Persistent cholinergic presynaptic deficits after neonatal chlorpyrifos exposure

The commonly-used organophosphate insecticide, chlorpyrifos (CPF), impairs brain cell development, axonogenesis and synaptogenesis. In the current stu dy, we administered CPF to neonatal rats on postnatal (PN) days 1-4 (1 mg/k g) or PN11-14 (5 mg/kg), treatments that were devoid of overt toxicity. We then examined two cholinergic synaptic markers, choline acetyltransferase a ctivity (ChAT) and [H-3]hemicholinium-3 binding (HC-3) in the hippocampus, midbrain, striatum, brainstem and cerebral cortex in the juvenile (PN30) an d young adult (PN60). Across all brain regions, CPF exposure evoked signifi cant reductions in both markers, with larger effects on HC-3 binding, which is responsive to neuronal impulse activity, than on ChAT, a constitutive m arker. Superimposed on the deficits, there were gender-selective effects an d distinct regional disparities in the critical exposure period for vulnera bility. In the hippocampus, either the early or late treatment regimen evok ed decreases in ChAT but the early regimen elicited a much larger decrease in HC-3; effects persisted into adulthood. In the midbrain, CPF administrat ion on PN1-4 elicited deficits similar to those seen in the hippocampus; ho wever, exposure on PN11-14 elicited changes preferentially in females. Gend er selectivity was also apparent in the striatum, in this case reflecting d eficits in females after CPF treatment on PN1-4. In contrast, the effects o f CPF on the brainstem were relatively more robust in males; effects in the cerebral cortex were less notable than in other regions. These results ind icate that neonatal CPF exposure produces widespread deficiencies in cholin ergic synaptic function that persist into adulthood. The effects are likely to contribute to gender-selective alterations in behavioral performance th at persist or emerge long after the termination of exposure and well after the restoration of cholinesterase activity. (C) 2001 Elsevier Science BN. A ll rights reserved.