Dibutyl phthalate disrupts ESR1-GPX4 redox signaling and aggravates ovarian dysfunction in a PCOS-like mouse model.

Dibutyl phthalate (DBP), a widely used phthalate plasticizer, has been implicated in reproductive toxicity, but the molecular mechanisms by which experimental DBP exposure affects ovarian granulosa-cell function remain incompletely defined. In an exploratory clinical cohort, urinary MiBP, MnBP, and DBP levels were higher in women with PCOS than in controls, suggesting a possible association between DBP-related exposure and PCOS status. In a DHEA-induced PCOS-like mouse model, repeated experimental DBP exposure at 20 mg/kg/day further aggravated ovarian dysfunction, including hormonal disturbance, follicular arrest, and ovarian morphological abnormalities. In KGN cells, DBP treatment at 10-100 μM impaired redox homeostasis and mitochondrial function, with 100 μM used for transcriptomic and mechanistic analyses. Mechanistically, DBP bound to ESR1, inhibited ESR1 nuclear translocation and transcriptional activity, and reduced ESR1 enrichment at the GPX4 promoter, which was accompanied by GPX4 suppression, lipid peroxidation, ROS accumulation, and mitochondrial dysfunction. E2 co-treatment partially restored ESR1-GPX4 signaling and attenuated DBP-induced oxidative and mitochondrial damage in KGN cells. These findings identify ESR1 as a molecular target of DBP and suggest that disruption of ESR1-GPX4 redox signaling may represent one mechanism by which DBP impairs granulosa-cell redox homeostasis and aggravates ovarian dysfunction under experimental exposure conditions.