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Characterization of Carbon Disulfide Neurotoxicity in C57BL6 Mice: Behavioral, Morphologic, and Molecular Effects

Environmental Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709

W.M. Valentine

Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee 37232

V. Moser

Neurotoxicology Division, National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, Research Triangle Park, North Carolina 27711

D.G. Graham

Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee 37232

D.L. Morgan

Environmental Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709

Female C57BL6 mice were exposed to 0 or 800 ppm carbon disulfide (CS₂), 6 h/d, 5 d/wk for 20 weeks. The neurologic function of all mice was assessed once at the end of exposures using a functional observational battery. General health effects included a decrease in body weight gain, piloerection, hunched body posture, and ptosis. Treatment-related effects included altered gait (uncoordinated placement of hind limbs and ataxia) and impaired function on an inverted screen test. In addition, rearing and locomotor movement were decreased in treated mice. Focal to multifocal axonal swelling was seen predominantly in the muscular branch of the posterior tibial nerve, and occasionally giant axonal swelling was detected in the lumbar segment of the spinal cord. Electron microscopic examination revealed swollen axons with massive accumulation of neurofilament proteins within the axoplasm. Covalent cross-linking of erythrocyte spectrin (surrogate protein to neurofilament protein) was demonstrated in mice exposed to CS₂ but not in mice receiving filtered air. These data provide supportive evidence that covalent cross-linking of neurofilament proteins is a significant feature of the axonal swellings in mice produced by inhalation exposure to CS₂.

Key Words: Peripheral neuropathy • functional observational battery • cross-linking spectrin • neurofilament proteins • carbon disulfide • axonal swelling • C57BL6 mice

Toxicologic Pathology, Vol. 28, No. 1, 142-148 (2000)
DOI: 10.1177/019262330002800118


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