Cadmium's Disguise Dupes the Estrogen Receptor

Stephen Safe


Nat Med. 2003;9(8) 


Cadmium is a toxic environmental pollutant that has worrisome estrogenic effects in cell culture. New data from rats show that cadmium can act as an estrogen mimic in the whole animal, inducing conditions ranging from uterine hyperplasia to early onset of puberty.

In the 1940s, a painful illness dubbed itai-itai ('ouch-ouch') disease took hold among thousands of post-menopausal women living along a stretch of the Jintsu River in Japan. The women suffered from bone loss and painful skeletal deformations, and many became bedridden. Later studies showed that these women suffered from high levels of cadmium poisoning because of effluent from an upstream mine. Only now are the biological mechanisms for the toxicity of cadmium and other heavy metals coming to light, with studies implicating cadmium as a kidney toxin and, recently, as an inhibitor of DNA mismatch repair in yeast[1].

In this issue, Martin and colleagues provide evidence in rats that cadmium acts as an estrogen mimic that can adversely affect estrogen-responsive tissues such as the uterus and mammary glands[2]. The data, in addition to pinpointing another mechanism for some of cadmium's effects, should also impact regulatory standards for cadmium exposure. Although the women of Jintsu River received massive doses of the heavy metal, the current study suggests that even low doses might adversely influence estrogen-dependent processes in rodents.

17ß-estradiol and other steroidal estrogens influence the development and function of multiple tissues, including the female and male reproductive tracts, the mammary glands, and the cardiovascular and skeletal systems[3]. Despite their important physiological actions, exposure to estrogens is an established risk factor for the development of breast and endometrial cancer in women[4].

The endocrine disruptor hypothesis[5,6], which has received extensive media attention, raises the specter of estrogens as harbingers of disease. It has been hypothesized that in utero or perinatal exposure to synthetic estrogenic compounds (xenoestrogens) and dietary phytoestrogens may be causing a global decrease in male reproductive capacity (including sperm counts) as well as an increase in breast cancer. While some scientists have challenged the validity of this hypothesis[7], a flurry of research continues to identify chemicals that induce estrogenic activity (Fig. 1).

Estrogens activate multiple ER -dependent responses. (a) 17ß-estradiol and prototypical xenoestrogens, phytoestrogens and metalloestrogens activate ER -dependent gene expression. (b) Activation of the estrogen receptor is required for normal physiological functions but also potentially mediates adverse effects, including breast and endometrial cancers and endocrine disruption.

The new report caps off a series of studies by Martin and colleagues on the estrogenic activity of several metal ions[8]. In experiments on MCF-7 breast cancer cells, the group had previously shown that divalent cadmium, copper, cobalt, nickel, lead, mercury, tin and chromium ions, as well as arsenite, selenite and vanadate, activate responses mediated by estrogen receptor- (ER ). They also found that the ligand-binding domain of ER is required for metalloestrogen-induced activation, as it is for other estrogenic compounds, and observed that different metal ions interact with distinct regions of the ligand-binding domain of ER . In several different estrogen-responsive in vitro assays, the estrogenic potencies of metal ions were 25-100% of the activity of 17ß-estradiol. Thus, metalloestrogens are more potent than phytoestrogens, most xenoestrogens of concern, and selective estrogen receptor modulators developed for the treatment of hormone-dependent cancers and estrogen deficiencies in women.

What has been missing is solid evidence that cadmium or other heavy metals have estrogenic effects in the whole animal. The paper by Martin and coworkers[1] should satisfy even the most skeptical among us with their finding that cadmium chloride is a potent estrogen mimic in female rats, at doses as low as 5-10 µg/kg (single intraperitoneal injection). Cadmium chloride induced several well-characterized estrogenic responses, including increased uterine weights, hyperplasia and hypertrophy of the endometrial lining, induction of uterine progesterone receptor and complement C3 gene expression, increased mammary epithelial density and induction of milk protein synthesis in the mammary gland. Both cadmium chloride and 17ß-estradiol gave comparable responses, and the antiestrogen ICI-182,780 inhibited cadmium chloride-induced activities. Moreover, in utero exposure to cadmium affected mammary gland development and onset of puberty in female offspring—both prototypical endocrine disruptor-like responses.

Cadmium-induced animal and human toxicities are generally observed at exposures up to 1,000 times higher than those used in this study[9]. Martin and colleagues did not carry out dose-response studies but their data indicate that global standards for cadmium intake may be lacking. They found that cadmium chloride induced potent estrogenic responses in rats at doses that are comparable to the Provisional Tolerable Weekly Intake (7 µg per kg per week) recommended by the World Health Organization. Background exposures in most human populations fall below that level, and in rats or humans the effect of such doses remains unknown[2].

One population in particular consistently takes in large amounts of cadmium: smokers. Cigarette smoking is a major contributor to the dietary intake of cadmium and to the bioaccumulation of cadmium in human tissue. Overall cadmium intake in smokers could exceed the Tolerable Weekly Intake. But cadmium's effects might not be straightforward. For example, smoking clearly protects against estrogen-dependent endometrial cancer[10]. Thus, humans might not experience the putative estrogenic effects of cadmium, or other components of cigarette smoke might neutralize these effects. On the other hand, there is evidence that cigarette smoking may contribute to breast cancer, depending on age of addiction[11].

If the cadmium-induced estrogenic responses reported in this study are considered to be harmful, application of currently used risk-assessment paradigms will set permissible levels of cadmium two or three orders of magnitude lower than current background levels in the diet. The problems for risk assessment of metalloestrogens and trace levels of xenoestrogens are compounded by high dietary intakes of phytoestrogens in items such as soybeans, fruit, vegetables and even wine. Phytoestrogens are also being used as health food supplements and for hormone replacement therapy. Moreover, diets also include many antiestrogenic compounds such as isoflavones, indole-3-carbinol and related compounds in cruciferous vegetables.

The US Environmental Protection Agency mandates development of standardized assays for estrogenic compounds, including assays comparable to those used by Martin and coworkers. Although it is clear that these assays will identify endocrine disruptors, the real question is how these results can be used to protect the public from the adverse health effects predicted by the endocrine disruptor hypothesis. Endocrine disruptors such as the metalloestrogens and xenoestrogens present a challenging risk assessment problem for regulatory agencies, as normal healthy diets contain high levels of phytochemicals that also activate multiple endocrine pathways[7].


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