Authors
Johnson, M.D., Kenney, N., Stoica, A., Hilakivi-Clarke, L., Singh, B., Chepko, G., Clarke, R., Sholler, P.F., Lirio, A.A., Foss, C., Reiter, R., Trock, B., Paik, S., Martin, M.

Title
Cadmium mimics the in vivo effects of estrogen in the uterus and mammary gland

Journal
Nature Medicine. Advance Online Publication. 13 July 2003.

Summary
Cadmium is primarily obtained as a byproduct of mining, smelting, and treatment of zinc, lead, and copper ore. Approximately 10% of cadmium is produced by iron and steel scrap recycling. The majority of all cadmium produced is used in batteries, and a smaller amount is used in plastic stabilizers, plating, coatings, and pigments. The World Health Organization (WHO) has estimated the daily dietary exposure of cadmium in the United States, Germany, the United Kingdom, and Sweden to be between 0.12 and 0.49µg/kg/day. Cigarette smoking contributes between 2 and 4µg of cadmium per pack. Many adverse health effects from acute and chronic cadmium exposure have been well documented, the primary health effects being kidney damage and lung cancer. A recent study by Michael D. Johnson and colleagues at Georgetown University has shown that cadmium can act as a potent estrogen in vivo with detectable effects at environmentally relevant levels.

Johnson et al. surgically removed the ovaries of female rats, eliminating the main estrogen source in these animals. The rats were allowed to recover and were then given a single dose of 5µg/kg of cadmium. A positive control group of animals received a pellet implant releasing 60µg/kg/day of estradiol. A third group was injected with both cadmium and the anti-estrogen, ICI-182,780. The observed responses from each of these groups were compared to those from an untreated control group of ovariectomized rats. The uterine responses were examined 4 days after treatment, and the mammary gland responses were measured 4 and 14 days after treatment. The uterine weight of animals treated with estradiol increased 3.8 times compared to controls. The cadmium-treated rats also had a growth in uterine weight of 1.9 times that of control animals. Exposure to ICI-182,780 eliminated the effect of cadmium and thus the uterine weight did not increase in animals treated with this chemical. These results suggest that the response of uterine tissue to cadmium exposure is mediated via the estrogen receptor. Histological examination of the tissues revealed that the increase in uterine weight was consistent with an estrogenic response and was not the result of toxicity. Mammary gland responses were also consistent with estrogen exposure. In animals exposed to cadmium and estradiol, epithelial density increased significantly compared to controls. The growth induced by cadmium was the result of expanding duct branches and increased alveolar structures. As with uterine tissue, the response was eliminated by ICI-182,780 exposure, suggesting that the effects of cadmium in the mammary gland are mediated by the estrogen receptor.

The authors of the present investigation also sought to determine the effect of cadmium on activation of genes under the control of estrogen. Johnson et al. measured changes in progesterone receptor (PGR) and C3 mRNA levels induced by estradiol and cadmium exposure. Estradiol exposure in the uterus produced a 3-fold increase in PGR mRNA and a 124-fold increase in C3 mRNA. Likewise, cadmium induced a 2-fold increase in PGR mRNA and a 12-fold increase in C3 mRNA. In the mammary gland, estradiol increased PGR mRNA 42-fold and C3 mRNA 416-fold. In animals exposed to cadmium, mammary expression of PGR mRNA increased 9-fold and C3 mRNA increased 16-fold. Increase in PGR and C3 mRNA expression in the uterus and mammary gland were blocked by ICI administration, indicating that the responses are mediated by the estrogen receptor.

It is well established that in utero exposure to estrogen affects the rate of sexual development and mammary gland development. To determine the effects of cadmium following in utero exposure, cadmium was administered to pregnant rats via injections. At low exposure levels, cadmium increased the body weights of female offspring compared with control offspring, induced an earlier onset of vaginal opening, and altered the structure of the mammary glands by increasing the epithelial area and the number of terminal end buds. These changes are consistent with in utero exposure to low doses of estrogen and provide additional proof that environmentally relevant doses of cadmium mimic the effects of estrogen.

Since cadmium is not known to bind to the estrogen receptor, there is a need to further investigate the mechanism(s) of action of this toxicant. Given the modest response of cadmium relative to estradiol, the potential that the mechanism involves alternative signaling pathways that also result in estrogen-like effects in the uterus and mammary gland must be explored. Regardless, there is concern surrounding the issue of cadmium exposure on human health, primarily due to the metal's long half-life of 10 to 30 years. The demonstrated effects of cadmium exposure on mammary gland development suggest that this metal may be a potential risk factor for breast cancer. The authors note that cadmium levels found in human breast tissue are typically much higher than those measured in exposed experimental animals. Further studies must be performed to determine whether exposure to environmentally low doses of cadmium over an extended period of time would have estrogenic effects in humans.