Multidimensional mechanistic analysis elucidates spermatogenesis disruption induced by bisphenol S.

Bisphenol S (BPS), a primary substitute for bisphenol A, has led to widespread environmental exposure globally. However, the effects of BPS on spermatogenesis disruption (SD) remain contentious, and the underlying mechanisms responsible for SD induced by BPS are not fully understood. In this study, we employed a multidimensional computational strategy, integrating network toxicology, bioinformatics, systematic machine learning, single-cell analysis, and biomolecular modeling, to comprehensively elucidate the molecular mechanisms by which BPS induces SD. Our findings suggest that BPS may disrupt spermatogenesis by interfering with multiple signaling pathways, including the cAMP signaling pathway, MAPK pathway, VEGF pathway, and PI3K-Akt pathway, thereby forming a synergistic toxic network. Through systematic screening utilizing 113 combinations of machine learning algorithms, we identified CTSK, GSTZ1, and PDE4D as core diagnostic biomarkers for SD, positing that these genes may serve as potential hub targets through which BPS disrupts spermatogenesis. Moreover, our analysis of testicular tissue-specific co-expression networks and single-cell data revealed that these hub genes are specifically expressed in testicular tissue, predominantly enriched in reproductive cell types such as Sertoli cells, peritubular myoid cells, spermatogonia, and spermatocytes. Biomolecular modeling further indicated a strong binding affinity between BPS and these hub proteins. This research not only provides critical insights into the reproductive toxicity risk assessment of BPS by elucidating its impact on spermatogenesis but also reveals novel biomarkers and potential intervention targets based on a multidimensional mechanistic analysis, thereby advancing the field of BPS reproductive toxicology.