Protein-Binding Patterns Drive the Transport of Mercury in Plasma and Red Blood Cells in Rats.

The fate of metals within biological systems is determined by their associated binding partners, specifically protein ligands. However, the mechanisms by which these protein targets regulate the transport of metal pollutants remain unclear. Here, protein-binding patterns were identified as drivers of the transport of mercuric compounds (methylmercury and inorganic mercury) in the bloodstream. We systematically investigated the transport of mercury (Hg) in rats following oral administration and analyzed the time-resolved patterns of Hg-binding proteins in the blood. Our findings demonstrated that Hg was differentially distributed between plasma and red blood cells (RBCs) over time, suggesting distinct transport pathways mediated by specific protein interactions. Methylmercury (MeHg) preferentially bound to hemoglobin and carbonic anhydrase in RBCs, together accounting for more than 97% of protein-bound MeHg. This selective binding retained MeHg within the RBCs and significantly prolonged its circulation time. In contrast, inorganic mercury (HgCl2) displayed a broader and more diverse protein-binding pattern. In RBCs, it bound primarily to hemoglobin and galectin-5, whereas in plasma, albumin and glutathione peroxidase 3 (Gpx3) were identified as its major binding partners. These protein-binding patterns drive the differential biological fates of mercury. The higher ratio of MeHg to proteins in RBCs resulted in a longer vascular circulation lifetime of MeHg in blood, leading to the prolonged transfer of MeHg from the blood to the brain. Conversely, the higher plasma protein binding of HgCl2 facilitated its partitioning from the blood into tissues such as the kidney and liver, where it could be rapidly cleared and excreted. In summary, Hg-binding proteins play a crucial role in regulating their retention in the blood and their subsequent transfer to tissues.