Bisphenol A Alternatives in Follicular Fluid: Novel Risk Factors for Ovarian Reserve Dysfunction

Bisphenol A (BPA), an endocrine-disrupting chemical frequently detected in follicular fluid (FF), has been implicated in ovarian reserve dysfunction. However, data on the presence of its structural analogues within ovarian follicles remain limited. This study aimed to characterize the exposure profiles of BPA and its alternative in human FF and to assess their potential associations with ovarian reserve dysfunction. FF samples were collected from 104 women, including 15 patients with polycystic ovary syndrome (PCOS), 34 patients with diminished ovarian reserve (DOR), and 55 control women. Concentrations of BPA and 34 alternatives were determined using ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). A total of 24 bisphenol compounds (BPs) were identified. Bisphenol S (BPS) was the most prevalent and abundant compound, with concentrations ranging from 33.3 to 2228.4 ng/L, significantly higher than those of BPA (2.2-435.0 ng/L). This study first detected 11 BPA alternatives and 11 BPS alternatives in FF. The total bisphenol concentration (Σ35BPs) exhibited a significant decreasing gradient: PCOS group > DOR group > control group. Significant concentration differences (p < 0.05) were observed among groups for 14 individual BPs. Spearman's correlation analysis showed that most BPs exhibited positive correlations (r = 0.20-0.61, p < 0.05), except dapsone (DDS). Ordinal logistic regression analysis showed that BPA, bisphenol AF (BPAF), benzyl 4-hydroxybenzoate (PHBB), DDS, and bisphenol F (BPF) were associated with ovarian reserve markers outside the normal range. In summary, this study confirms the widespread presence of BPA alternatives in the ovarian environment, suggesting their potential role in ovarian dysfunction and emphasizing the need for further mechanistic research and longitudinal follow-up studies.