title: Progressive deficit of retrograde axonal transport is associated with the pathogenesis of di-n-butyl dichlorvos axonopathy.
abstract: The induction of central-peripheral distal axonopathy in hens singly dosed with some organophosphorus (OP) compounds, such as di-n-butyl-2,2-dichlorovinyl phosphate (DBDCVP), requires greater than 80% organophosphorylation and subsequent intramolecular rearrangement ("aging") of a protein [neuropathy target esterase (NTE)] in the axon. Suprathreshold biochemical reaction, 24 h after dosing with DBDCVP (0.75-1.00 mg/kg s.c.), is shown to be associated with progressive decrement of retrograde axonal transport in sensory and motor fibers. The maximum transport deficit (about 70% reduction) is reached 7 days after DBDCVP, prior to the appearance of axonal degeneration and the onset of clinical signs of neuropathy (day 10-11). By contrast, phenylmethylsulfonyl fluoride (30 mg/kg s.c.), an agent that prevents the development of OP neuropathy by inhibiting NTE without the "aging" reaction, had no effect on axon transport, nerve fiber integrity, or clinical status and, when administered prior to a neurotoxic dose of DBDCVP (1.00 mg/kg s.c.), prevented DBDCVP effects. Paraoxon (0.2 mg/kg s.c.) neither inhibited NTE nor caused deficits in retrograde transport or neuropathy. Taken in concert, these studies demonstrate that induced deficits in retrograde transport are associated with the pathogenesis of OP-induced nerve-fiber degeneration and the threshold-initiating mechanism thereof.
mesh_terms: D000818:Animals; D001370:Axonal Transport / Q000187:drug effects*; D001369:Axons / Q000378:metabolism*; D002265:Carboxylic Ester Hydrolases / Q000378:metabolism; D002645:Chickens; D004006:Dichlorvos / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D007700:Kinetics; D009410:Nerve Degeneration / Q000187:drug effects; D010261:Paraoxon / Q000494:pharmacology; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D010664:Phenylmethylsulfonyl Fluoride / Q000494:pharmacology; D013744:Tetanus Toxin / Q000378:metabolism
chemical_list: D013744:Tetanus Toxin; C053753:di-n-butyl-2,2-dichlorovinyl phosphate; D010664:Phenylmethylsulfonyl Fluoride; D004006:Dichlorvos; D002265:Carboxylic Ester Hydrolases; C021859:neurotoxic esterase; D010261:Paraoxon