title: Repeated exposure to chlorpyrifos leads to prolonged impairments of axonal transport in the living rodent brain.
abstract: The toxicity of the class of chemicals known as the organophosphates (OP) is most commonly attributed to the inhibition of the enzyme acetylcholinesterase. However, there is significant evidence that this mechanism may not account for all of the deleterious neurologic and neurobehavioral symptoms of OP exposure, especially those associated with levels that produce no overt signs of acute toxicity. In the study described here we evaluated the effects of the commonly used OP-pesticide, chlorpyrifos (CPF) on axonal transport in the brains of living rats using manganese (Mn(2+))-enhanced magnetic resonance imaging (MEMRI) of the optic nerve (ON) projections from the retina to the superior colliculus (SC). T1-weighted MEMRI scans were evaluated at 6 and 24h after intravitreal injection of Mn(2+). As a positive control for axonal transport deficits, initial studies were conducted with the tropolone alkaloid colchicine administered by intravitreal injection. In subsequent studies both single and repeated exposures to CPF were evaluated for effects on axonal transport using MEMRI. As expected, intravitreal injection of colchicine (2.5μg) produced a robust decrease in transport of Mn(2+) along the optic nerve (ON) and to the superior colliculus (SC) (as indicated by the reduced MEMRI contrast). A single subcutaneous (s.c.) injection of CPF (18.0mg/kg) was not associated with significant alterations in the transport of Mn(2+). Conversely, 14-days of repeated s.c. exposure to CPF (18.0mg/kg/day) was associated with decreased transport of Mn(2+) along the ONs and to the SC, an effect that was also present after a 30-day (CPF-free) washout period. These results indicate that repeated exposures to a commonly used pesticide, CPF can result in persistent alterations in axonal transport in the living mammalian brain. Given the fundamental importance of axonal transport to neuronal function, these observations may (at least in part) explain some of the long term neurological deficits that have been observed in humans who have been repeatedly exposed to doses of OPs not associated with acute toxicity.
authors.affiliation: Department of Pharmacology and Toxicology, Georgia Regents University, Augusta, GA 30912, United States.
authors.forename: Caterina M
authors.initials: CM
authors.lastname: Hernandez
authors.affiliation: Department of Pharmacology and Toxicology, Georgia Regents University, Augusta, GA 30912, United States.
authors.forename: Wayne D
authors.initials: WD
authors.lastname: Beck
authors.affiliation: Department of Pharmacology and Toxicology, Georgia Regents University, Augusta, GA 30912, United States.
authors.forename: Sean X
authors.initials: SX
authors.lastname: Naughton
authors.affiliation: Department of Pharmacology and Toxicology, Georgia Regents University, Augusta, GA 30912, United States.
authors.forename: Indrani
authors.initials: I
authors.lastname: Poddar
authors.affiliation: Department of Pharmacology and Toxicology, Georgia Regents University, Augusta, GA 30912, United States.
authors.forename: Bao-Ling
authors.initials: BL
authors.lastname: Adam
authors.affiliation: Core Imaging Facility for Small Animals (CIFSA), Georgia Regents University, Augusta, GA 30912, United States.
authors.forename: Nathan
authors.initials: N
authors.lastname: Yanasak
authors.affiliation: Core Imaging Facility for Small Animals (CIFSA), Georgia Regents University, Augusta, GA 30912, United States.
authors.forename: Chris
authors.initials: C
authors.lastname: Middleton
authors.affiliation: Department of Pharmacology and Toxicology, Georgia Regents University, Augusta, GA 30912, United States. Electronic address: aterry@gru.edu.
authors.forename: Alvin V
authors.initials: AV
authors.lastname: Terry
mesh_terms: D000110:Acetylcholinesterase / Q000032:analysis; D000818:Animals; D001370:Axonal Transport / Q000187:drug effects*; D001921:Brain / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D004390:Chlorpyrifos / Q000633:toxicity*; D003287:Contrast Media; D007306:Insecticides / Q000633:toxicity*; D008279:Magnetic Resonance Imaging; D008297:Male; D008345:Manganese; D009900:Optic Nerve / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014795:Visual Pathways / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism
chemical_list: D003287:Contrast Media; D007306:Insecticides; D008345:Manganese; D000110:Acetylcholinesterase; D004390:Chlorpyrifos
keywords: Alzheimer's disease; Gulf War Illness; Manganese enhanced magnetic resonance imaging; Organophosphate; Pesticide