Chronic, intermittent exposure to chlorpyrifos in rats: protracted effects on axonal transport, neurotrophin receptors, cholinergic markers, and information processing.
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 alpha(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.
Terry
Alvin V
AV
Department of Pharmacology and Toxicology, University of Georgia College of Pharmacy, Augusta, Georgia 30912-2300, USA. aterry@mcg.edu
Gearhart
Debra A
DA
Beck
Wayne D
WD
Truan
Jacob N
JN
Middlemore
Mary-Louise
ML
Williamson
Leah N
LN
Bartlett
Michael G
MG
Prendergast
Mark A
MA
Sickles
Dale W
DW
Buccafusco
Jerry J
JJ
D000818:Animals; D001370:Axonal Transport / Q000187:drug effects*; D015415:Biomarkers; D004390:Chlorpyrifos / Q000494:pharmacology* / Q000633:toxicity; D002800:Cholinesterase Inhibitors; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D007306:Insecticides; D018782:Maze Learning / Q000187:drug effects; D026901:Membrane Transport Proteins / Q000187:drug effects*; D051381:Rats; D017475:Receptors, Nerve Growth Factor / Q000187:drug effects*; D011978:Receptors, Nicotinic / Q000187:drug effects*; D013997:Time Factors; D050494:Vesicular Acetylcholine Transport Proteins / Q000187:drug effects*; D064569:alpha7 Nicotinic Acetylcholine Receptor
D015415:Biomarkers; D002800:Cholinesterase Inhibitors; C579165:Chrna7 protein, rat; D007306:Insecticides; D026901:Membrane Transport Proteins; D017475:Receptors, Nerve Growth Factor; D011978:Receptors, Nicotinic; D050494:Vesicular Acetylcholine Transport Proteins; D064569:alpha7 Nicotinic Acetylcholine Receptor; C065637:choline transporter; D004390:Chlorpyrifos