March 1, 2001

A team of Dartmouth Medical School investigators has uncovered what may be a unique mechanism for the way chronic exposure to low levels of arsenic increases the risk of certain diseases. The work is described in the March issue of the journal Environmental Health Perspectives.

Arsenic at high doses has been known as the poison of choice since ancient times. Recently, it has become clear that decades of exposure to very low doses of arsenic - such as levels found in drinking water in many areas of the United States - may substantially increase the risk of vascular disease, diabetes and several types of cancer. Until now, little was known about how arsenic might contribute to these diseases, however.

Using cultured animal cells, a team led by toxicologist Joshua Hamilton, director of Dartmouth's Toxic Metals Research Program, found that exposure to very low concentrations of arsenic disrupts the function of the glucocorticoid receptor, a steroid hormone receptor that regulates a wide range of biological processes. Arsenic appears to suppress the ability of this critical receptor to respond to its normal hormone signal. Chemicals that disrupt steroid hormone receptor signaling are called endocrine disruptors. Arsenic, a metal, appears to act through a unique mechanism not previously shown for other endocrine disruptors such as pesticides.

"This is unlikely to be the only mechanism underlying diseases associated with low-level arsenic exposure, but we suspect it will be an important contributor," says Hamilton. The research was performed in Hamilton's laboratory in the Department of Pharmacology and Toxicology by former graduate student Ronald Kaltreider (now an assistant professor at York College in York Pa.) with the assistance of undergraduate student Alisa Davis and research assistant Jean Lariviere. The Toxic Metals group is one of the interdisciplinary research projects associated with the Center for Environmental Health Sciences at Dartmouth, which Hamilton also directs. The work is funded by a grant from the National Institute of Environmental Health Sciences and the Environmental Protection Agency through the Superfund Basic Research Program.

Glucocorticoids are steroid hormones in the same class as estrogen, progesterone and testosterone. Steroid hormones are chemical messengers secreted by glands into the bloodstream and carried to distant cells throughout the body where they help regulate the body's functions. Each hormone has a specific receptor it binds to in order to initiate its effects. Glucocorticoids, acting through their receptor, help regulate embryo development, stress, blood glucose levels, blood vessel function, and lung and skin development, and may also play a key role in suppressing cancer.

Prior to this study, endocrine disrupting chemicals were thought to act primarily in one of two ways. One way is by binding to a steroid receptor and mimicking the normal hormone, leading to an inappropriate activation of the receptor. The other way is by binding to the receptor and blocking the ability of the normal hormone to activate the receptor. Arsenic appears to act in a third way. Kaltreider's research demonstrated that arsenic does not inappropriately activate the glucocorticoid receptor, nor does it block its ability to bind hormone or be activated by hormone binding. Rather, in the presence of arsenic, the activated receptor is unable to stimulate the correct cascade of signals that usually results from hormone binding, particularly the ability to turn on certain hormone-responsive genes. Metals have not previously been shown to act as endocrine disruptors. Blocking the actions of the glucocorticoid receptor by arsenic in this unique way could explain, at least in part, many of the health effects observed in arsenic-exposed human populations.

Whether the effects observed in cultured cells also occur in animals or humans exposed to low doses of arsenic remains to be determined, and Hamilton's laboratory is actively pursuing that research. The researchers are also examining whether arsenic has a similar effect on the estrogen, progesterone and testosterone receptors, which could have further implications for arsenic's effects on human health.

Nancy Serrell
Center for Environmental Health Sciences

(Abstract) Arsenic and Endocrines: New Study Suggests Disruption