title: Subacute neurotoxicity induced in mice by potent organophosphorus neuropathy target esterase inhibitors.
abstract: The mouse is considered to be insensitive and the hen sensitive to clinical expression of organophosphorus-induced delayed neuropathy (OPIDN) which is associated with inhibition of neuropathy target esterase (NTE). This species difference is reevaluated with two optimized inhibitors of hen brain NTE by examining them for potential neurotoxic effects in mice. 2-Octyl-4H-1,3,2-benzodioxaphosphorin 2-oxide (OBDPO) and ethyl octylphosphonofluoridate (EOPF) inhibit mouse brain NTE in vitro by 50% at 0.12 and 0.02 nM and induce neurotoxic signs in mice at 10 and 5 mg/kg, respectively. The action of these compounds in both l- and 6-month-old mice, sometimes after early transient cholinergic signs, involves ataxia, paralysis, and death in 1 to 3 days and is accordingly referred to as subacute neurotoxicity. The neurotoxic signs are associated with brain edema and severe vacuolation in the grey matter of the brain and spinal cord, particularly the neuropile. Subacute neurotoxic signs are always associated with at least 80% inhibition of brain NTE activity 16-24 hr after treatment. Acetylcholinesterase and butyrylcholinesterase are much less sensitive than NTE to inhibition by OBDPO and EOPF both in vitro and in vivo. Selected carbamates, thiocarbamates, phosphinates, and sulfanyl fluorides are prophylactic agents and dipentyl 2,2-dichlorovinyl phosphate is a promoter for OBDPO-induced subacute neurotoxicity. Although this type of neurotoxicity in mice is similar to OPIDN in the correlation with NTE inhibition and the prophylactic action of reversible NTE inhibitors, it differs from OPIDN in the delay time prior to onset, the sensitivity of both young and old animals, and the high incidence of fatality. A full neuropathological study is desirable to further characterize this subacute neurotoxicity.
authors.affiliation: Environmental Chemistry and Toxicology Laboratory, Department of Environmental Science, Policy, and Management, University of California, Berkeley 94720-3112, USA.
authors.forename: S Y
authors.initials: SY
authors.lastname: Wu
authors.forename: J E
authors.initials: JE
authors.lastname: Casida
mesh_terms: D000818:Animals; D001259:Ataxia / Q000139:chemically induced; D015415:Biomarkers / Q000097:blood / Q000652:urine; D001921:Brain / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D001929:Brain Edema / Q000139:chemically induced; D002265:Carboxylic Ester Hydrolases / Q000037:antagonists & inhibitors*; D002800:Cholinesterase Inhibitors / Q000633:toxicity; D004791:Enzyme Inhibitors / Q000633:toxicity*; D007531:Isoflurophate / Q000031:analogs & derivatives / Q000633:toxicity; D008297:Male; D051379:Mice; D009943:Organophosphorus Compounds / Q000633:toxicity*; D010243:Paralysis / Q000139:chemically induced; D010261:Paraoxon / Q000633:toxicity; D012584:Sciatic Nerve / Q000187:drug effects / Q000473:pathology; D013116:Spinal Cord / Q000187:drug effects / Q000473:pathology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C092561:2-octyl-4H-1,3,2-benzodioxaphosphorin-2-oxide; D015415:Biomarkers; D002800:Cholinesterase Inhibitors; D004791:Enzyme Inhibitors; D009943:Organophosphorus Compounds; C100419:ethyl octylphosphonofluoridate; D007531:Isoflurophate; C005238:mipafox; D002265:Carboxylic Ester Hydrolases; C021859:neurotoxic esterase; D010261:Paraoxon