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

• Published in: Ecotoxicology and environmental safety Vol. 206; p. 111190
• Main Authors: Mantawy, Eman M., Said, Riham S., Kassem, Dina H., Abdel-Aziz, Amal Kamal, Badr, Amira Mohamed
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 15-12-2020
• Subjects: Apoptosis; MAPKs; N-Acetyl-L-cysteine; NADPH oxidase; Ovarian failure; N-Acetyl-L-cysteine; Ovarian failure; NADPH oxidase; Apoptosis; MAPKs
• ISSN: 0147-6513; 1090-2414
• DOI: 10.1016/j.ecoenv.2020.111190

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 γ-radiation-provoked POF. Immature female Sprague-Dawley rats were orally-administered NAC (50 mg/kg) and were exposed to a single whole-body dose of 3.2 Gy ϒ-radiation. NAC administration remarkably reversed abnormal serum estradiol and anti-Müllerian hormone levels by 73% and 40%, respectively while ameliorating the histopathological and ultrastructural alterations-triggered by γ-radiation. Mechanistically, NAC alleviated radiation-induced oxidative damage through significantly increased glutathione peroxidase 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/Bcl2 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.
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•NOX/MAPKs signaling pathway is implicated in radiation-induced ovarian toxicity.•NAC diminished radiation-induced oxidative stress by reducing NOX4 and p22 levels.•NAC inhibited ovarian apoptotic machinery via repressing p53/caspase-3 cascades.•NAC enhanced ovarian cell survival through increasing VEGF expression.