Novel molecular mechanisms underlying the ameliorative effect of N-acetyl-L-cysteine against Υ-radiation-induced premature ovarian failure in rats

Radiotherapy represents a critical component in cancer treatment. However, premature ovarian failure (POF) is a major hurdle of deleterious off-target effects in young females, which, therefore, call for an effective radioprotective agent. The present study aimed to explore the molecular mechanism underlying the protective effects of N-acetyl-L-cysteine (NAC) against gamma-radiation-provoked POF. Immature female Sprague-Dawley rats were orallyadministered NAC (50 mg/kg) and were exposed to a single whole-body dose of 3.2 Gy Upsilon-radiation. NAC administration remarkably reversed abnormal serum estradiol and anti-Miillerian hormone levels by 73% and 40%, respectively while ameliorating the histopathological and ultrastructural alterations-triggered by gamma-radiation. Mechanistically, NAC alleviated radiation-induced oxidative damage through significantly increased glutathione pemxidase activity by 102% alongside with decreasing NADPH oxidase subunits (p22 and NOX4) gene expressions by 48% and 38%, respectively compared to the irradiated untreated group. Moreover, NAC administration achieved its therapeutic effect by inhibiting ovarian apoptosis-induced by radiation through downregulating p53 and Bax levels by 33% and 16%, respectively while increasing the Bcl-2 mRNA expression by 135%. Hence, the Bax/Bc12 ratio and cytochrome c expression were subsequently reduced leading to decreased caspase 3 activity by 43%. Importantly, the anti-apoptotic property of NAC could be attributed to inactivation of MAPK signaling molecules; p38 and JNK, and enhancement of the ovarian vascular endothelial growth factor (VEGF) expression. Taken together, our results suggest that NAC can inhibit radiotherapy-induced POF while preserving ovarian function and structure through upregulating VEGF expression and suppressing NOX4/MAPK/p53 apoptotic signaling.