Redox-active metals in environmental oxidative stress and disease

Redox-active metals are central drivers of environmentally induced oxidative stress because they can cycle between oxidation states, catalyze reactive oxygen species (ROS) formation, and disrupt endogenous redox signaling. Unlike many organic toxicants that require metabolic activation, metals such as iron, copper, chromium, vanadium, manganese, cobalt, and nickel can directly participate in electron transfer reactions at biological interfaces, including the lung epithelial lining fluid, mitochondrial membranes, lysosomes, and inflamed tissues. Environmental exposure occurs through inhalation of metal-bearing particulate matter, ingestion via contaminated water and food, and dermal contact in occupational and community settings. Once internalized, these metals amplify oxidative burden through Fenton and Fenton-like chemistry, redox cycling, depletion of glutathione and thiol buffers, mitochondrial electron transport chain disruption, and induction of inflammatory NADPH oxidases. Oxidative injury propagates beyond macromolecular damage to include dysregulated redox signaling, epigenetic remodeling, altered proteostasis, and immune activation, creating a mechanistic bridge from exposure to chronic disease. Epidemiologic and toxicologic evidence links metal-rich air pollution and metal exposures to cardiometabolic disorders, neurodegenerative processes, chronic respiratory disease, kidney injury, and carcinogenesis, with susceptibility shaped by genetics, nutrition (iron status), co-exposures (ozone, PAHs, endotoxin), and life stage. This review synthesizes core mechanistic chemistry, biological targets, and disease-relevant pathways, then evaluates biomarker strategies (exposure, effect, and susceptibility) and discusses methodological advances that improve causal inference, including metal speciation, single-cell approaches, and exposome analytics. Finally, it highlights intervention opportunities spanning emission control, exposure reduction, nutritional modulation, and targeted therapeutics that restore redox homeostasis without suppressing physiologic ROS signaling.