In recent years, the production and application of organophosphate esters (OPEs) have increased significantly, raising widespread concern regarding environmental exposure. Although a large body of research has confirmed their adverse effects on human health, studies focusing on reproductive health remain in their infancy. This study detected OPEs in serum and follicular fluid (FF) samples from women of reproductive age, revealing the ubiquitous presence of OPEs in both matrices and a significant positive correlation between OPE levels in serum and FF. Notably, elevated serum levels of TDCIPP were significantly associated with an increased risk of diminished ovarian reserve (DOR) (OR: 8.32, 95% CI: 1.24-55.8), suggesting a potential risk of TDCIPP exposure for DOR. Subsequently, female ICR mice exposed to clinically relevant doses of TDCIPP for three months exhibited DOR-like alterations, including a reduction in primordial follicles, an increase in atretic follicles, hormonal dysregulation, and impaired fertility. Integrated untargeted metabolomics analysis, combined with in vitro cell experiments and in vivo animal studies, confirmed that TDCIPP induces ferroptosis in granulosa cells. Furthermore, network toxicology, molecular docking, rescue experiments, and Western blotting assays demonstrated that TDCIPP targets the epidermal growth factor receptor (EGFR), leading to a decrease in protein expression, thereby inhibiting SLC7A11 and GPX4 expression and subsequently triggering ferroptosis leading to DOR. This study is the first to integrate human epidemiological data with mouse exposure experiments, confirming that OPEs can penetrate the human ovarian blood-follicle barrier to enter follicles and pose reproductive health risks by investigating the association between OPEs and DOR.
Keywords: Diminished ovarian reserve; EGFR; Ferroptosis; Follicles; Organophosphate esters.
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