Phytoestrogen genistein hinders ovarian oxidative damage and apoptotic cell death-induced by ionizing radiation: co-operative role of ER-\u03b2, TGF-\u03b2, and FOXL-2

Yasmin Hamdy Haddad,Riham S Said,Engy M El Morsy,Rehab Kamel,Ebtehal El-Demerdash

doi:10.1038/s41598-020-70309-2

Yasmin Hamdy Haddad, Riham S Said + Show 3 more

Open Access

https://doi.org/10.1038/s41598-020-70309-2

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Abstract

Radiotherapy is a well-known cause of premature ovarian failure (POF). Therefore, we investigated the molecular influence of genistein (GEN) on the ovarian reserve of rats exposed to ϒ-radiation. Female Sprague Dawley rats were exposed to a 3.2 Gy γ-radiation to induce POF and/or treated with either GEN (5 mg/kg, i.p.) or Ethinyl estradiol (E2; 0.1 mg/kg, s.c.), once daily for 10 days. GEN was able to conserve primordial follicles stock and population of growing follicles accompanied with reduction in atretic follicles. GEN restored the circulating estradiol and anti-Müllerian hormone levels which were diminished after irradiation. GEN has potent antioxidant activity against radiation-mediated oxidative stress through upregulating endogenous glutathione levels and glutathione peroxidase activity. Mechanistically, GEN inhibited the intrinsic pathway of apoptosis by repressing Bax expression and augmenting Bcl-2 expression resulted in reduced Bax/Bcl-2 ratio with subsequent reduction in cytochrome c and caspase 3 expression. These promising effects of GEN are associated with improving granulosa cells proliferation. On the molecular basis, GEN reversed ovarian apoptosis through up-regulation of ER-β and FOXL-2 with downregulation of TGF-β expression, therefore inhibiting transition of primordial follicles to more growing follicles. GEN may constitute a novel therapeutic modality for safeguarding ovarian function of females’ cancer survivors.

Highlights

Radiotherapy is a well-known cause of premature ovarian failure (POF)
Radiotherapy depends on the generation of reactive oxygen species (ROS) in cancer cells as a result of water radiolysis leading to induction of oxidative stress and diminution of antioxidant defense mechanisms and within this process, healthy tissues are d amaged[3]
We investigated the effect of GEN on folliculogenesis, oxidative stress, apoptosis, proliferation markers as well as its impact on ER-β, forkhead box L2 protein (FOXL2), and transforming growth factor (TGF)-β expression

Summary

Introduction

Radiotherapy is a well-known cause of premature ovarian failure (POF). we investigated the molecular influence of genistein (GEN) on the ovarian reserve of rats exposed to Υ-radiation. GEN inhibited the intrinsic pathway of apoptosis by repressing Bax expression and augmenting Bcl-2 expression resulted in reduced Bax/Bcl-2 ratio with subsequent reduction in cytochrome c and caspase 3 expression. These promising effects of GEN are associated with improving granulosa cells proliferation. Radiotherapy depends on the generation of reactive oxygen species (ROS) in cancer cells as a result of water radiolysis leading to induction of oxidative stress and diminution of antioxidant defense mechanisms and within this process, healthy tissues are d amaged[3]. GEN was documented to delay ovarian ageing and prolong ovarian reproductive life[21], besides its protective effect against chemotherapy-induced ovarian toxicity[24]

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