Quercetin restores oocyte maturation and embryo development in DEHP-exposed mice via mitochondrial protection and...

Di(2-ethylhexyl) phthalate (DEHP) is a ubiquitous environmental endocrine-disrupting chemical known to impair female reproductive function. However, effective mitigation strategies and their underlying molecular mechanisms remain incompletely understood. Quercetin (QUE), a natural flavonoid with potent antioxidant and anti-apoptotic properties, represents a promising therapeutic candidate. In this study, we established a mouse model to evaluate the protective efficacy of QUE against DEHP-induced oocyte toxicity. Female ICR mice were treated with DEHP (500 mg/kg/day) with or without QUE (100 mg/kg/day) for 45 days. QUE co-treatment significantly alleviated DEHP-induced estrous cycle disruption, restored the ovarian reserve, and enhanced both nuclear and cytoplasmic oocyte maturation. Mechanistically, integrated network pharmacology and molecular docking analyses identified NRF2 and SIRT1 as key targets of QUE. Western blot validation confirmed that QUE reversed the DEHP-induced downregulation of NRF2 and normalized the compensatory overexpression of SIRT1. Functionally, QUE mitigated DEHP-triggered mitochondrial dysfunction, including aberrant clustering and loss of membrane potential, and suppressed the Bax/Caspase-dependent apoptotic pathway by downregulating Bax, Caspase-3, and Caspase-9 while upregulating Bcl-2. These protective effects ultimately led to improved preimplantation embryo development, reduced blastocyst apoptosis, normalized litter size, and prevention of abnormal postnatal catch-up growth trajectories in offspring. Collectively, our findings demonstrate that QUE counteracts DEHP-induced reproductive toxicity by preserving mitochondrial integrity and inhibiting apoptotic signaling via modulation of the SIRT1/NRF2 axis, providing a strong mechanistic foundation for dietary interventions against phthalate-associated female subfertility.