Metalloestrogens: an emerging class of inorganic xenoestrogens with potential to add to the oestrogenic burden of the human breast

What was reviewed?

This study, published in the Journal of Applied Toxicology, reviewed the concept and emerging evidence of metalloestrogens mimicking estrogenic activity. The review focused on how these metals interact with estrogen receptors (ERs) like organic xenoestrogens, potentially contributing to estrogenic activity in human breast tissue and increasing the risk of hormone-related cancers such as breast cancer. The review primarily covered in vitro and in vivo studies of various metal ions, including aluminum, antimony, arsenite, barium, cadmium, chromium (Cr(II)), cobalt, copper, lead, mercury, nickel, selenite, tin, and vanadate. The review also highlights significant research contributions from multiple studies and scholars focusing on the effects of metalloestrogens on human breast cancer cell lines, such as MCF-7 and T47D, as well as their impact on gene expression and cellular proliferation.

Most Important Findings:

Estrogenic Activity of Metals: The review found that various metal ions can act as estrogen agonists by binding to estrogen receptors, particularly ERα, and mimicking the actions of physiological estrogens. This was demonstrated in studies showing that metals such as cadmium, nickel, and aluminum could displace estradiol from the ligand-binding domain of ERα, leading to altered gene expression and increased cell proliferation in breast cancer cells.

Molecular Mechanisms: Metals such as cadmium were shown to bind directly to the ligand-binding domain (LBD) of the estrogen receptor, interfering with the receptor’s normal function. This binding alters the receptor’s ability to interact with estrogen response elements (EREs) on DNA, thereby affecting the transcription of estrogen-regulated genes. For instance, cadmium was found to downregulate ER levels and upregulate estrogen-regulated gene expression, driving cell proliferation.

Cooperative Action with Estrogens: The metals did not antagonize estradiol’s action; instead, they often enhanced the agonist actions of estradiol. In some cases, metals like copper and cobalt increased breast cancer cell proliferation when combined with estradiol, indicating a synergistic effect that may exacerbate estrogenic signaling in hormone-dependent cancers.

In Vivo Evidence: The review highlighted evidence of in vivo estrogenic activity in animal models, particularly for cadmium, which was shown to increase uterine weight, induce mammary gland development, and alter gene expression. The estrogenic effects of cadmium were noted at doses relevant to human exposure, raising significant concerns about environmental exposure to these metals.

Environmental and Occupational Exposure: The presence of metalloestrogens such as cadmium and aluminum in everyday consumer products (e.g., antiperspirants) and the environment (e.g., tobacco smoke, and industrial pollutants) implies widespread human exposure. These metals can accumulate in the body, especially in breast tissue, and may contribute to the burden of aberrant estrogen signaling involved in breast cancer development.

Greatest Implications:

Breast Cancer Risk: The review underscores the potential for metalloestrogens to increase the risk of breast cancer by contributing to estrogenic signaling within breast tissue. Given that breast cancer is often driven by estrogen receptor activation, the cumulative burden of environmental estrogens and metalloestrogens could enhance the likelihood of cancer development and progression.

Environmental Health and Toxicology: The widespread presence of these metals in the environment, their ability to accumulate in the body, and their newly recognized estrogenic activity suggest a need for revised regulatory guidelines and risk assessments for human exposure to metalloestrogens. This includes re-evaluating safe exposure levels, especially for metals like cadmium, which is already classified as a human carcinogen.

Endocrine Disruption: The concept of metalloestrogens extends the traditional understanding of endocrine-disrupting chemicals (EDCs) beyond organic compounds, emphasizing the need for further investigation into how inorganic metals may impact hormone-related diseases. This review calls for more research on the long-term effects of chronic exposure to metalloestrogens in both wildlife and humans.

Public Health Awareness: There is a strong implication for public health education regarding the sources of metalloestrogen exposure, such as antiperspirants, diet, cigarette smoke, and industrial pollutants. Raising awareness could lead to better personal care practices and lifestyle choices to reduce individual exposure to these potentially harmful metal ions.