Journal
TOXICOLOGY
Volume 256, Issue 3, Pages 175-182Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.tox.2008.11.017
Keywords
Organophosphate; Cholinesterases; Muscarinic receptors; Neurobehavior; Morris water maze; CREB
Categories
Funding
- Indian Council of Medical Research, New Delhi, India
- PGIMER, Chandigarh, India
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The present study was designed to explore the alternative mechanism (other than AChE inhibition) for chronic, low-level exposure to dichlorvos, an organophosphate, in vivo. Dichlorvos, at a dose of 1.0 and 6.0 mg/kg body weight (b.wt.) for 12 weeks, showed impairment in neurobehavioral indices viz. rota rod, passive avoidance and water maze tests. Though high dose of dichlorvos had a detrimental effect on acetylcholinesterase activity, no significant inhibition was seen with low dose of dichlorvos. Western blot analysis and immunofluorescence studies showed a significant reduction in the expression of M-1, M-2 and M-3 muscarinic receptor subtypes in high dose group animals, whereas in low dose group animals only the M-2 receptor subtype was reduced significantly. Further, the signal transduction cascade linked to these receptor subtypes was affected in high dose group animals whereas in low dose group only adenylyl cyclase-linked signaling pathway was impaired. Finally, the phosphorylation of CREB, a memory enhancing transcription factor, was significantly reduced in both low dose and high dose group animals. Thus, the present study reveals the significance Of M-2 muscarinic receptor linked adenylyl cyclase signaling pathway and phosphorylation of CREB in the development of neurobehavioral impairments after chronic low-level exposure to dichlorvos. (C) 2008 Elsevier Ireland Ltd. All rights reserved.
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