Although the neurotoxicity of
organophosphorus compounds is generally attributed to inhibition of
acetylcholinesterase, recent reports have indicated that direct interactions with
muscarinic receptors and signal transduction may be an additional mechanism of neurotoxicity. We have previously shown that the organophosphorus
insecticide O,O-diethyl O-3,5,6-trichloro-2-pyridinyl phosphorothioate (
chlorpyrifos) binds directly to
muscarinic receptors and inhibits
adenylate cyclase of rat striatum. We have further pursued those results in this study by investigating the effect of
chlorpyrifos oxon in NG108-15
neuroblastoma-
glioma cells and Chinese hamster ovary cells transfected with
cDNA for human m2 or
m4 muscarinic receptor subtypes. At millimolar concentrations,
chlorpyrifos oxon inhibited [3H]QNB binding in all cell lines. Likewise, [3H]CD binding was inhibited in NG108-15 and CHO-Hm2 cells. When the effect of
chlorpyrifos oxon on
adenylate cyclase was examined, the oxon was found to inhibit
adenylate cyclase at millimolar concentrations. Though this effect on cyclase required greater concentrations of oxon than the comparable effect in striatal cells, it displayed the common characteristic of being
atropine-insensitive, suggesting that the effect on cyclase was not
muscarinic receptor dependent. The inhibition of
adenylate cyclase produced by
chlorpyrifos oxon was not eliminated in
pertussis toxin treated cells, lending further support to the idea that it is not a receptor-mediated event, and suggesting a potential direct interaction of
chlorpyrifos oxon with the
adenylate cyclase molecule.