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TOXICOLOGY

Chronic, Intermittent Exposure to Chlorpyrifos in Rats: Protracted Effects on Axonal Transport, Neurotrophin Receptors, Cholinergic Markers, and Information Processing

Departments of Pharmacology and Toxicology (A.V.T., D.A.G., W.D.B., J.N.T., J.J.B.) and Cell Biology and Anatomy (D.W.S.) and Program in Clinical and Experimental Therapeutics (M.-L.M.), University of Georgia College of Pharmacy, Augusta, Georgia; Department of Pharmaceutical and Biomedical Sciences, University of Georgia College of Pharmacy, Athens, Georgia (L.N.W., M.G.B.); Department of Psychology, University of Kentucky, Lexington, Kentucky (M.A.P.); and Department of Veterans Affairs Medical Center, Augusta, Georgia (J.J.B.)

Persistent behavioral abnormalities have been commonly associated with acute organophosphate (OP) pesticide poisoning; however, relatively little is known about the consequences of chronic OP exposures that are not associated with acute cholinergic symptoms. In this study, the behavioral and neurochemical effects of chronic, intermittent, and subthreshold exposures to the OP pesticide, chlorpyrifos (CPF), were investigated. Rats were injected with CPF s.c. (dose range, 2.5–18.0 mg/kg) every other day over the course of 30 days and then were given a 2-week CPF-free washout period. In behavioral experiments conducted during the washout period, dose-dependent decrements in a water-maze hidden platform task and a prepulse inhibition procedure were observed, without significant effects on open-field activity, Rotorod performance, grip strength, or a spontaneous novel object recognition task. After washout, levels of CPF and its metabolite 3,5,6-trichloro-2-pyridinol were minimal in plasma and brain; however, cholinesterase inhibition was still detectable. Furthermore, the 18.0 mg/kg dose of CPF was associated with (brain region-dependent) decreases in nerve growth factor receptors and cholinergic proteins including the vesicular acetylcholine transporter, the high-affinity choline transporter, and the ₇-nicotinic acetylcholine receptor. These deficits were accompanied by decreases in anterograde and retrograde axonal transport measured in sciatic nerves ex vivo. Thus, low-level (intermittent) exposure to CPF has persistent effects on neurotrophin receptors and cholinergic proteins, possibly through inhibition of fast axonal transport. Such neurochemical changes may lead to deficits in information processing and cognitive function.

Address correspondence to: Dr. Alvin V. Terry, Jr., Professor of Pharmacology and Toxicology, Director, Small Animal Behavior Core, CB-3618, Medical College of Georgia, 1120 Fifteenth St., Augusta, GA 30912-2300. E-mail: aterry{at}mcg.edu