TY - JOUR
T1 - Diisopropylfluorophosphate impairs the transport of membrane-bound organelles in rat cortical axons
AU - Gao, Jie
AU - Naughton, Sean X.
AU - Wulff, Heike
AU - Singh, Vikrant
AU - Beck, Wayne D.
AU - Magrane, Jordi
AU - Thomas, Bobby
AU - Kaidery, Navneet Ammal
AU - Hernandez, Caterina M.
AU - Terry, Alvin V.
N1 - Publisher Copyright:
Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.
PY - 2016/3/1
Y1 - 2016/3/1
N2 - The extensive use of organophosphates (OPs) is an ongoing environmental health concern due to multiple reports of OPrelated 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.
AB - The extensive use of organophosphates (OPs) is an ongoing environmental health concern due to multiple reports of OPrelated 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.
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U2 - 10.1124/jpet.115.230839
DO - 10.1124/jpet.115.230839
M3 - Article
C2 - 26718240
AN - SCOPUS:84958986432
SN - 0022-3565
VL - 356
SP - 645
EP - 655
JO - The Journal of pharmacology and experimental therapeutics
JF - The Journal of pharmacology and experimental therapeutics
IS - 3
ER -