title: Repeated, intermittent exposures to diisopropylfluorophosphate in rats: protracted effects on cholinergic markers, nerve growth factor-related proteins, and cognitive function.
abstract: Organophosphates (OPs) pose a constant threat to human health due to their widespread use as pesticides and their potential employment in military and terrorist attacks. The acute toxicity of OPs has been extensively studied; however, the consequences of prolonged or repeated exposure to levels of OPs that produce no overt signs of acute toxicity (i.e. subthreshold levels) are poorly understood. Further, there is clinical evidence that such repeated exposures to OPs lead to prolonged deficits in cognition, although the mechanism for this effect is unknown. In this study, the behavioral and neurochemical effects of repeated, intermittent, and subthreshold exposures to the alkyl OP, diisopropylfluorophosphate (DFP) were investigated. Rats were injected with DFP s.c. (dose range, 0.25-1.0 mg/kg) every other day over the course of 30 days, and then given a 2 week, DFP-free washout period. In behavioral experiments conducted at various times during the washout period, dose dependent decrements in a water maze hidden platform task and a spontaneous novel object recognition (NOR) procedure were observed, while prepulse inhibition of the acoustic startle response was unaffected. There were modest decreases in open field locomotor activity and grip strength (particularly during the DFP exposure period); however, rotarod performance and water maze swim speeds were not affected. After washout, DFP concentrations were minimal in plasma and brain, however, cholinesterase inhibition was still detectable in the brain. Moreover, the 1.0 mg/kg dose of DFP was associated with (brain region-dependent) alterations in nerve growth factor-related proteins and cholinergic markers. The results of this prospective animal study thus provide evidence to support two novel hypotheses: (1) that intermittent, subthreshold exposures to alkyl OPs can lead to protracted deficits in specific domains of cognition and (2) that such cognitive deficits may be related to persistent functional changes in brain neurotrophin and cholinergic pathways.
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta, GA 30912, USA. aterry@mcg.edu
authors.forename: A V
authors.initials: AV
authors.lastname: Terry
authors.forename: J J
authors.initials: JJ
authors.lastname: Buccafusco
authors.forename: D A
authors.initials: DA
authors.lastname: Gearhart
authors.forename: W D
authors.initials: WD
authors.lastname: Beck
authors.forename: M-L
authors.initials: ML
authors.lastname: Middlemore-Risher
authors.forename: J N
authors.initials: JN
authors.lastname: Truan
authors.forename: G M
authors.initials: GM
authors.lastname: Schwarz
authors.forename: M
authors.initials: M
authors.lastname: Xu
authors.forename: M G
authors.initials: MG
authors.lastname: Bartlett
authors.forename: A
authors.initials: A
authors.lastname: Kutiyanawala
authors.forename: A
authors.initials: A
authors.lastname: Pillai
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage / Q000032:analysis / Q000633:toxicity*; D003071:Cognition / Q000187:drug effects*; D015151:Immunoblotting; D007531:Isoflurophate / Q000008:administration & dosage / Q000032:analysis / Q000633:toxicity*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009414:Nerve Growth Factors / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
chemical_list: D002800:Cholinesterase Inhibitors; D009414:Nerve Growth Factors; D007531:Isoflurophate; D002795:Choline O-Acetyltransferase; D000109:Acetylcholine