Mixed exposure to lead, methylmercury, and cadmium aggravates spatial memory deficits via dopamine signaling pathways in the mouse hippocampus

Background: Neurobehavioral disorders due to mixed exposure to toxic metals have been detected in many populations worldwide. This study investigates the impact of mixed-metal exposure on cognitive function and dopaminergic activity in mice. Methods: Spatial learning and memory were evaluated using the Morris water maze test. The expression of genes and proteins associated with dopaminergic neurotransmission in mice exposed to lead (Pb), methylmercury (MeHg), and cadmium (Cd) was examined in parallel. Male C57BL/6 mice (7 weeks old) were exposed to Pb (25 mg/L), MeHg (10 mg/L), Cd (15 mg/L), or a mixture (25 mg/L Pb + 10 mg/L MeHg + 15 mg/L Cd) in drinking water for 28 days. Results: Our results indicate significant deficits in cognitive function among metal-exposed groups, with the most pronounced impairments occurring in the mixed exposure group. In mice exposed to the metal mixture, dopamine levels in the hippocampus were significantly lower than those in control mice or, notably, in mice in the single-metal exposure groups. These findings were corroborated by real-time polymerase chain reaction and western blot analyses, which demonstrated altered expression of key dopaminergic markers, including tyrosine hydroxylase, dopamine transporters, and dopamine receptors. Conclusion: Our study underscores the detrimental effects of mixed-metal exposure on both cognitive function and dopaminergic signaling, highlighting the need for stringent environmental regulations to prevent or mitigate mixed exposure to toxic metals.