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

Abstract

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.

• Authors: Eman M Mantawy, Riham S Said, Dina H Kassem, Amal Kamal Abdel-Aziz, Amira Mohamed Badr
• Journal: Ecotoxicology and environmental safety (Ecotoxicol Environ Saf) Vol. 206 Pg. 111190 (Dec 15 2020) ISSN: 1090-2414 [Electronic] Netherlands
• PMID: 32871518 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 Elsevier Inc. All rights reserved.

Chemical References

• Apoptosis Regulatory Proteins
• Radiation-Protective Agents
• Vascular Endothelial Growth Factor A
• NADPH Oxidase 4
• Nox4 protein, rat
• Acetylcysteine

Topics

• Acetylcysteine (pharmacology)
• Animals
• Apoptosis (drug effects)
• Apoptosis Regulatory Proteins (metabolism)
• Disease Models, Animal
• Female
• Gamma Rays (adverse effects)
• Humans
• MAP Kinase Signaling System (drug effects, radiation effects)
• NADPH Oxidase 4 (metabolism)
• Ovary (drug effects, metabolism, radiation effects, ultrastructure)
• Oxidative Stress (drug effects, radiation effects)
• Primary Ovarian Insufficiency (etiology, metabolism, pathology, prevention & control)
• Radiation-Protective Agents (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Vascular Endothelial Growth Factor A (metabolism)