Interdisciplinary neurotoxicity inhalation studies: carbon disulfide and carbonyl sulfide research in F344 rats.
Interdisciplinary neurotoxicity inhalation studies: carbon disulfide and carbonyl sulfide research in F344 rats.
复制标题
DOI：
10.1016/j.taap.2005.02.037
复制
发表时间：
2005-09
影响因子：
3.8
通讯作者：
R. Sills;G. Harry;W. Valentine;D. Morgan
中科院分区：
文献类型：
--
作者：
R. Sills;G. Harry;W. Valentine;D. Morgan
对有害的空气污染物进行了吸入研究，其中包括针对中枢神经系统（脊髓）和周围神经系统（长髓鞘轴突的远端部分）的二硫化碳，以及针对中枢神经系统（大脑）的硫化羰。目的是通过对功能、结构和疾病机制的综合评价来研究这些化合物的神经毒性。通过跨学科研究，二硫化碳吸入研究的主要发现是二硫化碳在体内产生分子内和分子间蛋白质交联。在病变发生前观察到神经丝蛋白中的剂量依赖性共价交联与这一过程一致，这一过程有助于二硫化碳神经毒性特征性神经丝轴突损伤的发展。重要的是，大鼠珠蛋白上的缬氨酸-赖氨酸硫脲交联和红细胞血影蛋白上的赖氨酸-赖氨酸硫脲交联反映了轴突内发生的交联事件，并可能作为二硫化碳暴露和影响的生物标志物。在羰基硫研究中，使用磁共振显微镜（MRM），我们确定羰基硫靶向大脑中的听觉通路。MRM允许检查200个脑切片，并有可能确定最脆弱的神经毒性部位，这在我们传统的神经病理学评估中会被遗漏。电生理学研究集中在听觉系统，并证明听觉脑干诱发反应减少。类似地，机制研究集中于评估后丘和顶叶皮质中的细胞色素氧化酶活性。细胞色素氧化酶活性降低被认为是硫化羰神经毒性发病机制的一个促成因素。
Inhalation studies were conducted on the hazardous air pollutants, carbon disulfide, which targets the central nervous system (spinal cord) and peripheral nervous system (distal portions of long myelinated axons), and carbonyl sulfide, which targets the central nervous system (brain). The objectives were to investigate the neurotoxicity of these compounds by a comprehensive evaluation of function, structure, and mechanisms of disease. Through interdisciplinary research, the major finding in the carbon disulfide inhalation studies was that carbon disulfide produced intra- and intermolecular protein cross-linking in vivo. The observation of dose-dependent covalent cross-linking in neurofilament proteins prior to the onset of lesions is consistent with this process contributing to the development of the neurofilamentous axonal swellings characteristic of carbon disulfide neurotoxicity. Of significance is that valine–lysine thiourea cross-linking on rat globin and lysine–lysine thiourea cross-linking on erythrocyte spectrin reflect cross-linking events occurring within the axon and could potentially serve as biomarkers of carbon disulfide exposure and effect. In the carbonyl sulfide studies, using magnetic resonance microscopy (MRM), we determined that carbonyl sulfide targets the auditory pathway in the brain. MRM allowed the examination of 200 brain slices and made it possible to identify the most vulnerable sites of neurotoxicity, which would have been missed in our traditional neuropathology evaluations. Electrophysiological studies were focused on the auditory system and demonstrated decreases in auditory brain stem evoked responses. Similarly, mechanistic studies focused on evaluating cytochrome oxidase activity in the posterior colliculus and parietal cortex. A decrease in cytochrome oxidase activity was considered to be a contributing factor to the pathogenesis of carbonyl sulfide neurotoxicity.