The developmental neurotoxicity of organophosphorus insecticides: a direct role for the oxon metabolites.

ABSTRACT

Several extensively used organophosphorus ester (OP) insecticides are phosphorothionates. The oxon metabolites of phosphorothionates have long been known to be responsible for the acute cholinergic neurotoxicity associated with OP poisoning. In addition, there is now sufficient evidence to suggest that the oxon metabolites may also be directly responsible for the particular neurotoxicity that phosphorothionate insecticides, and especially chlorpyrifos (CP) and diazinon (DZ), are known to inflict on the developing organism. In vitro data reveal that the oxons, which are present at increased levels in the developing brain, have the ability to directly disrupt, at toxicologically relevant doses, separately a number of neurodevelopmental processes, including those of neuronal proliferation, neuronal differentiation, gliogenesis and apoptosis. In most cases, the effects of the oxons are very potent. Inhibition of neuronal and glial cell differentiation by the oxons in particular is up to 1000-times stronger than that caused by their parent phosphorothionates. The neurodevelopmental toxicity of the oxons is not related to the inhibition of the enzymatic activity of acetylcholinesterase (AChE), but may be due to direct oxon interference with the morphogenic activity that AChE normally shows during neurodevelopment. Other possible direct targets of the oxons include neurodevelopmentally important cell signaling molecules and cytoskeletal proteins which have been found to be affected by the oxons and to which covalent binding of the oxons has been recently shown. Future studies should aim at confirming the developmental neurotoxic capacity of the oxons under in vivo conditions and they must also be extended to include OP parent insecticides with a P=O moiety.