POTENTIATION OF ORGANOPHOSPHORUS-INDUCED DELAYED NEUROTOXICITY FOLLOWING PHENYL SALIGENIN PHOSPHATE EXPOSURES IN 2, 5, AND 8-WEEK-OLD CHICKENS

Phenylmethylsulfonyl fluoride (PMSF), a nonneuropathic inhibitor of ne urotoxic esterase (NTE), is a known potentiator of organophosphorus-in duced delayed neurotoxicity (OPIDN). The ability of PMSF posttreatment (90 mg/kg, sc, 4 hr after the last PSP injection) to modify developme nt of delayed neurotoxicity was examined in 2-, 5-, and 8-week-old Whi te Leghorn chickens treated either one, hire, or three times (doses se parated by 24 hr) with the neuropathic OP compound phenyl saligenin ph osphate (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 numb er of OP treatments, Two-week-old birds did not develop clinical signs of neurotoxicity in response to either single or repeated OP treatmen t 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, ho wever, significant amplified the clinical effects of one, two, or thre e doses of PSP, A single exposure to PSP induced slight to moderate si gns of delayed neurotoxicity in S-week-old birds with more extensive n eurotoxicity being noted following repeated dosing. As with 5-week-old birds, PMSF exacerbated the clinical signs of neurotoxicity when give n after one, two, or three doses of PSP in 8-week-old birds. Axonal de generation studies supported the clinical findings: PMSF posttreatment did not influence the degree of degeneration in 2-week-old chickens b ut resulted in more severe degeneration (relative to PSP only exposure ) in cervical cords from both 5- and 8-week-old birds. The results ind icate that PMSF does not alter the progression of delayed neurotoxicit y 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 non neuropathic NTE inhibitors, following virtually complete NTE inhibitio n by either single or repeated doses of a neuropathic agent in sensiti ve age groups, can modify bath the clinical and morphological indices of delayed neurotoxicity. This study further supports the hypothesis t hat potentiation of OPIDN occurs through a mechanism unrelated to NTE. (C) 1997 Society of Toxicology.