Alterations in rat axonal cytoskeletal proteins induced by in vitro and in vivo 2,5-hexanedione exposure.
Toxicol Appl Pharmacol 1985 Apr; 78(2):235-247
The effects of 2,5-hexanedione (110134) on axonal cytoskeletal proteins were studied in rats. Male Wistar-rats were administered 8 weeks, or for 8 weeks plus a 9 week recovery period. The animals were observed for clinical symptoms and weighed at the end of the study. The animals were killed and assayed for histopathologic changes in the peripheral and central nervous systems. Serum and axonal cytoskeletal proteins from the central nervous system were isolated. Axonal cytoskeletal proteins were studied by polyacrylamide gel electrophoresis. Serum and axonal cytoskeletal proteins were assayed for pyrrole adduct formation. Experimental rats gained weight at slower rates than control animals. Rats treated for 5 or 8 weeks with 2,5-hexadione showed ataxia and hindlimb paralysis. Swollen and degenerating axons were observed in the peripheral and central nervous systems. Nine weeks of recovery reversed the peripheral nerve damage, but had no effect on central nervous system damage. Gel electrophoresis detected discrete new protein bands in brain stem and spinal cord axonal protein preparations, and high molecular weight nonmigrating proteinaceous material in all treated animals. The concentration of nonproteinaceous material increased with length of exposure. Nine weeks of recovery reversed these changes. A 2,5-dimethyl-pyrrole adduct was detected in serum and axonal cytoskeletal protein in all treated animals after 2 weeks. Nine weeks of recovery after the 8 week exposure resulted in the pyrrole adduct disappearing from serum proteins; however, residual amounts of the adduct were still present in axonal cytoskeletal proteins. The authors conclude that the mechanism of action of 2,5-hexanedione and other gamma diketones involves the formation of pyrrole in axonal proteins.
NIOSH-Publication; NIOSH-Grant; Neurotoxic-effects; Cytology; Cytotoxins; Quantitative-analysis; Cytolysis; Cytotoxic-effects; Protein-chemistry; Proteins; Toxic-materials; Toxicology; Toxins; Toxic-effects
Biochem and Genetic Toxicology New York State Dept of Health Empire State Plaza Albany, N Y 12201
Neurotoxic Disorders; Neurotoxic-effects
Toxicology and Applied Pharmacology
New York State Dept of Health, New York, New York