Toxic Mechanisms Underlying Prostate Cancer Induction by Water Pollutants: Based on Network Toxicology, Molecular Docking, and Molecular Dynamics Simulations.

Abstract

Introduction: Addressing water pollutants remains a key priority in contemporary environmental governance, as waterborne pollutants pose significant risks to human health. We focus on four major classes of environmentally persistent water pollutants, namely volatile organic compounds (VOCs), polycyclic aromatic hydrocarbons (PAHs), organochlorine pesticides (OCPs), and polybrominated diphenyl ethers (PBDEs), due to their widespread occurrence and potential carcinogenicity. Integrating network toxicology, molecular docking, and molecular dynamics simulations, this study elucidates the molecular mechanisms by which these pollutants may contribute to prostate carcinogenesis.

Methods: We initially employed ProTox-3.0 and ADMETLAB 3.0 to predict the toxicity of the selected water pollutants. Potential targets for compounds representing four major classes of water pollutants were retrieved from the ChEMBL and SwissTargetPrediction databases. Disease genes related to prostate cancer were collected from the GeneCards, OMIM, and TTD databases. Utilizing the STRING database and Cytoscape software, a molecular regulatory network of toxicological targets and a protein-protein interaction (PPI) network associated with water pollutant-induced prostate cancer were constructed. Then, core genes were screened. Subsequently, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were performed, followed by molecular docking. Finally, molecular dynamics (MD) simulations were conducted based on the molecular docking results.

Results: Enrichment analysis revealed that multiple pathways associated with water pollutant exposure were significantly enriched among prostate cancer-related genes, indicating a potential link between pollutant carcinogenicity and prostate carcinogenesis. Molecular docking results indicated that 80 % of the 75 tested protein-ligand complexes exhibited binding energies lower than -5.0 kcal/mol. MD simulation results demonstrated that all four selected protein-ligand complexes maintained remarkable structural stability throughout the simulation trajectory.

Discussion: The integration of network toxicology, molecular docking, and MD simulations in this study provides a systematic framework for deciphering the molecular toxicological mechanisms by which water pollutants contribute to the development of prostate cancer. By integrating target information from multiple authoritative databases, we identified five core targets (TP53, EGFR, MYC, STAT3, and TNF) that play pivotal roles in mediating the carcinogenic effects of water pollutants. These targets offer key molecular anchors for understanding the pathogenic link between water pollution and prostate cancer. GO and KEGG enrichment analyses further elucidated the critical biological processes and signaling pathways involved (including the hypoxic response and the PI3K-Akt signaling pathway), which are closely associated with cell proliferation, apoptosis, inflammation, and angiogenesis, all of which are hallmarks of prostate cancer progression. Collectively, these findings suggest that the identified pollutant compounds form highly stable interactions with key prostate cancer targets, supporting their potential role in disease progression.

Conclusion: This study suggests that specific compounds within the four classes of typical water pollutants may exert potential carcinogenic effects on prostate cancer. Furthermore, these findings provide a theoretical framework and methodological reference for future investigations into the impact of water pollutants on other malignancies and chronic diseases.