Down‐regulation of muscarinic receptors and the m3 subtype in white‐footed mice by dietary exposure to parathion

Abstract

The effect of ad libitum dietary exposure (as occurs in the field) to parathion for 14 d was investigated on the muscarinic acetylcholine receptor (mAChR) in brains and submaxillary glands of adults of a field species, the white-footed mouse Peromyscus leucopus. Immunoprecipitation using subtype selective antibodies revealed that the relative ratios of the m1-m5 mAChR subtypes in Peromyscus brain were similar to those in rat brain. There was little variability in acetylcholinesterase (AChE) activity in control mice brains but large variability in 39 exposed mice, resulting from differences in food ingestion and parathion metabolism. Accordingly, data on radioligand binding to mAChRs in each mouse brain were correlated with brain AChE activity in the same mouse, and AChE inhibition served as a biomarker of exposure reflecting in situ paraoxon concentrations. Exposure to parathion for 14 d reduced maximal binding (Bmax) of [3H]quinuclidinyl benzilate ([3H]QNB), [3H]-N-methylscopolamine ([3H]NMS), and [3H]-4-diphenylacetoxy-N-methylpiperidine methiodide ([3H]-4-DAMP) by up to approximately 58% without affecting receptor affinities for these ligands. Maximal reduction in Bmax of [3H]QNB and [3H]-4-DAMP binding occurred in mice with highest AChE inhibition, while equivalent maximal reduction in Bmax of [3H]NMS occurred in mice with only approximately 10% AChE inhibition, without further change at higher parathion doses. This is believed to be due to the hydrophilicity of [3H]NMS, which limits its accessibility to internalized desensitized receptors. In submaxillary glands (mAChRs are predominantly m3 subtype), there were significant dose-dependent reductions in [3H]QNB binding and m3 mRNA levels in exposed mice, revealed by Northern blot analyses. The reduction in m3 receptors is suggested to result mostly from reduced synthesis at the transcription level, rather than from translational or posttranslational events. The data suggest that down-regulation of mAChRs occurs after dietary exposure for 14 d to sublethal concentrations of parathion in a field rodent species, and that significant though incomplete recovery in AChE and mAChRs occurs in 7 d following termination of exposure.

Cholinergic and Behavioral Neurotoxicity of Carbaryl and Cadmium to Larval Rainbow Trout (Oncorhynchus mykiss)

“…Organisms have several potential adaptations to ChE inhibition, including increased synthesis of ChE (Abbas and Hayton, 1997), decreased synthesis of ACh (Liu and Pope, 1996), and desensitization and downregulation of MChR (Jett et al, 1993;Nostrandt et al, 1997). Regression of B and K " against ChE activity is a measure of the response of MChR to ChE inhibition.…”

Comparative in vivo effects of parathion on striatal acetylcholine accumulation in adult and aged rats

“…Again, the degree of reduction in muscarinic agonist binding was greater in adult than in aged tissues. Numerous studies have demonstrated that prolonged acetylcholinesterase inhibition leads to adaptive down-regulation of muscarinic receptors (Costa et al, 1982;Russell and Overstreet, 1987;Jett et al, 1993;Pope et al, 1995). PS exposure has been shown to affect different subpopulations of muscarinic receptors in the adult rat brain (Chaudhuri et al, 1993;Olivier et al, 2001b).…”

Variation of cholinergic biomarkers in brain regions and blood components of captive mink

“…This spread is greater than the 2.4-fold difference reported here in control animals (Table 2). In another example, Jett et al (1993) reported that a normal range of AChE activity existed between 70 and 100 (arbitrary units) in the brains of control white-footed mice. By establishing such a range, they showed that following parathion exposure enzyme activity ranged between 25 and 95 in animals exposed to 100 ppm parathion and was less than 30 in the 500 ppm group.…”