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Selenium nanoparticles mitigate Cyclophosphamide-Induced premature ovarian failures in mice by activating PI3K/AKT
Gang Liu1, Lina Dai2, Rongrong Zhang1
1Clinical Research Center, Affiliated Hospital of Inner Mongolia Medical University, No. 1 Tongdao North Street, Hohhot, Inner Mongolia, 010030, China.
Abstract:
The therapeutic role and mechanisms of selenium nanoparticles (SeNPs) in cyclophosphamide (CTX)-induced premature ovarian failure (POF) remain unclear. In the present study, female mice were treated with CTX to induce POF, followed by SeNPs administration for 14 consecutive days. Ovarian weight, index, and serum hormone levels were measured to assess ovarian function. Histological examination of ovarian tissues was conducted to examine morphological changes, folliculogenesis, DNA damage, and apoptosis. Transcriptomic analysis was performed to identify the underlying molecular mechanisms, with in vitro studies on ovarian granulosa cells employed to validate the findings. The results confirmed that SeNPs administration effectively restored ovarian morphology and function, increasing the number of developing follicles and decreasing the number of atretic follicles. Notably, SeNPs significantly reversed CTX-induced hormonal disturbances: estradiol (E2) levels increased from 186.24 ± 14.72 pM (CTX group) to 258.28 ± 7.53 pM (SeNPs group); follicle-stimulating hormone (FSH) decreased from 20.74 ± 1.13 IU/L to 15.96 ± 1.07 IU/L; luteinizing hormone (LH) declined from 24.88 ± 1.16 ng/mL to 18.04 ± 1.60 ng/mL; and anti-Müllerian hormone (AMH) rose from 164.02 ± 8.57 pg/mL to 230.30 ± 12.01 pg/mL. Moreover, SeNPs attenuated CTX-induced DNA damage and apoptosis of granulosa cells. Transcriptomic analysis identified that SeNPs exert their protective effects against CTX-induced POF by activating the PI3K/AKT signaling pathway and inhibiting ferroptosis, as evidenced by the expression patterns of PI3K/AKT signaling pathway-related proteins and ferroptosis-related markers in granulosa cells. In conclusion, SeNPs effectively protect against CTX-induced POF by enhancing ovarian function, promoting folliculogenesis, and inhibiting DNA damage and apoptosis of granulosa cells. These protective effects are mediated through the activation of the PI3K/AKT signaling pathway and suppression of ferroptosis. Our findings suggest that SeNPs hold promise as a promising therapeutic strategy for ovarian dysfunction, particularly in the context of chemotherapy-induced POF.
Insights
Selenium nanoparticles (SeNPs) effectively treat cyclophosphamide-induced premature ovarian failure (POF) by restoring ovarian function and promoting follicle development. SeNPs protect granulosa cells from DNA damage and apoptosis via the PI3K/AKT pathway and by inhibiting ferroptosis.
Area of Science:
- Reproductive Biology
- Nanomedicine
- Toxicology
Background:
- Premature ovarian failure (POF) induced by chemotherapy, such as cyclophosphamide (CTX), poses a significant threat to female reproductive health.
- The therapeutic mechanisms of selenium nanoparticles (SeNPs) in mitigating CTX-induced POF are not fully understood.
- Understanding these mechanisms is crucial for developing novel therapeutic strategies for chemotherapy-induced ovarian dysfunction.
Purpose of the Study:
- To investigate the therapeutic effects and underlying mechanisms of selenium nanoparticles (SeNPs) in a mouse model of cyclophosphamide (CTX)-induced premature ovarian failure (POF).
- To evaluate the impact of SeNPs on ovarian morphology, function, hormone levels, and granulosa cell apoptosis.
- To elucidate the molecular pathways, including PI3K/AKT signaling and ferroptosis, involved in SeNPs' protective effects.
Main Methods:
- Premature ovarian failure (POF) was induced in female mice using cyclophosphamide (CTX).
- Mice were treated with selenium nanoparticles (SeNPs) for 14 consecutive days.
- Ovarian function was assessed via ovarian weight, index, serum hormone levels (E2, FSH, LH, AMH), histological examination, DNA damage, apoptosis assays, and transcriptomic analysis.
- In vitro studies on ovarian granulosa cells were conducted to validate findings.
Main Results:
- SeNPs administration significantly restored ovarian morphology and function, increasing developing follicles and decreasing atretic follicles.
- SeNPs reversed CTX-induced hormonal imbalances, normalizing estradiol, FSH, LH, and AMH levels.
- SeNPs attenuated CTX-induced DNA damage and apoptosis in granulosa cells.
- Transcriptomic analysis revealed that SeNPs activate the PI3K/AKT signaling pathway and inhibit ferroptosis in granulosa cells.
Conclusions:
- Selenium nanoparticles (SeNPs) demonstrate significant protective effects against cyclophosphamide (CTX)-induced premature ovarian failure (POF).
- SeNPs enhance ovarian function, promote folliculogenesis, and inhibit DNA damage and apoptosis of granulosa cells.
- The therapeutic benefits of SeNPs are mediated by the activation of the PI3K/AKT signaling pathway and the suppression of ferroptosis, suggesting their potential as a novel therapeutic strategy for chemotherapy-induced ovarian dysfunction.
