Possible role of endogenous protein phosphorylation in organophosphorus compound-induced delayed neurotoxicity.
Abou-Donia-MB; Patton-SE; Lapadula-DM
Cellular and molecular neurotoxicity: satellite symposium Cellular and Molecular Neurotoxicity of Environmental Agents, Aug. 26-27, 1983, San Diego, California. Narahashi T, ed. New York: Raven Press, 1984 Sep; :265-283
The effect of organophosphorus compounds on in-vitro phosphorylation of brain and spinal cord synaptosomal cytosol and membranes was studied in the chicken. Proteins isolated from Leghorn-hen and male Sprague-Dawley-rat differed in molecular weight and calcium-2+ (Ca2+) and calmodulin phosphorylation dependency. Roosters given a single oral dose of 750mg/kg tri-o-cresyl-phosphate (78308) (TOCP) displayed ataxia on day seven after treatment, which advanced to complete paralysis by day 14. On autopsy, swelling, vacuolation, and fragmentation of axons and myelin sheaths were observed in the spinal column and sciatic nerves. Phosphorylation of cytosolic proteins of molecular weight 70 and 55 kilodaltons (kD) and membrane protein of 20kD increased by 149%, 196% and 146%, respectively, after treatment. A correlation between severity of ataxia and increased Ca2+ dependency was observed for the 55kD protein. Hens treated with 750mg/kg TOCP displayed ataxia from day seven, paralysis by day 21 and improvement after day 28. Weight loss of 37% was noted at day 35. Phosphorylation of the 55kD and 70kD brain cytosol proteins peaked on day 14 and decreased on day 21. Spinal cord cytosol brain membrane 50kD and 60kD protein phosphorylation peaked on day seven. Hens treated with leptophos (21609905) displayed earlier and more severe neurological effects with brain cytosolic protein phosphorylation significantly increased over TOCP treated animals. No neurological or phosphorylation effects were seen in rats or chicks 21 days after TOCP treatment. Increased phosphorylation of brain, but not spinal cord, axolemmal proteins in the presence of added Ca2+ and calmodulin was observed in TOCP treated hens. The authors conclude that increased phosphorylation of the 55kD band, tentatively identified as tubulin, is associated with the observed neurological effects.
NIOSH-Grant; Neurotoxic-effects; Organo-phosphorus-compounds; Organo-phosphorus-pesticides; Central-nervous-system; Laboratory-animals; Anticholinesterase-insecticides; Enzyme-inhibitors
Pharmacology Duke University Department of Pharmacology Durham, N C 27710
Cellular and molecular neurotoxicity: satellite symposium Cellular and Molecular Neurotoxicity of Environmental Agents, Aug. 26-27, 1983, San Diego, California
Duke University, Durham, North Carolina