Developmental neurotoxic effects of chlorpyrifos on acetylcholine and serotonin pathways in an avian model.
The developmental neurotoxicity of organophosphates such as chlorpyrifos (CPF) involves multiple mechanisms that ultimately compromise the function of specific neurotransmitter systems, notably acetylcholine (ACh) and serotonin (5-hydroxytryptamine, 5HT). Studies in mammalian models incorporate both direct effects on brain development and indirect effects mediated through maternal physiology and maternal/neonatal interactions. We examined the effects of CPF in an avian model, which does not share these potential confounds. Chick eggs were injected with CPF (10 or 20 mg/kg) on incubation days 2 and 6 and markers of ACh and 5HT systems were examined at hatching. The higher dose caused a reduction in cholinesterase activity but there was no consistent downregulation of m(2)-muscarinic ACh receptors as would have been expected from ACh hyperstimulation. Both doses evoked significant reductions in the presynaptic high-affinity choline transporter, the rate-limiting factor in ACh biosynthesis, as monitored by binding of hemicholinium-3. Choline acetyltransferase, a constitutive marker for ACh terminals, was unaffected. This suggests that CPF reduces ACh presynaptic activity rather than compromising the development of ACh projections per se. CPF exposure also reduced the expression of cerebrocortical 5HT(1A) receptors. These effects in the chick model recapitulate many of the actions of early gestational CPF exposure in rats, and thus suggest that CPF exerts direct actions on the immature brain to compromise the development of ACh and 5HT pathways.
Slotkin
Theodore A
TA
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA. t.slotkin@duke.edu
Seidler
Frederic J
FJ
Ryde
Ian T
IT
Yanai
Joseph
J
D000014:Abnormalities, Drug-Induced / Q000473:pathology; D000109:Acetylcholine / Q000378:metabolism*; D000110:Acetylcholinesterase / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001667:Binding, Competitive / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects* / Q000254:growth & development / Q000503:physiopathology; D001923:Brain Chemistry / Q000187:drug effects* / Q000502:physiology; D002642:Chick Embryo; D002645:Chickens; D004390:Chlorpyrifos / Q000633:toxicity*; D002800:Cholinesterase Inhibitors / Q000633:toxicity; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D009434:Neural Pathways / Q000187:drug effects* / Q000254:growth & development / Q000503:physiopathology; D009498:Neurotoxins / Q000633:toxicity; D010063:Ovum / Q000187:drug effects; D011869:Radioligand Assay; D043585:Receptor, Muscarinic M2 / Q000187:drug effects / Q000378:metabolism; D044282:Receptor, Serotonin, 5-HT1A / Q000187:drug effects / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D018675:Toxicity Tests; D050494:Vesicular Acetylcholine Transport Proteins / Q000187:drug effects / Q000378:metabolism
D002800:Cholinesterase Inhibitors; D009498:Neurotoxins; D043585:Receptor, Muscarinic M2; D050494:Vesicular Acetylcholine Transport Proteins; D044282:Receptor, Serotonin, 5-HT1A; D012701:Serotonin; D000110:Acetylcholinesterase; D004390:Chlorpyrifos; D000109:Acetylcholine