Cadmium exposure at low environmental levels induces cognitive decline in aged male mice

Cadmium (Cd) is a neurotoxic metal that accumulates via dietary, environmental, and occupational sources and is closely linked to oxidative stress and neuroinflammation. Little is known about the mechanistic effects of low-dose environmental Cd as found in the human diet on cognition in aged mice. Male aged mice (C57BL/6 J, 20 months old) received water with or without 3.3 mg/L Cd for 12 weeks. Cognitive function was assessed using the Y-maze, thiol/disulfide redox states were analyzed by high-performance liquid chromatography, brain Cd levels were determined by inductively coupled plasma mass spectrometry, hippocampal morphology was examined by histological analysis, and metabolomics was analyzed by high-resolution mass spectrometry. Low-dose environmental Cd exposure led to brain Cd accumulation and impaired cognitive function in aged male mice, accompanied by reduced hippocampal neuronal density in the cornu ammonis 1 region. Cd shifted the plasma redox toward a more oxidizing state, along with elevated hydroxytetradecanoic acid and decreased N-oleoylethanolamine in the brain. Cd decreased bioactive signaling lipids (lysophosphatidic acid, oleamide, sphingomyelin, sphingosine) and selectively acylcarnitine levels in the brain. Increased pyridoxal phosphate and lipoamide and decreased glutamine brain levels suggest potential compensatory responses. Exposure to low environmental levels of Cd in aged male mice disrupts redox homeostasis and systemic lipid metabolism, leading to cognitive decline, accompanied by compensatory responses. The results suggest that environmental Cd at levels found in the human diet could contribute to cognitive decline.