Analyses of neurotoxicity following multiple metal exposures among adults living along the Yangtze River in Anhui Province, China: In vitro experiments with mild cognitive impairment integrating community population cohort.

This study aimed to investigate the association between multiple metals exposure and mild cognitive impairment (MCI) among adults residing along the Yangtze River in Anhui Province, China. We integrated network toxicology, epidemiological cohort studies and in vitro experiments under human-realistic doses to elucidate the potential biological mechanisms of MCI induced by multiple metals exposure. Among the 1337 participants, cadmium (Cd) was positively associated with incident MCI (OR = 1.13, 95% CI: 1.01-1.26) and exhibited the strongest positive weight in the multiple-mixture models. Network toxicology analysis and molecular docking simulations evaluated the binding affinity of Cd to the targets related to cognitive function, and identified NFKB1 as the core key target. Cell experiments based on the actual Cd exposure concentrations of study population indicate that Cd can promote the activation of NF-κB in SH-SY5Y cells, and upregulate the expression of inflammatory factors. Population validation experiment showed that TNF-α and IL-6 partially mediated the association between Cd and MCI. Collectively, this study clarifies the potential biological mechanisms of MCI induced by multiple metals exposure, providing novel exposure biomarkers and therapeutic targets for the comprehensive prevention and treatment of MCI.