Synergistic toxicity of methylmercury and cadmium through NRF2 suppression and mercury retention

Methylmercury (MeHg) is a potent environmental toxicant that frequently coexists with other heavy metals, raising concerns about combined toxic effects. Increasing evidence indicates that co-exposure to multiple metals can lead to synergistic or greater-than-additive effects; however, the molecular mechanisms underlying such interactions remain poorly understood. Among the tested metals, only co-exposure with Cd markedly enhanced MeHg cytotoxicity. Here, our objective was to evaluate the impact of MeHg co-exposure on cytotoxicity of various heavy metals in HeLa cells. We used cell viability assays, western blot analysis, and reverse-transcription-quantitative polymerase chain reactions to determine toxicity. Co-treatment with MeHg significantly reduced cell viability compared with that of Cd alone. Mechanistically, MeHg suppressed nuclear factor erythroid 2-related factor 2 (NRF2) expression more strongly at earlier time points than Cd alone, thereby impairing antioxidant and detoxification responses. This suppression was accompanied by increased intracellular mercury (Hg) retention, leading to enhanced cytotoxicity. Our results provide a mechanistic basis for metal-metal interactions and highlight the importance of considering co-exposure scenarios in environmental risk assessment.