Impact of lead (Pb)-induced neurotoxicity on protein synthesis and cellular stress responses in LUHMES cells.

Exposure to lead (Pb) poses significant risks to human brain development. This study investigates the molecular mechanisms underlying Pb acetate-induced neurotoxicity in LUHMES cells, which represent a human fetal-derived dopaminergic neuronal precursor model particularly suited for studies of neurotoxicity and Parkinson's disease. Morphological analyses revealed that Pb acetate exposure at concentrations exceeding 10 µM induced cytotoxicity and disrupted neurite outgrowth. Distinct gene expression changes associated with Pb exposure were determined through RNA-sequencing. Principal component analysis highlighted significant alterations in gene expression at higher Pb concentrations (10 µM) compared with lower Pb concentrations (1 µM) and controls. Notably, Pb acetate exposure impaired ribosomal function, Spliceosome and protein processing in the endoplasmic reticulum (ER) pathways. Furthermore, these three pathways related that Pb acetate exposure resulted in the upregulation of genes related to ER-associated degradation and apoptosis, whereas the ubiquitin ligase complex was disrupted, suggesting compromised protein homeostasis. These findings underscore the potential of ribosomal processes and ER stress pathways as biomarkers of Pb acetate exposure. This study provides advanced mechanistic insights into the toxicological effects of lead (Pb) as a heavy metal, with a specific emphasis on its influence on cellular processes related to proteostasis and stress response pathways. Our findings further highlight the importance of LUHMES cells as a human-derived neuronal model for elucidating neurodevelopmental toxicity and identifying molecular biomarkers of Pb exposure, particularly those associated with dysregulation in ribosomal function and endoplasmic reticulum (ER) stress signaling.