title: Diisopropylfluorophosphate Impairs the Transport of Membrane-Bound Organelles in Rat Cortical Axons.
abstract: The extensive use of organophosphates (OPs) is an ongoing environmental health concern due to multiple reports of OP-related neurologic abnormalities. The mechanism of the acute toxicity of OPs has been attributed to inhibition of acetylcholinesterase (AChE), but there is growing evidence that this may not account for all the long-term neurotoxic effects of OPs. In previous experiments (using ex vivo and in vitro model systems) we observed that the insecticide OP chlorpyrifos impaired the movements of vesicles and mitochondria in axons. Here, using a time-lapse imaging technique, we evaluated the OP-nerve agent diisopropylfluorophosphate (DFP) across a wide range of concentrations (subnanomolar to micromolar) for effects on fast axonal transport of membrane-bound organelles (MBOs) that contain the amyloid precursor protein (APP) tagged with the fluorescent marker Dendra2 (APPDendra2). Both 1 and 24 hours of exposure to DFP and a positive control compound, colchicine, resulted in a decrease in the velocity of anterograde and retrograde movements of MBOs and an increase in the number of stationary MBOs. These effects occurred at picomolar (100 pM) to low nanomolar (0.1 nM) concentrations that were not associated with compromised cell viability or cytoskeletal damage. Moreover, the effects of DFP on axonal transport occurred at concentrations that did not inhibit AChE activity, and they were not blocked by cholinergic receptor antagonists. Given the fundamental importance of axonal transport to neuronal function, these observations may explain some of the long-term neurologic deficits that have been observed in humans who have been exposed to OPs.
authors.affiliation: Department of Pharmacology and Toxicology, Georgia Regents University, Augusta, Georgia (J.G., V.S., S.X.N., W.D.B., B.T., N.A.K., C.M.H., A.V.T.); Department of Pharmacology, University of California-Davis, Davis, California (H.W.); Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, New York (J.M.).
authors.forename: Jie
authors.initials: J
authors.lastname: Gao
authors.affiliation: Department of Pharmacology and Toxicology, Georgia Regents University, Augusta, Georgia (J.G., V.S., S.X.N., W.D.B., B.T., N.A.K., C.M.H., A.V.T.); Department of Pharmacology, University of California-Davis, Davis, California (H.W.); Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, New York (J.M.).
authors.forename: Sean X
authors.initials: SX
authors.lastname: Naughton
authors.affiliation: Department of Pharmacology and Toxicology, Georgia Regents University, Augusta, Georgia (J.G., V.S., S.X.N., W.D.B., B.T., N.A.K., C.M.H., A.V.T.); Department of Pharmacology, University of California-Davis, Davis, California (H.W.); Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, New York (J.M.).
authors.forename: Heike
authors.initials: H
authors.lastname: Wulff
authors.affiliation: Department of Pharmacology and Toxicology, Georgia Regents University, Augusta, Georgia (J.G., V.S., S.X.N., W.D.B., B.T., N.A.K., C.M.H., A.V.T.); Department of Pharmacology, University of California-Davis, Davis, California (H.W.); Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, New York (J.M.).
authors.forename: Vikrant
authors.initials: V
authors.lastname: Singh
authors.affiliation: Department of Pharmacology and Toxicology, Georgia Regents University, Augusta, Georgia (J.G., V.S., S.X.N., W.D.B., B.T., N.A.K., C.M.H., A.V.T.); Department of Pharmacology, University of California-Davis, Davis, California (H.W.); Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, New York (J.M.).
authors.forename: Wayne D
authors.initials: WD
authors.lastname: Beck
authors.affiliation: Department of Pharmacology and Toxicology, Georgia Regents University, Augusta, Georgia (J.G., V.S., S.X.N., W.D.B., B.T., N.A.K., C.M.H., A.V.T.); Department of Pharmacology, University of California-Davis, Davis, California (H.W.); Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, New York (J.M.).
authors.forename: Jordi
authors.initials: J
authors.lastname: Magrane
authors.affiliation: Department of Pharmacology and Toxicology, Georgia Regents University, Augusta, Georgia (J.G., V.S., S.X.N., W.D.B., B.T., N.A.K., C.M.H., A.V.T.); Department of Pharmacology, University of California-Davis, Davis, California (H.W.); Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, New York (J.M.).
authors.forename: Bobby
authors.initials: B
authors.lastname: Thomas
authors.affiliation: Department of Pharmacology and Toxicology, Georgia Regents University, Augusta, Georgia (J.G., V.S., S.X.N., W.D.B., B.T., N.A.K., C.M.H., A.V.T.); Department of Pharmacology, University of California-Davis, Davis, California (H.W.); Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, New York (J.M.).
authors.forename: Navneet Ammal
authors.initials: NA
authors.lastname: Kaidery
authors.affiliation: Department of Pharmacology and Toxicology, Georgia Regents University, Augusta, Georgia (J.G., V.S., S.X.N., W.D.B., B.T., N.A.K., C.M.H., A.V.T.); Department of Pharmacology, University of California-Davis, Davis, California (H.W.); Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, New York (J.M.).
authors.forename: Caterina M
authors.initials: CM
authors.lastname: Hernandez
authors.affiliation: Department of Pharmacology and Toxicology, Georgia Regents University, Augusta, Georgia (J.G., V.S., S.X.N., W.D.B., B.T., N.A.K., C.M.H., A.V.T.); Department of Pharmacology, University of California-Davis, Davis, California (H.W.); Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, New York (J.M.) aterry@gru.edu.
authors.forename: Alvin V
authors.initials: AV
authors.lastname: Terry
mesh_terms: D000818:Animals; D001369:Axons / Q000187:drug effects* / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D002462:Cell Membrane / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000633:toxicity; D005260:Female; D007531:Isoflurophate / Q000633:toxicity*; D015388:Organelles / Q000187:drug effects* / Q000378:metabolism; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D002800:Cholinesterase Inhibitors; D007531:Isoflurophate