Melatonin improves oxidative state and lactate metabolism in rodent Sertoli cells.

Antioxidant actions of melatonin and its impact on testicular function and fertility have already been described. Considering that Sertoli cells contribute to provide structural support and nutrition to germ cells, we evaluated the effect of melatonin on oxidative state and lactate metabolism in the immature murine TM4 cell line and in immature hamster Sertoli cells. A prooxidant stimulus applied to rodent Sertoli cells expressing MT1/MT2 receptors, increased lipid peroxidation whereas decreased antioxidant enzymes (superoxide dismutase 1, catalase, peroxiredoxin 1) expression and catalase activity. These changes were prevented by melatonin. Furthermore, melatonin stimulated lactate dehydrogenase (LDH) expression/activity via melatonin receptors, and increased intracellular lactate production in rodent Sertoli cells. Interestingly, oral melatonin supplementation in infertile men positively regulated LDHA testicular mRNA expression. Overall, our work provides insights into the potential benefits of melatonin on Sertoli cells contributing to testicular development and the future establishment of a sustainable spermatogenesis.

Pleiotropic actions of melatonin in testicular peritubular myoid cells of immature Syrian hamsters.

BACKGROUND: Peritubular myoid cells are emerging as key regulators of testicular function in adulthood. However, little is known about the role of testicular peritubular myoid cells (TPMCs) in the development of the male gonad. We found that, compared to testes of young adult hamsters, gonads of 21 day-old animals show increased melatonin concentration, seminiferous tubular wall thickening and a heterogeneous packaging of its collagen fibers thus raising the question whether melatonin may be involved in the regulation of TPMCs. METHODS: We established primary cultures of TPMCs from immature hamsters (ihaTPMCs), which we found express melatonergic receptors. RESULTS: Exogeneous melatonin decreased the levels of inflammatory markers (NLRP3 inflammasome, IL1ß) but increased the expression of cyclooxygenase 2 (COX2, key enzyme mediating prostaglandin synthesis) and of the glial cell line-derived neurotrophic factor (GDNF) in ihaTPMCs. Melatonin also stimulated ihaTPMCs proliferation and the expression of extracellular matrix proteins such as collagen type I and IV. Furthermore, collagen gel contraction assays revealed an enhanced ability of ihaTPMCs to contract in the presence of melatonin. CONCLUSION: Melatonin regulates immune and inflammatory functions as well as contractile phenotype of the peritubular wall in the hamster testis. GENERAL SIGNIFICANCE: If transferable to the in vivo situation, melatonin-dependent induction of ihaTPMCs to produce factors known to exert paracrine effects in other somatic cell populations of the gonad suggests that the influence of melatonin may go beyond the peritubular wall and indicates its contribution to testicular development and the establishment of a normal and sustainable spermatogenesis.

Melatonin daily oral supplementation attenuates inflammation and oxidative stress in testes of men with altered spermatogenesis of unknown aetiology.

We have previously shown an inverse correlation between testicular melatonin concentration and inflammation/oxidative stress-related markers levels in infertile men showing unexplained azoospermia. Here, we evaluated the impact of melatonin oral supplementation (daily 3 mg dose used to treat sleep disorders) in the incidence of local inflammation, oxidative stress, and tubular wall fibrosis development in young and middle-aged infertile adult men. Compared with testes without histological alterations, gonads with morphological abnormalities showed lower melatonin concentration along with increased macrophage numbers, TBARS generation, and expression levels of inflammation-related markers and antioxidant enzymes, as well as tubular wall collagen fibers disorganization and thickening. Melatonin oral supplementation not only increased its own testicular levels but also decreased inflammation- and oxidative stress-related markers levels, and improved the tubular wall aspect. Overall, our work provides insights into the potential benefits of melatonin on the inflammatory and oxidative status in testes of patients suffering from unexplained infertility.

ß-adrenergic receptors in the up-regulation of COX2 expression and prostaglandin production in testicular macrophages: Possible relevance to male idiopathic infertility.

Catecholaminergic neuronal elements (CNE) and macrophages (MACs) are increased in testes of patients with idiopathic infertility. Now, we describe an anatomical proximity between CNE and MACs, expression of specific α- and ß-adrenergic receptors (ADRs) subtypes in MACs, and a positive correlation between the number of MACs and cyclooxygenase (COX2) expression - key enzyme in prostaglandin (PG) synthesis and an inflammatory marker - in testes of infertile men. To examine a potential effect of adrenergic input on COX2 expression, we used two additional experimental models: non-testicular human MACs (THP1 cell line) and non-human testicular MACs purified from adult Syrian hamsters. We found that epinephrine and norepinephrine up-regulate COX2 expression and PGD2 production through ß1-and ß2-ADRs. Our results demonstrate the existence of a yet unknown link between CNE and MACs in the human testis that could trigger inflammation and tissue homeostatic dysregulation associated with pathogenesis or maintenance of infertility states.