Sills Robert C, Harry G Jean, Valentine William M, Morgan Daniel L
Laboratory of Experimental Pathology, National Institute of Environmental Health Sciences, 111 Alexander Drive, South Campus, MD B3-08, PO Box 12233, Research Triangle Park, NC 27709, USA.
Toxicol Appl Pharmacol. 2005 Sep 1;207(2 Suppl):245-50. doi: 10.1016/j.taap.2005.02.037.
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.
对有害空气污染物二硫化碳和羰基硫进行了吸入研究。二硫化碳作用于中枢神经系统（脊髓）和周围神经系统（有髓长轴突的远端部分），羰基硫作用于中枢神经系统（大脑）。目的是通过对疾病的功能、结构和机制进行全面评估，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剂量依赖性的共价交联，这与该过程导致二硫化碳神经毒性特征性的神经丝状轴突肿胀的发展是一致的。重要的是，大鼠球蛋白上的缬氨酸 - 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，并有可能作为二硫化碳暴露和效应的生物标志物。在羰基硫研究中，使用磁共振显微镜（MRM），我们确定羰基硫作用于大脑中的听觉通路。MRM允许检查200个脑切片，并能够识别神经毒性最脆弱的部位，而这些部位在我们传统的神经病理学评估中会被遗漏。电生理研究集中在听觉系统，结果表明听觉脑干诱发反应降低。同样，机制研究集中在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的降低被认为是羰基硫神经毒性发病机制的一个促成因素。
