端部分 影响神经纤维 然而，这些轴突产生的机制 其对人类的神经毒性尚不清楚。 在这些动物模型中， 神经生物学方法可以阐明机制， 这些毒性神经病变的后果。 例如，我们对 丙烯酰胺强烈表明， 由缓慢的轴突运输缺陷引起，特别是 神经丝蛋白 我们的假设是 神经丝的运输可能导致神经病理学 发生在2，5-HD和CD神经病中。 为了研究这个问题，辐射测量， 凝胶荧光和形态测定技术将用于评估 在慢轴突运输系统内特定多肽的运输 并将这些变化与轴突病理学的发生联系起来， CD和2，5-HD曝光后。 我们建议大剂量短期 这两种毒素的施用将导致类似于 那些发生在急性丙烯酰胺中毒，而在后期， 当远端轴突变性发生时， 轴突损伤的神经元。 我们的研究旨在区分 这些药物的直接毒性作用来自轴突的继发性后果， 损伤 了解导致毒性神经轴突损伤的机制 疾病对理解神经毒性有重要意义， 通常使用的有机溶剂已知产生人类神经疾病。

During the past 20 years, there have been increasing concerns over the neurotoxicity of some organic solvents used in industry. For example, carbon disulfide (CD), 2,5-hexanedione (2,5-HD), and acrylamide have been linked to outbreaks of polyneuropathy in exposed workers. In each of these human disorders, exposure to the toxin results in degeneration of distal axons associated with accumulations of neurofilaments in distal portions of affected nerve fibers. However, the mechanism by which these axons produce their neurotoxicity in humans is unknown. In animal models of these disorders, neurobiological approaches can clarify the mechanisms and consequences of these toxic neuropathies. For example, our studies of acrylamide strongly suggest that the neurofibrillary axonal pathology results from a defect in slow axonal transport, particularly of neurofilament proteins. Our hypothesis is that similar alterations in transport of neurofilaments may result in the neurofibrillary pathology occurring in 2,5-HD and CD neuropathies. To study this issue, radiometric, gel fluorographic, and morphometric techniques will be used to assess the transport of specific polypeptides within the slow axonal transport system and to correlate these changes with the axonal pathology occurring following CD and 2,5-HD exposures. We suggest that high-dose, short-term administration of these two toxins will result in abnormalities similar to those occurring in acute acrylamide intoxication, while, at later stages, when distal axonal degeneration occurs, there will be a secondary response of neurons to axonal injury. Our studies are designed to differentiate the direct toxic affects of these agents from secondary consequences of axonal injury. Knowledge of mechanisms leading to toxic neurofibrillary axonal disorders has important implications for understanding the neurotoxicity of commonly used organic solvents known to produce human neurological disease.