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ToxSci Advance Access published online on January 12, 2005
Toxicological Sciences, doi:10.1093/toxsci/kfi081
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Toxicological Sciences © Society of Toxicology 2005; all rights reserved.
Received November 16, 2004
Accepted January 5, 2005

Neurotoxicology

Effects of Repeated Oral Postnatal Exposure to Chlorpyrifos on Cholinergic Neurochemistry in Developing Rats

Jason R. Richardson 1 and Janice E. Chambers 1*

1 Center for Environmental Health Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi State, MS 39762

* To whom correspondence should be addressed.
Janice E. Chambers, E-mail: chambers{at}cvm.msstate.edu


  Abstract

The neurochemical effects of repeated postnatal exposure to chlorpyrifos (CPS) were studied in developing rats. Rats were gavaged daily from postnatal day (PND) 1-21 with CPS in corn oil starting at 1.5 mg/kg (low dosage group) and increasing gradually to 3 mg/kg and then to 6 mg/kg (high dosage group). Brain cholinesterase (ChE) activity was significantly inhibited on PND6,12, 22 and 30, with maximum inhibition on PND6 of 49 and 59% and recovering to 18 and 33% on PND30 in the low and high dosage groups, respectively. On PND22 and 30, 94% or greater of the inhibited ChE could not be reactivated by the oxime TMB-4 in both treatment groups, indicating aging of the phosphorylated ChE. Total muscarinic acetylcholine receptors (mAChR) were reduced in a dose-related manner on PND12 and 22, with substantial recovery by PND30. M1/M3 mAChR were significantly reduced on PND6 and 12 only in the high dosage group, and on PND22 in both groups, while M2/M4 mAChR were reduced in the high dosage group on PND22 and 30. On PND30 choline acetyltransferase activity and vesicular acetylcholine transporter levels were decreased by 12 and 22%, respectively, only in the high dosage group. High-affinity choline transporter levels were decreased at all time points in the high dosage group and on PND6, 22, and 30 in the low dosage group. The results presented here demonstrate that repeated postnatal exposures to CPS result in transient reductions of mAChR and more persistent alternations of presynaptic cholinergic neurons. In addition, the long-term reduction of brain ChE activity observed following repeated postnatal exposure to CPS is attributable to permanent inactivation or "aging" of the enzyme.

Keywords: developmental neurotoxicity; chlorpyrifos; choline acetyltransferase; organophosphate "aging"; muscarinic receptors; cholinesterase.
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