Methylmercury interaction with lymphocyte cholinergic muscarinic receptors in developing rats

Cerebral cholinergic muscarinic receptors (MR) have been suggested as one of the sensitive biochemical endpoints of the central nervous system altered by developmental exposure to the widespread seafood contaminant methylinercury (MeHg). In adult rats, MeHg has been shown to alter MR binding both in the brain and lymphocytes, supporting the use of MR in blood cells as a surrogate marker of CNS changes. The effects of MeHg have been evaluated on rat lymphocyte MR binding (using [H-3]QNB as specific muscarinic ligand) in vivo (after perinatal exposure) and in vitro. For comparison, in vitro studies were also performed on human lymphocytes. Exposure to 1 mg MeHg/kg/day during pregnancy and lactation (from GD7 to PND7) significantly enhanced lymphocyte MR density in both adult and young rats 21 days after delivery, with a more pronounced effect in the mothers (B-max increase of 139%) than in the male offspring (+ 49%) and female offspring (+ 73%) as compared with their respective controls (33 +/- 4, 41 +/- 8, and 37 +/- 4 mu mol/million cells), in accordance with the higher Hg levels detected in the adult blood (11.3 +/- 2.2 mu g/mL) than in pups (1.3 +/- 0.4 mu g/L in both genders). A lower MeHg dose (0.5mg/kg/day) was without any effect on lymphocyte MRs. In in vitro studies, MeHg was an almost equipotent inhibitor of H-3-QNB binding to rat and human lymphocyte MRs (IC50 values were 4.1 +/- 0.29, 5.2 +/- 0.51, and 5.0 +/- 0.9 mu M for total rat lymphocytes, rat T lymphocytes, and total human lymphocytes, respectively). Notably, the IC50 values for MeHg to lymphocyte MRs were comparable to the Hg levels reached in blood (5-50 mu M) of the PND21 rats exposed to MeHg. The finding that the MR binding is a target for the effects of MeHg in peripheral blood cells is in accordance with our previous data in brain [Coccim et al., 2006. Effects of developmental co-exposure to methylmercury and 2,2',4,4,5,5'-hexachlorobiphenyI (PCB153) on cholinergic muscarinic receptors in rat brain. Neurotoxicology, in press], and supports the use of this peripheral endpoint as a biomarker of MeHg-induced cerebral muscarinic alterations. The similarity of MeHg IC50 binding data between human and rat in peripheral tissues suggests the possible application of such biomarker to humans exposed to environmental chemicals. (c) 2006 Elsevier Inc. All rights reserved.