Exploratory transcriptomic and network-based analysis of methylmercury exposure in human neuronal developmental...

Methylmercury (MeHg) is a well-recognized environmental neurotoxicant with a marked impact on neurodevelopment. However, studies integrating stage-specific transcriptomic responses in human neuronal development remain limited.

This study aimed, in an exploratory manner, to integrate and compare transcriptomic profiles induced by MeHg across distinct stages of human neuronal development, in order to evaluate shared and differential transcriptional responses among models representing early neuroepithelial differentiation, neural progenitor expansion, and mature neuronal function.

MeHg-associated genes were retrieved from the Comparative Toxicogenomics Database (CTD), GeneCards, and PubChem. Three human transcriptomic datasets from GEO were analyzed, corresponding to early neuroepithelial differentiation (UKN1), neural progenitor expansion (hNPT), and mature dopaminergic neurons (LUHMES). Differentially expressed genes were identified using GEO2R. Integrated analyses included protein-protein interaction network construction, hub gene identification using centrality algorithms in Cytoscape, and functional enrichment, transcription factor, and disease ontology analyses.

Integration of databases identified a set of four genes (CASP3, GPX1, MT2A, and SOD2) consistently present across all resources. Differential expression analysis across the three neuronal models revealed both shared and model-specific transcriptional responses to MeHg exposure. A conserved set of three overexpressed genes (BRD7, HSPH1, and MCM5) was identified across all models, whereas no common repressed gene signature was observed across the three systems, although partial overlaps were detected between pairs of models. Network analysis highlighted central genes associated with general stress-related processes, including apoptosis, oxidative stress, and inflammatory signaling. Functional enrichment analyses indicated activation of broad cellular stress response pathways, with additional enrichment in processes related to cell cycle regulation and genome maintenance. Disease ontology analysis showed enrichment in broad disease categories, without evidence supporting disease-specific mechanistic interpretation.

This integrative transcriptomic and network-based analysis provides an exploratory framework to prioritize candidate genes and biological processes associated with methylmercury exposure across human neuronal developmental models. The results indicate consistent involvement of general stress-related processes but do not support the identification of specific mechanisms or universal regulatory patterns across models. The absence of a conserved repression signature further highlights transcriptional heterogeneity among developmental stages. Overall, these findings should be interpreted as hypothesis-generating and intended to guide future experimental validation rather than to infer defined molecular mechanisms.