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

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.

The Role of Oxidative Stress and Natural Antioxidants in Ovarian Aging

“…Specifically, genistein decreased the recruitment of primordial cells and increased the number of mature follicles and corpora lutea by upregulating ovarian SOD and GSH levels, and downregulating IL-1β and MAD levels, which means preservation of ovarian function and follicular reservoirs ( Saleh and Mansour, 2016 ). Moreover, compared with estradiol, genistein was superior in preserving all stages of healthy follicles, enhancing GCs proliferation, and reducing the population of atretic follicles in ϒ-radiation-induced POF rats ( Haddad et al, 2020 ).…”

Ginseng alleviates folliculogenesis disorders via induction of cell proliferation and downregulation of apoptotic markers in nicotine-treated mice

“…A recent study has reported the disappearance of ovarian cysts after a 14-day oral regimen of Korean red ginseng extract in an animal model [ 57 ]. Similarly, genistein, a phytoestrogen that binds to the ERs, protects ovarian follicles against radiotherapy and increases primordial, preantral, and antral follicles, and reduces atretic follicle counts through inhibition of apoptosis markers and upregulation of ERs in the ovary [ 58 ]. In a rat model of polycystic ovaries induced by estradiol valerate, ginseng normalizes ovarian morphology, reduces antral follicle counts, and increases corpus luteum numbers via regulation of nerve growth factor expression [ 59 ].…”

Could Polyphenols Really Be a Good Radioprotective Strategy?

“…Several evidences underline genistein-induced radioprotection for the hematopoietic acute radiation injury, and the ability of the compound to act as a selective estrogen receptor β-agonist was also explored, as it is involved in its radioprotective mechanism of action [ 55 ]. The up-regulation of ER-β and FOXL-2 by genistein, with associated downregulation of TGF-β expression was implied also in reversing radiotherapy-induced premature ovarian failure [ 56 ]. Soy isoflavones are overall prone to modify clinical responses to RT, acting both with radiosensitizing and radioprotective effects.…”