Bisphenol P induces ovarian dysfunction by directly targeting PTGS2 and disrupting steroid hormone synthesis.

Emerging evidence suggests structural analogues of bisphenol A (BPA), including the increasingly used substitute bisphenol P (BPP), pose substantial reproductive risks. However, BPP's ovarian toxicity remains uncharacterized. This study used an integrated approach combining in vivo models, network toxicology, transcriptomics, molecular docking, and biophysical techniques to elucidate the mechanisms of BPP-induced ovarian injury in peripubertal female mice. Eight-week BPP exposure caused significant ovarian injury, including follicular atresia, disorganized granulosa cells, elevated DNA damage, and apoptosis. While the ovarian index was unchanged, serum hormone trends indicated decreased estradiol (E2) and increased luteinizing hormone (LH). An integrated network toxicology and transcriptomics approach identified prostaglandin-endoperoxide synthase 2 (PTGS2) as a pivotal target. The direct interaction between BPP and PTGS2 was confirmed by molecular docking and quantitatively validated using microscale thermophoresis (MST, Kd = 61.2 ± 29.9 μM) and surface plasmon resonance (SPR, Kd = 2.6 ± 0.6 μM). Mechanistically, BPP triggered a multi-level suppression of the steroidogenic pathway, significantly downregulating genes encoding gonadotropin receptors (Lhcgr, Fshr), key transcription factors (Nr5a1, Foxl2), and rate-limiting enzymes (Star, Cyp11a1, Hsd3b, Cyp19a1). Our findings demonstrate that BPP acts as a potent ovarian toxicant by directly targeting PTGS2 and instigating a comprehensive transcriptional blockade of steroid hormone synthesis, revealing a novel mechanistic pathway for this emerging environmental contaminant. Collectively, this work elucidates a novel mechanism of BPP-induced ovarian toxicity and establishes an integrated assessment framework that paves the way for evaluating the reproductive health risks of emerging environmental contaminants.