[A review of studies of the delayed neurotoxicity induced by organophosphorus esters].
Organophosphorus esters have been used in the plastics industry as antioxidants and plasticizers, in agriculture as insecticides, and in the military as nerve agents. Some of these compounds have organophosphorus ester-induced delayed neurotoxicity (OPIDN) different from the acute toxicity caused by the acetylcholine esterase inhibiting activity. this review describes recent progress in studies on OPIDN and, discusses the future direction of studies. OPIDN is characterized by a more than 7 day incubation period, lower limb paralysis accompanied by axonal degeneration, and age- and species-specificity. Younger animals and rodents are not very sensitive to OPIDN. As well as fast recovery of inhibited neurotoxic esterase or neuropathy target esterase (NTE) in the sciatic nerve, detoxicating mechanisms including carboxylesterases are contributing to age- and species-specificity for OPIDN. Although, anterograde axonal transport does not seem to be affected by OPIDN, slow down of retrograde axonal transport was observed. Inhibition of NTE, and aging of inhibited NTE has been thought to be responsible for OPIDN, but there are some arguments against the role of NTE in OPIDN. Phosphorylation of cytoskeletal proteins by kinases such as calcium dependent-calmodulin kinase II and/or high affinity neurotoxic compound binding site(s) are possible candidates for the initiation of OPIDN. Triphenyl phophite (TPP), a compound commonly used in the plastics industry, has delayed neurotoxicity that is somewhat different from OPIDN. The onset of TPP-induced neuropathy is earlier than that of OPIDN, and rodents are sensitive to TPP. In addition to the axonal damage, cell damage is observed in TPP-induced neuropathy. Mitochondrial energy metabolism-related enzymes could be the target of this neuropathy. Future studies should be focused on the relation of OPIDN to the phosphorylation of cytoskeletal proteins and high affinity binding site(s), and on the development of rodent models. These studies would answer the questions related to OPIDN, and further contribute toward elucidating the pathogenesis of degenerative neuronal diseases.
Department of Public Health, Akita University School of Medicine, Japan.
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Katoh
D000375:Aging; D000818:Animals; D001370:Axonal Transport / Q000187:drug effects; D002265:Carboxylic Ester Hydrolases / Q000378:metabolism; D004734:Energy Metabolism; D004952:Esters; D006801:Humans; D009422:Nervous System Diseases / Q000139:chemically induced*; D009943:Organophosphorus Compounds / Q000009:adverse effects* / Q000633:toxicity; D017905:Phosphites / Q000009:adverse effects / Q000633:toxicity; D013045:Species Specificity
D004952:Esters; D009943:Organophosphorus Compounds; D017905:Phosphites; C013318:triphenyl phosphite; D002265:Carboxylic Ester Hydrolases; C021859:neurotoxic esterase