Interdisciplinary neurotoxicity inhalation studies: Carbon disulfide and carbonyl sulfide research in F344 rats
- 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 (United States)
- Laboratory of Neurobiology, National Institute of Environmental Health Sciences, 111 Alexander Drive, South Campus, PO Box 12233, Research Triangle Park, NC 27709 (United States)
- Department of Pathology and Center in Molecular Toxicology, Vanderbilt University Medical Center, Nashville, TN 37232 (United States)
- Laboratory of Molecular Toxicology, NIEHS, Research Triangle Park, NC 27709 (United States)
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.
- OSTI ID:
- 20721916
- Journal Information:
- Toxicology and Applied Pharmacology, Vol. 207, Issue 2,suppl.1; Conference: ICT X 2004: 10. international congress of toxicology: Living in a safe chemical world, Tampere (Finland), 11-15 Jul 2004; Other Information: DOI: 10.1016/j.taap.2005.02.037; PII: S0041-008X(05)00325-X; Copyright (c) 2005 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); ISSN 0041-008X
- Country of Publication:
- United States
- Language:
- English
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