Superfund Research Program
Arsenic as an Endocrine Disrupter
The overall goal of this project is to determine how toxic metals alter expression of certain genes, and whether these effects contribute to the ability of these metals to cause cancer and other diseases in humans. Project researchers are specifically focusing on the carcinogenic metals, chromium(VI) and arsenic(III), which are present at high concentrations at many Superfund and other toxic waste sites, and are also of significant concern in other environmental and occupational settings. Each of these metals has been previously shown to cause profound changes in expression of specific genes at very low doses that are roughly comparable to those that might occur from chronic human exposures in an occupational setting or from environmental contamination. Recent studies have demonstrated that both arsenic and chromium directly interact with the glucocorticoid receptor (GR), which is one of the steroid hormone receptors responsible for mediating the biological effects of cortisol and other corticosteroid hormones. This occurs at very low doses of these metals, and leads to alterations in expression of genes that are regulated by this receptor, altering both their baseline expression and their normal response to hormones. However, the specific effects of each metal are different.
Chromium treatment alone appeared to mimic a hormone signal, activating the receptor and causing an increase in expression of GR-regulated genes. However, prior chromium treatment also suppressed the ability of GR to subsequently respond to glucocorticoid hormone. Arsenic appeared to irreversibly inactivate the receptor. Arsenic treatment alone suppressed baseline expression of GR-responsive genes, and totally blocked the subsequent responsiveness of GR to its normal hormone signal. Arsenic pre-treatment also blocked the responsiveness of GR to chromium alone or to chromium plus hormone. Thus, the arsenic effect was dominant over the effects of chromium or hormone treatments. Based on these results, project investigators propose that these toxic metals may represent a new class of "endocrine disrupters" that directly target GR and perhaps other steroid receptors, leading to altered function and changes in receptor-mediated gene expression. Such effects could contribute to the actions of these metals in carcinogenesis and other disease processes in significant ways. Assessment of these effects is important and relevant to exposures at Superfund sites, and to other types of environmental and occupational exposures to these metals. Results contribute to the understanding of mechanisms by which these metals cause disease. Of great practical importance, such studies may provide very sensitive and specific molecular biomarkers of toxic metal exposure. It is anticipated that some of these responsive genes may be commonly altered by a number of metals and other toxins, whereas others may be metal-specific, providing important new tools for future environmental and epidemiological studies.