Mechanistic Insights into Lead Acetate-Induced Neurotoxicity Using RNA-Seq Analysis

Lead acetate (Pb-acet) is a neurotoxicant that significantly impacts human brain development. This study used LUHMES cells, a human embryonic stem cell-derived neuronal model, to explore its molecular toxicity mechanisms. RNA sequencing (RNA-seq) showed distinct gene expression changes due to Pb-acet exposure. Principal Component Analysis (PCA) highlighted significant gene expression alterations at high toxicant concentrations (Ld10) compared to low concentrations (Ld1) and controls. Pb-acet disrupted pathways related to ribosome function and RNA splicing, and activated endoplasmic reticulum (ER) stress pathways, including PERK, ATF6, and IRE1. It also upregulated genes linked to ER-associated degradation (e.g., SVIP) and apoptosis (Bcl2 and CHOP), and disrupted the ubiquitin ligase complex, indicating impaired protein homeostasis. This study identifies ribosomal processes and ER stress pathways as potential biomarkers of Pb-acet exposure, demonstrating the utility of LUHMES cells in neurodevelopmental toxicity and environmental biomarker research.