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Neonatal chlorpyrifos exposure alters synaptic development and neuronal activity in cholinergic and catecholaminergic
K Dam1, S J Garcia, F J Seidler
1Department of Pharmacology and Cancer Biology, Duke University Medical Center, Box 3813 DUMC, Durham, NC 27710, USA.
Insights
Chlorpyrifos (CPF) exposure in neonatal rats disrupts brain development, affecting both cholinergic and catecholaminergic pathways. This developmental neurotoxicity suggests a prolonged vulnerability window for children.
Area of Science:
- Neuroscience
- Developmental Toxicology
- Environmental Health
Background:
- Infant and child exposure to chlorpyrifos (CPF) can exceed safe levels following routine home use.
- Developmental neurotoxicity of pesticides is a significant public health concern.
Purpose of the Study:
- To investigate the effects of early-life chlorpyrifos (CPF) exposure on the developing cholinergic and catecholaminergic systems in neonatal rats.
- To determine the impact of CPF on synaptic development and function during critical periods of synaptogenesis.
Main Methods:
- Neonatal rats were treated with CPF on postnatal days 1-4 or 11-14 at doses that did not cause overt toxicity.
- Choline acetyltransferase (ChAT) activity and hemicholinium-3 (HC-3) binding were measured as indices of cholinergic synapse development and activity.
- Catecholamine pathways (norepinephrine, dopamine) were assessed via transmitter turnover to evaluate synaptic activity.
Main Results:
- CPF exposure altered cholinergic function differently in the forebrain and brainstem depending on the timing of exposure.
- Both early and late CPF treatments increased catecholamine synaptic activity (transmitter turnover).
- The cerebellum showed the most significant effects, and impacts on catecholamine systems were independent of cholinesterase inhibition levels.
Conclusions:
- Postnatal CPF exposure disrupts the development of both cholinergic and catecholaminergic pathways during synaptogenesis.
- These disruptions suggest a critical window of developmental vulnerability to CPF that may extend into childhood.
- CPF's neurodevelopmental effects highlight the need for caution regarding pesticide exposure in early life.
Abstract:
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.