Melatonin prevents the estrogenic effects of sub‐chronic administration of cadmium on mice mammary glands and uterus

Abstract

Cadmium (Cd) is a heavy metal classified as a human carcinogen. Occupational exposure, dietary consumption and cigarette smoking are sources of Cd contamination. Cd-induced carcinogenicity depends on its oxidative and estrogenic actions. A possible role of Cd in breast cancer etiology has been recently suggested. Melatonin, because of its antioxidant and antiestrogenic properties could counteract the toxic effects of this metalloestrogen. Our aim was both to determine the effects of relevant doses of Cd on mice mammary glands and uterus and to test whether melatonin would counteract its effects. Female mice of different ages and estrogenic status (prepuberal, adult intact, adult ovariectomized) were treated with CdCl(2) (2-3 mg/kg, i.p.), melatonin (10 microg/mL in drinking water), CdCl(2) + melatonin, or diluents. Whereas in prepuberal animals Cd disturbs mammary ductal growth and reduces the number of terminal end buds, in adults, regardless of the steroidal milieu, Cd exerts estrogenic effects on mammary glands, increasing lobuloalveolar development and ductal branching. Uterine weight also increased as a result of Cd treatment. The effects of Cd are partially inhibited by melatonin. In adult ovariectomized mice, Cd concentration in blood of animals treated with CdCl(2) + melatonin was lower than in mice receiving only Cd; the opposite effects were found in non-castrated animals. As Cd mimics the effect of estrogens, the high incidence of breast cancer in tobacco smokers and women working in industries related with Cd could be explained because of the properties of this metal. The effects of melatonin point to a possible role of this indoleamine as a preventive agent for environmental or occupational Cd contamination.

Metals and Breast Cancer

“…There is also increasing evidence that cadmium activates the genomic and nongenomic pathways of ERα in vivo [4, 47-55]. The rodent uterotropic response assay is the most commonly used laboratory model to test for the estrogenicity of compounds in vivo.…”

Zinc and multi-mineral supplementation should mitigate the pathogenic impact of cadmium exposure

“…Activation of NADPH oxidase, as well as mitochondrial damage, is believed to play a role in Cd-induced oxidative stress [19,43,87,88]. Other nutraceutical antioxidants, such as astaxanthin, lipoic acid, melatonin, Nacetylcysteine, and phase II inducers, may likewise have potential for mitigating Cd's pathogenic impact [89][90][91][92][93][94][95][96][97][98][99] -though it should be acknowledged that oxidative stress is unlikely to be the only mechanism mediating Cd's adverse effects. The researchers who reported high Cd levels in vegans, also note that whole plant-based foods tend to rich in phytochemical antioxidants which might to some degree offset the toxic impact of Cd [46].…”

Cadmium in human and animal organisms. III. Effect on reproductive system

“…Результати багатьох досліджень свідчать про те, що Cd 2+ може впливати на статеву систему та спричиняти ендокринні розлади внаслі док імітації або гальмування дії ендогенних статевих гомонів, особливо естрогенів [4,38]. У зв'язку з цим його вважають потужним металоестрогеном і зараховують до деструкторів ендокринної системи [32,36,71].…”

“…Однак результати більшості досліджень свідчать, що Кадмій діє подібно до естрогенів у клітинах різних органів (молочна залоза, матка, яєчник, тонка кишка), і такий ефект не притаманний іншим важким металам. Вважають, що вплив Cd 2+ на експресію генів опосередкований конкурентним зв'я зу ванням з рецепторами ERα, ERβ і не залежить від естрогенів [4,34,38].…”