ToxSci Advance Access originally published online on January 12, 2005
Toxicological Sciences 2005 84(2):352-359; doi:10.1093/toxsci/kfi081
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Effects of Repeated Oral Postnatal Exposure to Chlorpyrifos on Cholinergic Neurochemistry in Developing Rats
Center for Environmental Health Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi State, Mississippi 39762
Received November 16, 2004; accepted January 5, 2005
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 PND 6, 12, 22, and 30, with maximum inhibition on PND 6 of 49 and 59% and recovering to 18 and 33% on PND 30 in the low and high dosage groups, respectively. On PND 22 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 PND 12 and 22, with substantial recovery by PND 30. M1/M3 mAChR were significantly reduced on PND 6 and 12 only in the high dosage group, and on PND 22 in both groups, while M2/M4 mAChR were reduced in the high dosage group on PND 22 and 30. On PND 30 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 PND 6, 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 alterations 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.
Key Words: developmental neurotoxicity; chlorpyrifos; choline acetyltransferase; organophosphate "aging"; muscarinic receptors; cholinesterase.
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