Interdisciplinary neurotoxicity inhalation studies: Carbon disulfide and carbonyl sulfide research in F344 rats

ArticleinToxicology and Applied Pharmacology 207(2 Suppl):245-50 · October 2005with7 Reads
DOI: 10.1016/j.taap.2005.02.037 · Source: PubMed
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.
    • "Other important pathways that have been perturbed by exposure to COS implicate apoptosis, vascular response, and inflammation, which fit with the morphological changes that subsequently develop as a result of exposure. Other hypotheses have been proposed for carbonyl sulfide neurotoxicity (Morgan et al. 2004; Nutt et al. 1996; Sills et al. 2005). Previous studies by our group using a range of COS concentrations in rats have shown decreases in mitochondrial cytochrome oxidase c activity in the posterior colliculus at time points of three weeks or more of exposure to COS, suggesting that inhibition of oxidative phosphorylation may also contribute to neuronal cell death. "
    [Show abstract] [Hide abstract] ABSTRACT: Carbonyl sulfide (COS) is an odorless gas that produces highly reproducible lesions in the central nervous system. In the present study, the time course for the development of the neurotoxicological lesions was defined and the gene expression changes occurring in the posterior colliculus upon exposure to COS were characterized. Fischer 344 rats were exposed to 0 or 500 ppm COS for one, two, three, four, five, eight, or ten days, six hours per day. On days 1 and 2, no morphological changes were detected; on day 3, 10/10 (100%) rats had necrosis in the posterior colliculi; and on day 4 and later, necrosis was observed in numerous areas of the brain. Important gene expression changes occurring in the posterior colliculi after one or two days of COS exposure that were predictive of the subsequent morphological findings included up-regulation of genes associated with DNA damage and G1/S checkpoint regulation (KLF4, BTG2, GADD45g), apoptosis (TGM2, GADD45g, RIPK3), and vascular mediators (ADAMTS, CTGF, CYR61, VEGFC). Proinflammatory mediators (CCL2, CEBPD) were up-regulated prior to increases in expression of the astrocytic marker GFAP and macrophage marker CSF2rb1. These gene expression findings were predictive of later CNS lesions caused by COS exposure and serve as a model for future investigations into the mechanisms of disease in the central nervous system.
    Full-text · Article · May 2009
    • "Even general pathologists are familiar if not expert with the usual battery of procedures used to perform a postmortem anatomic assessment of neural integrity. However, newer techniques combining structural evaluation with region-specific molecular and functional analyses have substantially improved the potential for assembling a truly integrated picture of the nervous system in health and disease (Sills et al. 2005 ). It behooves us as biomedical researchers to have an understanding of the strengths and limitations of these newer techniques. "
    [Show abstract] [Hide abstract] ABSTRACT: Our understanding of the mechanisms that incite neurological diseases has progressed rapidly in recent years, mainly owing to the advent of new research instruments and our increasingly facile ability to assemble large, complex data sets acquired across several disciplines into an integrated representation of neural function at the molecular, cellular, and systemic levels. This mini-review has been designed to communicate the principal technical advances and current issues of importance in neuropathology research today in the context of our traditional neuropathology practices. Specific topics briefly addressed in this paper include correlative biology of the many facets of the nervous system; conventional and novel methods for investigating neural structure and function; theoretical and technical issues associated with investigating neuropathology end points in emerging areas of concern (developmental neurotoxicity, neurodegenerative conditions); and challenges and opportunities that will face pathologists in this field in the foreseeable future. We have organized this information in a manner that we hope will be of interest not only to professionals with a career focus in neuropathology, but also to general pathologists who occasionally face neuropathology questions.
    Full-text · Article · Oct 2008
  • [Show abstract] [Hide abstract] ABSTRACT: Carbonyl sulfide (COS), a chemical listed by the original Clean Air Act, was tested for neurotoxicity by a National Institute of Environmental Health Sciences/National Toxicology Program and U.S. Environmental Protection Agency collaborative investigation. Previous studies demonstrated that COS produced cortical and brainstem lesions and altered auditory neurophysiological responses to click stimuli. This paper reports the results of expanded neurophysiological examinations that were an integral part of the previously published experiments (Morgan et al., 2004, Toxicol. Appl. Pharmacol. 200, 131-145; Sills et al., 2004, Toxicol. Pathol. 32, 1-10). Fisher 334N rats were exposed to 0, 200, 300, or 400 ppm COS for 6 h/day, 5 days/week for 12 weeks, or to 0, 300, or 400 ppm COS for 2 weeks using whole-body inhalation chambers. After treatment, the animals were studied using neurophysiological tests to examine: peripheral nerve function, somatosensory-evoked potentials (SEPs) (tail/hindlimb and facial cortical regions), brainstem auditory-evoked responses (BAERs), and visual flash-evoked potentials (2-week study). Additionally, the animals exposed for 2 weeks were examined using a functional observational battery (FOB) and response modification audiometry (RMA). Peripheral nerve function was not altered for any exposure scenario. Likewise, amplitudes of SEPs recorded from the cerebellum were not altered by treatment with COS. In contrast, amplitudes and latencies of SEPs recorded from cortical areas were altered after 12-week exposure to 400 ppm COS. The SEP waveforms were changed to a greater extent after forelimb stimulation than tail stimulation in the 2-week study. The most consistent findings were decreased amplitudes of BAER peaks associated with brainstem regions after exposure to 400 ppm COS. Additional BAER peaks were affected after 12 weeks, compared to 2 weeks of treatment, indicating that additional regions of the brainstem were damaged with longer exposures. The changes in BAERs were observed in the absence of altered auditory responsiveness in FOB or RMA. This series of experiments demonstrates that COS produces changes in brainstem auditory and cortical somatosensory neurophysiological responses that correlate with previously described histopathological damage.
    Full-text · Article · Feb 2007
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