Network-Based In-silico Analysis Suggests Potential Links Between 4‑Nonylphenol Exposure and Medulloblastoma-Related Signalling
Pratibha Gaurav
Zoology Department, MMV, Banaras Hindu University, Varanasi, India.
Avantika Pal
Department of Bioinformatics, MMV, Banaras Hindu University, Varanasi, India.
Gautam Geeta Jiwatram *
Zoology Department, MMV, Banaras Hindu University, Varanasi, India.
*Author to whom correspondence should be addressed.
Abstract
Introduction: Endocrine-disrupting chemicals (EDCs), particularly 4-Nonylphenol (4-NP), pose significant neurodevelopmental risks. However, their mechanistic involvement in medulloblastoma (MB), a common pediatric brain tumour, remains largely unexplored.
Objectives: This study aimed to elucidate the molecular mechanisms through which 4-NP exposure may contribute to MB pathogenesis, with a specific focus on cerebellar granule cell precursors (GCPs), using an integrative bioinformatics approach.
Methods: Potential gene targets of 4-NP and MB-associated genes were retrieved from the Swiss Target Prediction and Gene Cards databases, respectively. A total of 35 overlapping genes were identified and subjected to protein–protein interaction (PPI) network construction using STRING and Cytoscape. Pathway and gene ontology enrichment analyses were conducted using Enrichr, while transcription factors (TFs) and miRNA interactions were analysed using TRRUST v2 and MIENTURNET, respectively.
Results: Potential 4-NP targets (SwissTargetPrediction; algorithm thresholds 0.65 for 2D and 0.85 for 3D) and MB-associated genes were intersected to identify 35 overlapping genes, which were analysed using STRING (confidence score ≥0.7) for network and enrichment analyses. PPI analysis revealed NFKB1, PTGS2, and ESR2 as central hubs, indicating dysregulation in Notch2, PI3K-Akt, and NF-κB signaling pathways. Further regulatory analysis highlighted TP53 and RELA as major TFs and hsa-miR-150-5p and hsa-miR-146a-5p as key miRNAs targeting hub genes. These findings suggest a multi-hit disruption mechanism involving Notch2-mediated proliferation, inflammatory PI3K-Akt/NF-κB signalling, and epigenetic reprogramming via miRNAs.
Conclusion: This in silico network-based study provides the first comprehensive evidence linking 4-NP exposure to MB molecular pathways. It identifies PTGS2 as a potential biomarker and suggests Notch2/PI3K inhibition as a therapeutic strategy. The study underscores the urgent need to reassess 4-NP safety limits in consumer products and offers new insights at the interface of environmental toxicology and pediatric neuro-oncology.
Keywords: 4-Nonylphenol, medulloblastoma, notch2 signalling, PI3K-Akt pathway, NF-κB, transcription factors, miRNA, granule cell precursors, neurotoxicity