Maternal Bisphenol S Exposure Impairs Testicular Development and Sperm Function in Male Offspring by Disrupting the Immune‐Endocrine Network

Bisphenol S (BPS), a widely used substitute for bisphenol A, is an environmental contaminant with endocrine-disrupting properties. However, the transgenerational impact of maternal BPS exposure during gestation on male offspring reproductive health and the underlying molecular mechanisms remains unknown. This study shows that gestational exposure of mice to environmentally relevant concentrations of BPS (3, 30, and 300 µg/kg) dose- and time-dependently impairs testicular development and sperm function in male offspring. Integrated transcriptomic, physiological, and molecular analyses revealed that maternal BPS exposure remodeled the testicular transcriptome and disrupted the immune-endocrine crosstalk within the testis. This disruption was characterized by the aberrant activation of immune and inflammatory pathways, including antigen presentation, concomitant suppression of steroidogenic and metabolic processes, and induction of the renin-angiotensin system. Deconvolution analysis identified loss of Leydig cells and increased Tcell infiltration, and quantitative realtime PCR validated the dysregulation of key hub genes such as Ren1, H2-D1, Naip6, Tlr1, H2-M3, Pycard, B2m, H2-Aa, Naip1, and Cd74. Notably, western blotting revealed that HLA-DPB1, a key component of the antigen presentation pathway, was significantly downregulated at the protein level in testicular tissues. Immunofluorescence co-localization with cell-specific markers defined the precise cellular localization in the testis. Collectively, these multilevel disruptions resulted in impaired seminiferous epithelial cyclicity, enhanced interstitial collagen deposition in the testes, and severe deficits in sperm motility. Our findings reveal a novel transgenerational mechanism underlying BPS-induced testicular injury and provide robust experimental evidence of the reproductive toxicity of environmentally relevant BPS in male offspring.