THE NEUROTOXICOLOGY OF CARBON DISULFIDE & 2,5-HEXANEDION

在过去的20年里，人们越来越担心 工业用有机溶剂的神经毒性。例如, 二硫化碳(CD)、2，5-己二酮(2，5-HD)和丙烯酰胺 与暴露工人的多发性神经病的爆发有关。在其中的每一个中 人体失调，暴露于毒素会导致远端退行性变 与远端神经丝堆积相关的轴突 影响神经纤维。然而，这些轴突产生的机制 它们对人类的神经毒性尚不清楚。在这些动物模型中 紊乱，神经生物学的方法可以澄清机制和 这些毒性神经病的后果。例如，我们对 丙烯酰胺强烈提示神经原纤维轴突病理 由轴突运输缓慢的缺陷所致，尤其是 神经丝蛋白。我们的假设是，类似的变化 神经丝运输可能导致神经纤维性病变 发生在2，5-HD和CD神经病中。为了研究这个问题，辐射测量， 凝胶荧光照相和形态测量技术将被用来评估 特定多肽在慢轴突转运系统中的转运 并将这些变化与发生的轴突病理联系起来 在CD和2，5-HD曝光之后。我们建议大剂量、短期的 服用这两种毒素会导致类似于 发生在急性丙烯酰胺中毒时，而在后期， 当发生远端轴突变性时，会有二次反应。 神经元对轴突损伤的影响。我们的研究旨在区分 这些物质对轴突继发后果的直接毒性影响 受伤。对中毒性神经原纤维轴突形成机制的认识 精神障碍对理解神经毒性具有重要意义 已知会导致人类神经系统疾病的常用有机溶剂。

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.