Cystoskeletal proteins as targets for organophosphorus compound and aliphatic hexacarbon-induced neurotoxicity.
Abou-Donia-MB; Lapadula-DM; Suwita-E
Toxicology 1988 May; 49(2/3):469-477
Studies of the mechanisms of organophosphorus induced delayed neurotoxicity (OPIDN) and aliphatic hexacarbon induced neurotoxicity were summarized. OPIDN was investigated by administering 0 or 750 milligrams per kilogram tri-o-cresyl-phosphate (78308) (TOCP) to adult Leghorn-hens. Aliphatic hexacarbon induced neurotoxicity was studied in male Sprague-Dawley-rats which were given 0 to 1 percent 2,5-hexanedione (110134) (25HD) in their drinking water for 70 days. The animals were killed at various times, the brains, spinal cords, or sciatic nerves were removed, neurofilament, microtubule, cytoskeletal protein, cold/stable microtubule, and cytosolic and membrane bound protein preparations were made, and these were examined by one or two dimensional gel electrophoresis, immunoblotting, and immunoreactive techniques. The extent of calcium ion (Ca+2) and calmodulin dependent kinase protein phosphorylation was determined. TOCP induced delayed neurotoxicity in hens and increased Ca+2 and calmodulin dependent kinase phosphorylation of cytoskeletal proteins in the brain, spinal cord, and sciatic nerve. The greatest increase occurred in the sciatic nerve, followed by the spinal cord and brain in that order. These proteins were identified as alpha-tubulin, beta-tubulin, microtubulin associated protein-2, and more basic proteins having molecular weights on the order of 50 to 65 kilodaltons. Adenosine- triphosphatase activity was not affected by TOCP. The pattern of phosphorylation suggested that the increased protein phosphorylation was due to changes in calmodulin-kinase-II activity. In rats 25HD induced protein cross linking of neurofilaments in the spinal cord in a dose dependent manner. The extent of phosphorylation of neurofilament proteins was also decreased. The authors conclude that the mechanisms of OPIDN and hexacarbon induced neurotoxicity involve alterations in cytoskeletal proteins.
NIOSH-Publication; NIOSH-Grant; Organo-phosphorus-compounds; Ketones; Neurotoxic-effects; In-vivo-studies; Laboratory-animals; Protein-chemistry; Enzyme-activity; Laboratory-techniques
Pharmacology Duke University Department of Pharmacology Durham, N C 27710
Neurotoxic Disorders; Neurotoxic-effects
Duke University, Durham, North Carolina