Network Toxicology and Molecular Docking Reveal the Risk and Potential Mechanisms of VOCs-induced Male Reproductive...

Volatile organic compounds (VOCs) are widely released into the environment through industrial production and daily human activities, posing potential threats to male reproductive health and fertility. This study aims to investigate the potential adverse effects of VOCs as atmospheric pollutants on the male reproductive system and to elucidate the underlying molecular mechanisms.

An integrated approach combining network toxicology, molecular docking, and molecular dynamics (MD) simulations was employed, with prostatitis, erectile dysfunction (ED), epididymitis, and urethritis selected as representative male reproductive diseases. Data from PubChem, ADMETlab 2.0, and SwissADME databases were integrated to screen 17 classes of VOCs and their associated disease-related targets, followed by the identification of core target genes. GO and KEGG pathway enrichment analyses were conducted to elucidate the underlying molecular mechanisms. Molecular docking validation was performed, and MD was conducted on the key protein CASP3.

The potential overlapping targets of VOCs with prostatitis, ED, epididymitis, and urethritis were identified as 481, 387, 210, and 182, respectively. Molecular docking and MD results showed that CASP3, ranked as the top core target, exhibited stable binding with VOCs. KEGG pathway analysis indicated that all four diseases were enriched in cancer-related pathways, oxidative stress pathways, and apoptosis-related pathways.

VOCs bind to key proteins such as CASP3, AKT1, and EGFR, activating signaling pathways including PI3K/Akt, HIF-1α/mTOR, EGFR, and nNOS, thereby disrupting oxidative stress and cellular metabolic disorders, which promote the onset and progression of diseases. CASP3 plays a key role in maintaining the stability of the complex with VOCs through hydrophobic and hydrogen bonding interactions. By interfering with fundamental biological processes, VOCs may induce multi-organ damage in the reproductive system, forming a comorbidity spectrum characterized by inflammation and functional impairment.

This study demonstrates that VOCs induce male reproductive diseases by binding to key proteins and activating multiple signaling pathways. Monitoring VOC exposure and conducting individual risk assessments hold significant public health implications, while also providing potential therapeutic targets for reproductive diseases.