Dual role of reactive oxygen species in the effects of cadmium on microglial survival and phagocytosis

Cadmium (Cd), a significant occupational and environmental pollutant, poses significant health risks due to its bioaccumulation and long biological half-life. Although Cd exposure has been identified as a risk factor for neurodegenerative disorders, including Alzheimer's disease and Parkinson's disease, its specific effects on microglia-the resident immune cells of the central nervous system (CNS)-remain poorly understood. Here, we demonstrate that Cd exerts dual, dose-dependent effects on primary microglia. High doses (1-2 μM) triggered oxidative stress, apoptosis, and viability loss, whereas subtoxic doses (0.125-0.5 μM) enhanced phagocytic activity and ATP production. Notably, low-dose Cd elevated glutathione (GSH) levels, suggesting adaptive redox activation. Pretreatment with <i>N</i>-acetylcysteine (NAC) prevented high-dose Cd-induced cytotoxicity but suppressed the stimulatory effects of low-dose Cd on phagocytic activity and ATP production. Interestingly, NAC pretreatment paradoxically amplified phagocytosis at 1 μM Cd, despite partial ROS reduction. Collectively, our findings reveal that mild oxidative stress from low-dose Cd exposure promotes microglial phagocytosis <i>via</i> antioxidant responses, offering new insights into Cd's neurotoxic mechanisms.