Structure-Dependent Mechanistic Divergence in Male Reproductive Toxicity Between Bisphenol A and Its Analog Bisphenol S: Integration of Network Toxicology and Molecular Docking

Bisphenol A (BPA), a widespread endocrine-disrupting chemical, has been associated with male reproductive health, yet its structural analog bisphenol S (BPS), selected as a primary alternative, may also pose similar risks. Their comparative reproductive toxic mechanisms remain poorly defined. By integrating network toxicology and molecular docking, we predicted and compared BPA- and BPS-related target and pathway profiles in male reproductive toxicity, and identified candidate hub genes potentially dysregulated in testicular pathology using public datasets. Both chemicals shared ESR1 and TP53 as overlapping targets, and enrichment analysis showed that both were enriched in ESR1/AR signaling and endocrine resistance pathways. BPA was preferentially linked to impairment of immune-barrier function with AKT1, TGFB1, TLR4, and STAT3, whereas BPS mapped to metabolic-oxidative stress processes via MDM2, EGFR, and GSTP1. Immune infiltration analysis linked BPA-related genes inversely to NK cell abundance. Transcription factor analysis identified MYCN and PGR as hub nodes with distinct downstream networks. Molecular docking predicted generally favorable binding of both chemicals to key targets, with target-dependent differences in predicted affinity. These in silico results suggest that BPA and BPS may affect male reproductive health through partly distinct mechanisms, with BPA more closely associated with immune-related pathways and BPS with metabolic-oxidative stress pathways.