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.
Radiotherapy is one of the most important strategies in cancer treatment. Seriously, radiotherapy resulted in premature ovarian failure (POF) and infertility, 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 also damaged. Moreover, germ cells seem to be much more susceptible to oxidative stress induced by radiotherapy than somatic cells. Seriously, ROS generated by ionizing radiation are capable of inducing tissue apoptosis by direct and indirect pathways leading to oxidative damage of cellular macromolecules (mainly DNA, proteins and lipids). Curiously, apoptosis was identified as the mechanism responsible for oocyte loss caused by radiotherapy. Soybeans products contain high amounts of isoflavones known as soy phytoestrogens which act as natural selective estrogen receptor modulators (SERMs). The most prominant phytoestrogen in soybean is genistein (GEN), which shows estrogenic properties through estrogen receptor beta (ER-β) binding. GEN has different pharmacological properties through its chemoprotective activity against cancers and cardiovascular diseases. GEN was also reported to protect against acute myelotoxicity, intestinal, lung, and testicular injuries-induced by radiation. The radioprotective effects of GEN was attributed to its antioxidant, anti-apoptotic, antiinflammatory and anti-fibrotic activities. Concerning its effects on the ovaries, previous report confirmed the protective effect of GEN against ovarian carcinogenesis. Also, GEN slowed down follicular development, considerably improving the ovarian follicular stock and extend the ovarian lifespan. In this context, GEN was documented to delay ovarian ageing and prolong ovarian reproductive life, besides its protective effect against chemotherapy and radiotherapy induced ovarian toxicity.
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