Organophosphates induce distal axonal damage, but not brain oedema, by inactivating neuropathy target esterase

Journal Article · Sat May 15 00:00:00 EDT 2010 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2010.02.010· OSTI ID:21344953

Read, David J; Yong, Li ^[1]; Chao, Moses V ^[2]; Cavanagh, John B ^[3]; Glynn, Paul ^[1]

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1. MRC Toxicology Unit, University of Leicester, Hodgkin Building, Lancaster Road, Leicester LE1 9HN (United Kingdom)
2. Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, NY 10016 (United States)
3. Department of Clinical Neuroscience, Institute of Psychiatry, London SE5 8AF (United Kingdom)

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 3 weeks 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 3 weeks 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.

• OSTI ID: 21344953
• Journal Information: Toxicology and Applied Pharmacology, Vol. 245, Issue 1; Other Information: DOI: 10.1016/j.taap.2010.02.010; PII: S0041-008X(10)00061-X; Copyright (c) 2010 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
BRAIN
CHICKENS
DAMAGE
DOSES
ESTERASES
HYDROLASES
INACTIVATION
LIMBS
MEN
MICE
NERVE CELLS
ORGANIC PHOSPHORUS COMPOUNDS
SERINE
TOXICITY
AMINO ACIDS
ANIMAL CELLS
ANIMALS
BIRDS
BODY
CARBOXYLIC ACIDS
CENTRAL NERVOUS SYSTEM
ENZYMES
FOWL
HYDROXY ACIDS
MALES
MAMMALS
MAN
NERVOUS SYSTEM
ORGANIC ACIDS
ORGANIC COMPOUNDS
ORGANS
PRIMATES
PROTEINS
RODENTS
SOMATIC CELLS
VERTEBRATES