| Organophosphate compounds (OP) are widely used as pesticides throughout the world including China. Dimethoate is a kind of moderate acute toxicity organophosphate pesticides (OPP). Due to its high efficacy of broad killing pests and low persistent in environment, it is widely used in agriculture throughout China. As OPP, it is an inhibitors of serine esterase, a class of hydrolyses containing acetyl cholinesterase (AchE, EC 3.1.1.7), which hydrolyses acetylcholine. It has been shown that acute and prolonged exposure to organophosphates leads to inhibition of AchE which may be accompanied by signs and symptoms of cholinergic over-stimulation. In addition of AchE inhibition, chronic exposure to organophosphates may also cause a "down-regulation" in the number of muscarinic receptors, which was determined by radioligand binding assay with [3H]quinuclidinyl benzilate ([3H]QNB) as the ligand, resulting in sub sensitivity to the increased levels of acetylcholine at synaptic sites and leading to the development of "tolerance" to many of clinical effects of the organophosphates. It was suggested the decrease of [3H]QNB binding number of muscarinic receptor was an adaptation to the toxicity of OPP.This study, including animal experiment, human study and cell culture, is to investigate systematically the relationship between M receptors and toxic effects exposed to dimethoate. M3 receptor gene in peripheral blood lymphocyte (PBL) was observed in populations either occupationally exposed or non-exposed to dimethoate in order to explore the possibility that M3 gene expression as a biomarker of exposure to OPP.In the acute animal experiment, AchEs in whole blood and brain were both inhibited with a dose-effect relationship. The modification of brain AchE paralleled with whole blood AchE. Activity of whole blood AchE may reflect that in brain when acutely exposed to dimethoate.Activity of whole blood AchE became more inhibited after 14-day or 28-day pretreatment with 25 mg/kg dimethoate compared to non-pretreatment group. The longer of pretreated with low dosage dimethoate, the lower of AchE activity. But despite the period pretreated with dimethoate longer or short, when challenged by higher dosage of dimethoate, AchEs in whole blood and brain became still moreinhibited with a dose-effect pattern.Not only AchEs in blood and brain were inhibited when exposed to dimethoate, but also the density and affinity of M1 and M2 muscarinic receptors subtypes could be affected. It showed a decrease trend of receptor density and an increase trend of receptor affinity following the increase of dimethoate dosage. When pretreated with a low level (25 mg/kg dimethoate) of dimethoate for 14 days or 28 days, animal developed tolerance to the toxicity of dimethoate. However, when challenged by higher (50 mg/kg and 100 mg/kg dimethoate, respectively), there was still change of the density and affinity of receptor. But the change was lesser in the group with 28-day pretreatment compared to in those of 14-day pretreatment group.The density of muscarinic subtype M1 decreased parallely with the M1 receptor mRNA expression level. This indicated that the decrease of gene expression of M1 receptor might explain one of the mechanisms of the decrease of M1 receptor density. It was not seen in M2 receptor density and its mRNA level. It may be related to different modulation mechanisms involving in M1 or M2 muscarinic receptor and their mRNA. Further investigation is needed to be addressed.In the 14-day pretreatment animals, it was found that basal M3 gene expression in peripheral lymphocytes correlate with the M1 gene expression in the brain. But in the 28-day pretreatment animals, only the induced M3 gene expression could reflect the M1 gene expression level in the brain.The basal and induced M3 gene expression of peripheral lymphocytes from workers exposed to dimethoate were assayed. It was found that induced expression was high than basal expression in workers exposed to dimethoate, while it was contrary in the control gro...
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