Environmental Metal Exposure and Brain-Derived Neurotrophic Factor (BDNF): A Systematic Review of Human and Experimental Evidence

BACKGROUND: Brain-derived neurotrophic factor (BDNF) is central to synaptic plasticity and neurodevelopment. Toxic metal exposure is linked to oxidative stress and neuroinflammation, yet its effects on BDNF signaling remain unclear. OBJECTIVES: To systematically synthesize evidence from human and experimental studies on the association between environmental or occupational metal exposure and BDNF alterations, and to highlight research gaps with an emphasis on hexavalent chromium (Cr(VI)). METHODS: PubMed, Scopus, and ScienceDirect were searched following PRISMA guidelines. Eligible studies included human observational research and animal models reporting quantitative associations between metal exposure (biomarkers/environmental measures) and BDNF outcomes (protein or gene expression). Data were extracted on exposure assessment, BDNF measurement, and neurobehavioral outcomes. Study quality was assessed using NOS (human studies) and SciRAP (experimental studies). RESULTS: Nineteen studies were included. Across metals such as Pb, Hg, Cd, As, Mn, and mixtures, exposure was associated with altered BDNF levels in blood or brain tissue, often alongside oxidative stress markers, inflammatory changes, and cognitive or behavioral impairment in animal models. Most human studies reported decreased circulating BDNF with higher exposure, while experimental evidence suggested context-dependent regulation across exposure windows and brain regions. CONCLUSIONS: The available evidence supports a biologically plausible link between metal exposure and BDNF dysregulation. No eligible studies evaluated BDNF in relation to Cr(VI), indicating a major research gap. Future studies should integrate neurotrophic biomarkers with exposome-oriented designs to clarify chromium-related neurotoxicity and support Adverse Outcome Pathway (AOP)-informed frameworks.