title: Organophosphates induce distal axonal damage, but not brain oedema, by inactivating neuropathy target esterase.
abstract: Single doses of organophosphorus compounds (OP) which covalently inhibit neuropathy target esterase (NTE) can induce lower-limb paralysis and distal damage in long nerve axons. Clinical signs of neuropathy are evident 3weeks post-OP dose in humans, cats and chickens. By contrast, clinical neuropathy in mice following acute dosing with OPs or any other toxic compound has never been reported. Moreover, dosing mice with ethyloctylphosphonofluoridate (EOPF) - an extremely potent NTE inhibitor - causes a different (subacute) neurotoxicity with brain oedema. These observations have raised the possibility that mice are intrinsically resistant to neuropathies induced by acute toxic insult, but may incur brain oedema, rather than distal axonal damage, when NTE is inactivated. Here we provide the first report that hind-limb dysfunction and extensive axonal damage can occur in mice 3weeks after acute dosing with a toxic compound, bromophenylacetylurea. Three weeks after acutely dosing mice with neuropathic OPs no clinical signs were observed, but distal lesions were present in the longest spinal sensory axons. Similar lesions were evident in undosed nestin-cre:NTEfl/fl mice in which NTE had been genetically-deleted from neural tissue. The extent of OP-induced axonal damage in mice was related to the duration of NTE inactivation and, as reported in chickens, was promoted by post-dosing with phenylmethanesulfonylfluoride. However, phenyldipentylphosphinate, another promoting compound in chickens, itself induced in mice lesions different from the neuropathic OP type. Finally, EOPF induced subacute neurotoxicity with brain oedema in both wild-type and nestin-cre:NTEfl/fl mice indicating that the molecular target for this effect is not neural NTE.
authors.affiliation: University of Leicester, Leicester LE1 9HN, UK.
authors.forename: David J
authors.initials: DJ
authors.lastname: Read
authors.forename: Yong
authors.initials: Y
authors.lastname: Li
authors.forename: Moses V
authors.initials: MV
authors.lastname: Chao
authors.forename: John B
authors.initials: JB
authors.lastname: Cavanagh
authors.forename: Paul
authors.initials: P
authors.lastname: Glynn
mesh_terms: D000818:Animals; D001369:Axons / Q000187:drug effects* / Q000201:enzymology; D001929:Brain Edema / Q000139:chemically induced; D001930:Brain Injuries / Q000139:chemically induced / Q000201:enzymology; D002265:Carboxylic Ester Hydrolases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D006614:Hindlimb / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology; D010755:Organophosphates / Q000633:toxicity*; D014508:Urea / Q000031:analogs & derivatives* / Q000633:toxicity
chemical_list: D010755:Organophosphates; C004506:4-bromophenylacetylurea; D014508:Urea; D002265:Carboxylic Ester Hydrolases; C021859:neurotoxic esterase