title: Potentiation of organophosphorus-induced delayed neurotoxicity following phenyl saligenin phosphate exposures in 2-, 5-, and 8-week-old chickens.
abstract: Phenylmethylsulfonyl fluoride (PMSF), a nonneuropathic inhibitor of neurotoxic esterase (NTE), is a known potentiator of organophosphorus-induced delayed neurotoxicity (OPIDN). The ability of PMSF posttreatment (90 mg/kg, sc, 4 hr after the last PSP injection) to modify development of delayed neurotoxicity was examined in 2-, 5-, and 8-week-old White Leghorn chickens treated either one, two, or three times (doses separated by 24 hr) with the neuropathic OP compound phenyl saligenin phosphate (PSP, 5 mg/kg, sc). NTE activity was measured in the cervical spinal cord 4 hr after the last PSP treatment. Development of delayed neurotoxicity was measured over a 16-day postexposure period. All PSP-treated groups exhibited > 97% NTE inhibition regardless of age or number of OP treatments. Two-week-old birds did not develop clinical signs of neurotoxicity in response to either single or repeated OP treatment regimens nor following subsequent treatment with PMSF. Five-week-old birds were resistant to the clinical effects of a single PSP exposure and were minimally affected by repeated doses. PMSF posttreatment, however, significantly amplified the clinical effects of one, two, or three doses of PSP. A single exposure to PSP induced slight to moderate signs of delayed neurotoxicity in 8-week-old birds with more extensive neurotoxicity being noted following repeated dosing. As with 5-week-old birds, PMSF exacerbated the clinical signs of neurotoxicity when given after one, two, or three doses of PSP in 8-week-old birds. Axonal degeneration studies supported the clinical findings: PMSF posttreatment did not influence the degree of degeneration in 2-week-old chickens but resulted in more severe degeneration (relative to PSP only exposure) in cervical cords from both 5- and 8-week-old birds. The results indicate that PMSF does not alter the progression of delayed neurotoxicity in very young (2 weeks of age) chickens but potentiates PSP-induced delayed neurotoxicity in the presence of 0-3% residual NTE activity in older animals. We conclude that posttreatment with neuropathic or nonneuropathic NTE inhibitors, following virtually complete NTE inhibition by either single or repeated doses of a neuropathic agent in sensitive age groups, can modify both the clinical and morphological indices of delayed neurotoxicity. This study further supports the hypothesis that potentiation of OPIDN occurs through a mechanism unrelated to NTE.
authors.affiliation: Division of Toxicology, College of Pharmacy and Health Sciences, Northeast Louisiana University, Monroe 71209, USA.
authors.forename: P
authors.initials: P
authors.lastname: Harp
authors.forename: D
authors.initials: D
authors.lastname: Tanaka
authors.forename: C N
authors.initials: CN
authors.lastname: Pope
mesh_terms: D000367:Age Factors; D000818:Animals; D001369:Axons / Q000187:drug effects / Q000473:pathology; D002265:Carboxylic Ester Hydrolases / Q000037:antagonists & inhibitors*; D002645:Chickens; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000633:toxicity*; D005260:Female; D007531:Isoflurophate / Q000031:analogs & derivatives* / Q000633:toxicity; D009943:Organophosphorus Compounds / Q000633:toxicity*; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced*; D010664:Phenylmethylsulfonyl Fluoride / Q000633:toxicity*; D013116:Spinal Cord / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology
chemical_list: D004791:Enzyme Inhibitors; D009943:Organophosphorus Compounds; D007531:Isoflurophate; C005238:mipafox; C046357:phenylsaligenin cyclic phosphate; D010664:Phenylmethylsulfonyl Fluoride; D002265:Carboxylic Ester Hydrolases; C021859:neurotoxic esterase