Heavy metals (Pb, Cd, MeHg, As) as risk factors for cognitive dysfunction: A general review of metal mixture mechanism in Brain

Human exposure to toxic heavy metals is a global challenge. Concurrent exposure of heavy metals, such as lead (Pb), cadmium (Cd), methylmercury (MeHg) and arsenic (As) are particularly important due to their long lasting effects on the brain. Although, the exact mechanism of neurotoxicity of metal mixture (Pb, Cd, As and MeHg) is unclear, but their main target region is hippocampus and they share many common pathways for causing cognitive dysfunction. The combination of metal may produce additive/synergetic effects due to their common binding affinity with NMDA receptor (Pb, As, MeHg), Na⁺ − K⁺ ATP-ase pump (Cd, MeHg), biological Ca⁺² (Pb, Cd, MeHg), Glu neurotransmitter (Pb, MeHg), which can lead to imbalance between the pro-oxidant elements (ROS) and the antioxidants (reducing elements). In this process, ROS dominates the antioxidants factors such as GPx, GS, GSH, MT-III, Catalase, SOD, BDNF, and CERB, and finally leads to cognitive dysfunction. The present review illustrates an account of the current knowledge about the individual metal induced cognitive dysfunction mechanisms and analyse common Mode of Actions (MOAs) of metal mixture (Pb, Cd, As, MeHg). This review aims to help advancement in mixture toxicology and development of next generation predictive model (such as PBPK/PD) combining both kinetic and dynamic interactions of metals.