Neonatal chlorpyrifos exposure alters synaptic development and neuronal activity in cholinergic and catecholaminergic pathways.
After routine home application of chlorpyrifos (CPF), infant and child exposures can exceed acceptable levels. We treated neonatal rats daily on postnatal days (PN) 1-4 (1 mg/kg) or days 11-14 (5 mg/kg), treatments that evoked no overt signs of toxicity. Effects on the development of cholinergic neuronal function were assessed using choline acetyltransferase (ChAT) activity and hemicholinium-3 (HC-3) binding as indices of synaptic proliferation and synaptic activity, respectively. In the forebrain, early CPF treatment caused a decrease in ChAT without affecting HC-3 binding; late treatment decreased HC-3 binding without affecting ChAT. In the brainstem, early treatment had no effect on either parameter but late treatment decreased both ChAT and HC-3 binding. Effects of CPF were not limited to development of cholinergic synapses but also involved catecholamine pathways. For norepinephrine or dopamine, either early or late CPF treatment evoked an increase in synaptic activity (transmitter turnover). The cerebellum, a region with sparse cholinergic innervation, was affected the most. Effects on catecholamine systems were unrelated to the magnitude or temporal pattern of cholinesterase inhibition. Our results suggest that CPF exposure during the postnatal period of synaptogenesis elicits widespread disruption of cholinergic and catecholaminergic pathways. As this is the period in which patterns of synaptic responsiveness is programmed by neural input, the period of developmental vulnerability to CPF is likely to extend into childhood.
Dam
K
K
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Box 3813 DUMC, Durham, NC 27710, USA.
Garcia
S J
SJ
Seidler
F J
FJ
Slotkin
T A
TA
D000818:Animals; D000831:Animals, Newborn; D001933:Brain Stem / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D002395:Catecholamines / Q000378:metabolism*; D002531:Cerebellum / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D004390:Chlorpyrifos / Q000633:toxicity*; D002795:Choline O-Acetyltransferase / Q000378:metabolism*; D002800:Cholinesterase Inhibitors / Q000633:toxicity*; D004298:Dopamine / Q000378:metabolism; D006426:Hemicholinium 3 / Q000378:metabolism; D009474:Neurons / Q000187:drug effects*; D009638:Norepinephrine / Q000378:metabolism; D016548:Prosencephalon / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013569:Synapses / Q000187:drug effects*
D002395:Catecholamines; D002800:Cholinesterase Inhibitors; D006426:Hemicholinium 3; D002795:Choline O-Acetyltransferase; D004390:Chlorpyrifos; D004298:Dopamine; D009638:Norepinephrine