Disulfidptosis-Associated Neurotoxicity Induced by Cadmium Under an Environmentally Relevant Cadmium Exposure Scenario

Cadmium (Cd) is a widespread environmental pollutant associated with neurotoxicity, but its underlying mechanisms remain unclear. Disulfidptosis is a regulated cell death driven by disulfide stress under conditions of impaired cellular reducing capacity. This study investigated the potential involvement of disulfidptosis-associated molecular alterations in Cd-induced neurotoxicity. Male Sprague Dawley (SD) rats were exposed to cadmium chloride (Low-Dose Group: CdCl2: 0.036 mg/kg bw; High-Dose Group: CdCl2: 3.6 mg/kg bw) by oral gavage for 30 days. Neurobehavioral performance was assessed using the open field test, elevated plus maze, and Morris water maze. Hippocampal ultrastructure, redox-related metabolites, and disulfidptosis-associated genes were analyzed. In addition, bioinformatics analysis was performed by integrating cadmium-related, neurodegenerative disease-related, and disulfidptosis-related genes. The results showed that high-dose Cd exposure impaired locomotor activity, increased anxiety-like behavior, and disrupted spatial learning and memory (p < 0.05), accompanied by mitochondrial damage in hippocampal neurons. Bioinformatics analysis identified seven overlapping genes and enrichment of ferroptosis and oxidative phosphorylation pathways. Biochemically, cadmium exposure significantly increased the NADP+/NADPH ratio ([Control: 1.07 ± 0.044] vs. [High-dose: 3.80 ± 0.059], p < 0.05) and decreased the GSH/GSSG ratio ([Control: 2.80 ± 0.059] vs. [High-dose: 1.14 ± 0.091], p < 0.05), indicating severe redox imbalance. At the molecular level, cadmium exposure upregulated SLC7A11 mRNA expression by 1.48 ± 0.12-fold (p < 0.01) and SLC3A2 by 1.91 ± 0.55-fold (p < 0.05), while downregulating NDUFS1 expression to 0.84 ± 0.01-fold of control levels (p < 0.01) in hippocampal tissues. These findings suggest that high-dose Cd exposure induced neurotoxicity is associated with mitochondrial dysfunction, redox imbalance, and disulfidptosis-associated molecular alterations.