Cadmium (Cd), because of oxidative and estrogenic actions, behaves as a human carcinogen. Melatonin (Mel), the pineal hormone, has antiestrogenic as well as antioxidant properties, providing protection against Cd damage. We previously demonstrated that, in adult female mice receiving Cd, melatonin co-treatment increases the Cd concentration in blood. However, among ovariectomized animals, those co-treated with melatonin had lower blood concentration of Cd than those receiving Cd alone. Cd in blood represents the equilibrium between the circulating metal and that deposited in tissues bound to Metallothionein (MT), ubiquitous proteins essential for cell protection. Therefore, our objective was to address whether melatonin could also counteract the effects of Cd by modulating MT expression, as well as the role of Estradiol (E2) on the interactions Cd-Melatonin-Metallothionein.

In vitro, MCF-7 (ER+), HeLa and MDA cells (ER-) were cultured in media with estrogen-depleted serum and treated with 1 mM CdCl2, 100 nM Mel and 10 nM E2. In vivo studies were carried out on adult male mice pre-treated with 200 mg/kg E2 or 10 mg/kg Mel 30 minutes before injection of 0.5 mg/kg CdCl₂ to study the MT expression on liver and kidney during the light/dark cycle. We found that both, Melatonin and E2 treatments significantly increased Cd-induced MT gene expression, thus preventing Cd toxicity. These results could explain the differences observed in Cd concentration in blood among ovariectomized and uncastrated mice treated with melatonin. The protective effects of melatonin point to its possible role as a preventive agent for environmental or occupational Cd contamination.