POSSIBLE INVOLVEMENT OF A NEUROTROPHIC FACTOR DURING THE EARLY STAGESOF ORGANOPHOSPHATE-INDUCED DELAYED NEUROTOXICITY

Little is known regarding early biochemical events in organophosphate- induced delayed neurotoxicity (OPIDN) except for the essential inhibit ion of neurotoxic esterase (NTE). We hypothesized that a trophic facto r may be produced in situ shortly after exposure to the OF which parti cipates in the progression of OPIDN. To bioassay for such a growth-mod ulating factor(s), we treated chickens with the neuropathic agents dii sopropylfluorophosphate (DFP) or cyclic phenyl saligenin phosphate (PS P), with or without phenylmethylsulfonyl fluoride (PMSF, a chemical wh ich markedly modifies OPIDN). Soluble extracts of cervical spinal cord (a region of the nervous system which degenerates with OPIDN) were co llected 24 h later and these were incubated with human neuroblastoma S Y5Y cells in culture. The cells were allowed to grow for another 6 day s and observed for changes in morphology and growth. After 3 days in c ulture, tissue extracts from OF-treated chickens caused SY5Y cells to begin to elongate and extend processes (neurites), similar to cells tr eated with nerve growth factor(1 mu g/ml). Extracts from chickens not receiving OP had no or minimal effects on cell morphology. In addition , extracts from chickens in which OPIDN was prevented by pretreatment with PMSF did not cause the marked extension of cell processes exhibit ed after exposure of SY5Y cells to extracts from chickens given regime ns known to cause OPIDN. In parallel-treated animals, DFP and PSP caus ed clinical dysfunction characteristic of OPIDN, PMSF posttreatment ma rkedly amplified the clinical deficits and PMSF pretreatment prevented OPIDN. In vivo DFP treatment also caused a marked reduction in the ac tivity of the growth-related enzyme ornithine decarboxylase (ODC) in s pinal cord but DFP was without effect on ODC activity in vitro (up to 1 mM final concentration), Characterization of this growth-modulating factor(s) may aid in the elucidation of pathological mechanisms of OPI DN.