Lead Is Toxic to Neuronal Cells by Inducing Oxidative Stress and Activating Neuroinflammatory Pathways

Background/Objectives: Exposure to lead (Pb) is a serious public health concern for which there is no safe level. The aim of this study was to investigate the toxicity of Pb to undifferentiated (uSH-SY5Y) and differentiated (dSH-SY5Y) human neuroblastoma cells and to evaluate gene transcription in response to sub-lethal lead exposure. Methods: Pb was applied to uSH-SY5Y and dSH-SY5Y cells across a concentration range of 0–5 mM for 4, 6, and 24 h, and cell viability was assessed using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase assays. Results: Pb induced a significant concentration- and exposure-dependent reduction in cell viability. Pb significantly impacted cellular bioenergetics and reduced ATP production in a concentration- and exposure duration-dependent manner, triggering elevated levels of deleterious reactive oxygen species. Transcriptomic profiling in dSH-SY5Y cells after a sub-lethal 24 h exposure to 1.25 mM Pb revealed 757 upregulated and 2206 downregulated genes. From Gene Ontology and KEGG pathway enrichment analysis, biological processes were predominantly associated with immune and inflammatory processes, including cytokine-mediated signalling. Upregulated differentially expressed genes (DEGs) included those for PI3K/Akt and cytokine signalling, and downregulated DEGs included genes linked to spinocerebellar ataxia, mitophagy, cytokine receptor interaction and cellular metabolism. Protein–protein interaction analysis identified six key hub-upregulated genes with a primarily inflammatory focus (CD44, CXCR4, PTGS2, IL1β, TNF, MMP9) and one downregulated gene (CD4) as potential regulators of Pb-induced cellular responses. Disease association analyses revealed links to chemical carcinogenesis and neurodegenerative diseases. Conclusions: Collectively, these findings provide molecular insights into Pb-induced neurotoxicity and highlight a network of genes that converge on neurological and inflammatory pathways, which are candidates for further mechanistic investigation and possible therapeutic targeting following Pb poisoning.