Melatonin counteracts cadmium-induced rat testicular toxicity via the mechanistic target rapamycin (mTOR) pathway.

The protective action of melatonin (MLT) against the harmful effects of cadmium (Cd) on testicular activity in rats has been documented previously; however, the involved molecular mechanisms have yet to be elucidated. Herein, we investigate the involvement of the mammalian target of rapamycin (mTOR) on the ability of MLT to counteract the damage induced by Cd on the rat testicular activity. Our study confirmed that Cd has harmful effects on the testes of rats and the protective action exerted by MLT. We reported, for the first time, that the addition of rapamycin (Rapa), a specific mTOR inhibitor, to animals co-treated with Cd and MLT completely abolished the beneficial effects exerted by MLT, indicating that the mTOR pathway partially modulates its helpful effects on Cd testicular toxicity. Interestingly, Rapa-alone treatment, provoking mTOR inhibition, produced altered morphological parameters, increased autophagy of germ and somatic cells, and reduced serum testosterone concentration. In addition, mTOR inhibition also reduced protein levels of markers of steroidogenesis (3ß-Hydroxysteroid dehydrogenase) and blood-testis barrier integrity (occludin and connexin 43). Finally, Rapa altered sperm parameters as well as the ability of mature spermatozoa to perform a proper acrosome reaction. Although further investigation is needed to better clarify the molecular pathway involved in MLT action, we confirm that MLT alleviating Cd effects can be used as a supplement to enhance testicular function and improve male gamete quality.

First evidence of the protective role of melatonin in counteracting cadmium toxicity in the rat ovary via the mTOR pathway.

Herein, the first evidence of the ability of melatonin (MLT) to counteract cadmium (Cd) toxic effects on the rat ovary is reported. Cd treatment, enhancing oxidative stress, provoked clear morphological, histological and biomolecular alterations, i.e. in the estrous cycle duration, in the ovarian and serum E2 concentration other than in the steroidogenic and folliculogenic genes expression. Results demonstrated that the use of MLT, in combination with Cd, avoided the changes, strongly suggesting that it is an efficient antioxidant for preventing oxidative stress in the rat ovary. Moreover, to explore the underlying mechanism involved, at molecular level, in the effects of Cd-MLT interaction, the study focused on the mTOR and ERK1/2 pathways. Interestingly, data showed that Cd influenced the phosphorylation status of mTOR, of its downstream effectors and of ERK1/2, inducing autophagy and apoptosis, while cotreatment with MLT nullified these changes. This work highlights the beneficial role exerted by MLT in preventing Cd-induced toxicity in the rat ovary, encouraging further studies to confirm its action on human ovarian health with the aim to use this indolamine to ameliorate oocyte quality in women with fertility disorders.

Melatonin protects bone against cadmium-induced toxicity via activation of Wnt/ß-catenin signaling pathway.

Among heavy metals, cadmium (Cd) is one of the most toxic for health due to it accumulation in several tissues including bone. Since melatonin (MLT) favors new bone formation through several pathways including Wnt/ß-catenin, here we assessed whether MLT has a protective role against Cd induced toxicity in the rat bone tissue. Adult male Wistar rats receiving 50 mg CdCl2/L and/or 3 mg/L MLT were used and were sacrificed 30 days after the treatment. Femurs and plasma were collected and analyzed by various biochemicals, molecular and histological investigation. The results showed that Cd exposure induced bone disorder characterized by histopathological alterations, a decreased alkaline phosphatase activity and plasmatic concentration of osteocalcin. Moreover, also the expression levels of some osteogenic-related genes (Runx2, Ocn and Alp) were down-regulated after Cd treatment. Since mechanistically Cd toxicity reduced the Kinase activity of GSK3ß and protein levels of Wnt3a and ß-catenin, we observed that MLT administration significantly ameliorated the toxic effects induced by the metal. Our findings provide clues about a potential protective effect of MLT against Cd-induced bone metabolism destruction and that the protection was partially mediated via the Wnt/ß-catenin signaling pathway.

Melatonin prevents cadmium-induced bone damage: First evidence on an improved osteogenic/adipogenic differentiation balance of mesenchymal stem cells as underlying mechanism.

Melatonin (MLT) plays a role in preserving bone health, a function that may depend on homeostatic effects on both mature osteoblasts and mesenchymal stem cells (MSCs) of the bone tissue. In this study, these functions of MLT have been investigated in rat bone (femur) and in human adipose MSC (hMSC) during chronic exposure to low-grade cadmium (Cd) toxicity, a serious public health concern. The in vivo findings demonstrate that MLT protects against Cd-induced bone metabolism disruption and accumulation of bone marrow adipocytes, a cue of impaired osteogenic potential of skeletal MSC niches. This latter symptom was recapitulated in hMSCs in which Cd toxicity stimulated adipogenic differentiation. MLT was found to rescue, at least in part, the osteogenic differentiation properties of these cells. This study reports on a new bone cytoprotection function of MLT pertinent to Cd toxicity and its interfering effect on skeletal MSC differentiation properties that is worth investigating for its possible impact on human bone pathophysiology.