| Low-Level Exposure to Methylmercury Modifies Muscarinic Cholinergic Receptor Binding Characteristics in Rat Brain and Lymphocytes: Physiologic Implications and New Opportunities in Biologic Monitoring Teresa Coccini,1 Giovanna Randine,2 Stefano M. Candura,1,3 Rossella E. Nappi,2,3 Leon D. Prockop,4 and Luigi Manzo1,3 1Toxicology Division, IRCCS Salvatore Maugeri Foundation, Institute of Pavia, Pavia, Italy
2Department of Obstetrics and Gynecology, IRCCS Policlinico S. Matteo
3University of Pavia Medical School, Pavia, Italy
4Department of Neurology, University of South Florida, Tampa, Florida, USA 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 [3H]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 (Bmax) in the hippocampus and cerebellum without affecting receptor affinity (Kd) . The effect of MeHg did not occur immediately ; it was not apparent until 2 weeks after the termination of treatment. No significant changes in [3H]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. Key words: biomarker, brain, cholinergic system, lymphocyte, methylmercury, muscarinic receptor, neurotoxicity. Environ Health Perspect 108:29-33 (2000) . [Online 2 December 1999] http://ehpnet1.niehs.nih.gov/docs/2000/108p29-33coccini/ abstract.html Address correspondence to T. Coccini, Toxicology Division, Salvatore Maugeri, Foundation Medical Centre, Via Ferrata 8, I-27100 Pavia, Italy. Telephone: 39 0382 556605. Fax: 39 0382 556615. E-mail: tcoccini@fsm.it We thank P. Baiardi (Medical Informatics, S. Maugeri Foundation) for statistical analysis and D. Acerbi for expert technical assistance. We are also indebted to E. Faustman for insightful comments and suggestions. This study was supported by grants from the European Commission (grant ENV4-CT96-0173) and the Italian Ministry of Health. Received 14 May 1999 ; accepted 30 July 1999.
The full version of this article is available for free in HTML or PDF formats. |
