Melatonin epigenetic potential on testicular functions and fertility profile in varicocele rat model is mediated by silent information regulator 1

Background and Purpose Varicocele is a leading cause of male infertility. Melatonin is a highly pleiotropic neurohormone. We aimed to characterize the melatonin epigenetic potential in varicocele and the involved molecular mechanisms. Experimental Approach Fifty-two male albino rats were randomly divided into four groups (13 rats each): control (I), melatonin (II), varicocele (III) and melatonin treated varicocele (IV) groups. Left varicocele was induced by partial left renal vein ligation. Reproductive hormones, epididymal sperm functional parameters, testicular 3/17 beta-hydroxysteroid dehydrogenases, antioxidant enzymes, malondialdehyde, nicotinamide adenine dinucleotide phosphate oxidase, 8-hydroxy-2 '-deoxyguanosine and histopathological/Johnsen's score were evaluated. Flow cytometry and Comet were carried out to explore extent of sperm and testicular DNA damage. Testicular expression of silent information regulator 1 (SIRT1), forkhead transcription factors-class O (type1) (FOXO1), tumour suppressor gene, P53, cation channels of sperm (CatSper) and steroidogenic acute regulatory protein was evaluated by western blot technique. Testicular expression of Bcl-2 and its associated X protein and nuclear factor kappa-light-chain-enhancer of activated B cells were assayed by immunohistochemical staining. Testicular miR-34a expression was quantified by quantitative reverse transcription-polymerase chain reaction. Key Results The varicocele induced testicular histological injury, enhanced oxidative stress, P53-mediated apoptosis, DNA damage and increased testicular miR-34a expression paralleled with down-regulated SIRT1/FOXO axis. Melatonin treatment of varicocele rats displayed antioxidant/anti-apoptotic efficacy and improved reproductive hormones axis, CatSper expression and fertility parameters. MiR-34a/SIRT1/FOXO1 epigenetic axis integrates testicular melatonin mediated intracellular transduction cascades in varicocele. Conclusion and Implications Melatonin can be used as an adjuvant therapy to improve varicocele and its complication.

Automated summary

This study aimed to investigate the epigenetic potential of melatonin in varicocele and its molecular mechanisms. The results showed that varicocele caused testicular injury, increased oxidative stress, apoptosis mediated by P53, DNA damage, and upregulated miR-34a expression, while downregulating the SIRT1/FOXO axis. Melatonin treatment improved these changes, including antioxidant/anti-apoptotic effects, reproductive hormone axis, CatSper expression, and fertility parameters.