Differential profiles of cholinesterase inhibition and neurobehavioral effects in rats exposed to fenamiphos or profenofos.
The relationship between cholinesterase (ChE) inhibition and neurobehavioral changes was examined using two ChE-inhibiting organophosphorus (OP) pesticides, fenamiphos and profenofos. Both pesticides produce considerable blood ChE inhibition, but relatively little brain inhibition up to almost lethal doses. Interestingly, pronounced neurobehavioral signs were produced by fenamiphos but not profenofos. After a single oral dose, both pesticides greatly inhibited blood ChE (87-98% inhibition), yet whole brain ChE was only inhibited by 9-14% at the highest doses. Fenamiphos produced dose-dependent effects on many behavioral measures. Despite the similar ChE inhibition profile, profenofos produced no observable changes in behavior. Treatment with anticholinergic drugs was used to evaluate the contribution of peripheral versus central ChE inhibition. Scopolamine (SCO) and methylscopolamine (MSC) were used as central/peripheral and peripheral-only cholinergic receptor blockers, respectively, in combination with fenamiphos. Neither drug altered the effects of fenamiphos on ChE inhibition. Some behavioral effects of fenamiphos were blocked or attenuated only by SCO, whereas other effects were blocked by both drugs. These data indicate that some of the pronounced neurobehavioral changes observed following fenamiphos dosing may be centrally mediated (blocked by SCO only), despite the small amount of inhibition of brain ChE. Other behavioral changes may be mediated more peripherally (blocked by both MSC and SCO). To test the hypothesis that regionally specific ChE inhibition may be responsible for these effects, the same dose of fenamiphos used in the previous studies was given and one half of the brain was dissected into regions. There was significant ChE inhibition in the pons and medulla, cerebellum, striatum, hippocampus, and half-brain but not in the rest-of-brain and frontal cortex; however, the magnitude of inhibition was relatively small across the regions measured. Thus, the centrally mediated neurobehavioral effects of fenamiphos could not be explained based on differential regional brain ChE inhibition alone. Despite the low level of brain ChE inhibition, some behavioral effects of fenamiphos were centrally mediated, and there was little regional specificity of ChE inhibition that could account for the behavioral changes observed.
McDaniel
Katherine L
KL
Neurotoxicology Division (Mail Code B105-04), National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA.
Moser
Virginia C
VC
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D002802:Cholinesterases / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D004347:Drug Interactions; D008297:Male; D009043:Motor Activity / Q000187:drug effects*; D018727:Muscarinic Antagonists / Q000494:pharmacology; D019832:N-Methylscopolamine / Q000494:pharmacology; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D063086:Organothiophosphates / Q000494:pharmacology*; D051381:Rats; D020318:Rats, Long-Evans; D012472:Salivation / Q000187:drug effects; D012601:Scopolamine / Q000494:pharmacology; D014018:Tissue Distribution / Q000187:drug effects; D014202:Tremor / Q000209:etiology
D002800:Cholinesterase Inhibitors; D018727:Muscarinic Antagonists; D009943:Organophosphorus Compounds; D063086:Organothiophosphates; C024273:profenofos; D012601:Scopolamine; D002802:Cholinesterases; C002698:fenamiphos; D019832:N-Methylscopolamine