Low-level exposure to methylmercury modifies muscarinic cholinergic receptor binding characteristics in rat brain and lymphocytes: physiologic implications and new opportunities in biologic monitoring.

Abstract

Methylmercury (MeHg) affects several parameters of cholinergic function. These alterations are thought to play a role in MeHg neurotoxicity. In vitro experiments have indicated that MeHg acts as a strong competitive inhibitor of radioligand binding to muscarinic cholinergic receptors (mAChRs) in rat brain. Furthermore, rat brain mAChRs share several pharmacologic characteristics of similar receptors present on lymphocytes. Using the muscarinic antagonist [(3)H]quinuclidinyl benzilate (QNB) to label receptors, we investigated the in vivo interactions of MeHg with rat brain mAChRs. We also investigated whether MeHg-induced central mAChR changes are reflected by similar alterations in splenic lymphocytes. Exposure to low doses of MeHg--0.5 or 2 mg/kg/day in drinking water--for 16 days significantly increased (20-44% of control) mAChRs density (B(max)) in the hippocampus and cerebellum without affecting receptor affinity (K(d)). The effect of MeHg did not occur immediately; it was not apparent until 2 weeks after the termination of treatment. No significant changes in [(3)H]QNB binding were observed in the cerebral cortex. In splenic lymphocytes, mAChR density was remarkably increased (95-198% of control) by day 14 of MeHg exposure and remained enhanced 14 days after the cessation of treatment. These results suggest up-regulation of mAChRs in selected brain regions (hippocampus and cerebellum) after prolonged low-level ingestion of MeHg in rats. These cerebral effects are delayed in onset and are preceded by a marked increase in density of mAChRs on lymphocytes. In chronic MeHg exposure, peripheral lymphocytes may represent a sensitive target for the interaction of MeHg with mAChRs and, therefore, may be predictive indicators of later adaptive response involving cerebral mAChRs. Additionally, the effect of MeHg on lymphocyte mAChRs in vivo indicates that this receptor system should be investigated further as a possible target for MeHg immunotoxicity.ImagesFigure 1Figure 2Figure 3

No changes in lymphocyte muscarinic receptors and platelet monoamine oxidase-B examined as surrogate central nervous system biomarkers in a Faroese children cohort prenatally exposed to methylmercury and polychlorinated biphenyls

“…For example, cerebral and lymphocyte mAChR binding was similarly modified by treatments with cholinergic agonist or antagonist drugs (Costa et al 1990) as well as by MeHg (Coccini et al 2000) and organophosphorus insecticides (Fitzgerald & Costa 1993). Changes in mAChRs were also observed in developing rats exposed perinatally to MeHg (Coccini et al 2007a) or to mixtures of MeHg and PCBs (Coccini et al 2007b).…”

“…In vitro experiments have indicated that MeHg acts as a strong competitive inhibitor of radioligand binding to mAChRs in the rat (Castoldi et al 1996) and human brain tissue (Basu et al 2005). Brain mAChRs share several pharmacological characteristics of similar receptors present on lymphocytes and parallel changes in the density of mAChRs have been shown to occur in lymphocytes and brain tissue following exposure to pharmacological agents and neurotoxicant chemicals acting at the cholinergic system (Coccini et al 2000, Costa et al 1990, Fitzgerald & Costa 1993). MeHg was shown to alter cerebral mAChR density both in brain and lymphocytes following repeated oral administration to adult rats with changes in peripheral mAChR binding even preceding those observed in brain (Coccini et al 2000, 2006).…”

“…Brain mAChRs share several pharmacological characteristics of similar receptors present on lymphocytes and parallel changes in the density of mAChRs have been shown to occur in lymphocytes and brain tissue following exposure to pharmacological agents and neurotoxicant chemicals acting at the cholinergic system (Coccini et al 2000, Costa et al 1990, Fitzgerald & Costa 1993). MeHg was shown to alter cerebral mAChR density both in brain and lymphocytes following repeated oral administration to adult rats with changes in peripheral mAChR binding even preceding those observed in brain (Coccini et al 2000, 2006). Moreover, perinatal MeHg exposure can enhance the lymphocyte mAChR density in rats (Coccini et al 2007a), thus supporting the use of this endpoint as a peripheral marker of MeHg-induced cerebral cholinergic alterations in the developing organism.…”

In vivo and in vitro changes in neurochemical parameters related to mercury concentrations from specific brain regions of polar bears (Ursus maritimus)

“…Methylmercury has been shown to affect neurochemical parameters in the brain: rats exposed to MeHg showed decreased monoamine oxidase (MAO) activity [35], decreased acetylcholinesterase (AChE) activity [36], and increased muscarinic acetylcholine receptor (mAChR) density [37]. Acetylcholine (ACh), a major neurotransmitter in the central nervous system, binds nicotinic ACh receptors (nAChRs) and mAChRs [38].…”

Methylmercury: A potential environmental risk factor contributing to epileptogenesis

“…Mutations in the α4-subunit gene (CHRNA4) or the β-subunit of the neuronal nicotinic acetylcholine receptor (nAChR) are associated with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), a focal syndrome characterized by nocturnal motor seizures (for review, see Lerche et al, 2001; Graves, 2006). MeHg has the potential to affect both nicotinic (Shamoo et al, 1976; Eldefrawi et al, 1977) and muscarinic receptors (Abd-Elfattah and Shamoo, 1981; Castodi et al, 1996; Coccini et al, 2000; Limke et al, 2004a; Roda et al, 2008). However, whether these effects of MeHg on nicotinic or muscarinic receptors lead to increased or decreased excitability remains to be determined.…”