Superfund Research Program
Arsenic as an Endocrine Disrupter
There is growing concern about environmental exposure to the toxic metals, arsenic and chromium, and their effects on human health and the environment. Certain geographic areas of the U.S., including most of New Hampshire and Maine, areas of Michigan, and several large regions of the West and Southwest, have substantial levels of arsenic in groundwater from natural geological sources. In addition, arsenic is present in over 70% of all Superfund sites, in combination with other toxic metals and toxic organic compounds. Elevated arsenic in drinking water is strongly associated with a significant increase in risk of diabetes, vascular disease, and several forms of cancer in exposed populations. Chromium(VI) is a human lung carcinogen under certain high dose, occupational exposure conditions, and is also present in the environment as a contaminant from various human activities.
The overall goal of this research project is to determine the molecular mechanisms underlying the effects of arsenic and chromium on human disease. Project investigators are specifically focusing on the ability of these metals to selectively alter the expression of specific target genes, and the role this may play in arsenic- or chromium-induced disease. Previous work indicated that a steroid hormone receptor, the glucocorticoid receptor (GR), was a specific target for effects of each metal (Kaltreider et al., 1998; Hamilton et al., 2000). Recent studies have revealed that arsenic can almost completely block GR-mediated regulation of glucocorticoid-responsive genes, and this appears to occur through a unique endocrine disrupting mechanism not previously described (Kaltreider et al., 2001). Arsenic does not activate GR, suggesting that it does not mimic the natural hormone (as some other organic endocrine disruptors have been shown to do). In addition, arsenic does not block binding of hormone to GR (as some other organic endocrine disruptors do) or the ability of GR to be activated, translocate to the nucleus or bind to DNA in response to hormone binding. However, once inside the nucleus, the hormone-activated GR fails to regulate several normally hormone-responsive genes. Project investigators postulate that this is a result of arsenic binding directly to GR, at a site other than the site for hormone binding, and blocking its ability to interact with other key proteins that are required for gene regulation inside the nucleus. The researchers are actively investigating this and other possible mechanisms to explain these effects. GR is known to play a key role both in glucose regulation by the body, and in normal vascular tissue function. Thus, disruption of GR function by arsenic might be expected to contribute to arsenic's ability to increase risk of type 2 diabetes and vascular disease. GR has also been shown to play a key role in normally suppressing the cancer process in two relevant animal cancer models, one for skin cancer and the other for lung. Moreover, loss of GR function was shown to be permissive to the cancer process in these and several related skin and lung cell culture models.
Since skin and lung cancer are substantially elevated in arsenic-exposed human populations, researchers hypothesize that the ability of arsenic to block GR function may contribute to these disease processes. Animal and human studies will determine whether there is direct evidence for this. The researchers also previously observed effects of chromium(VI), the carcinogenic form of chromium, on GR function. However, these recent studies revealed that this is an indirect effect, involving metabolism of chromium(VI) outside the cell to the nutritional form of chromium, i.e., chromium(III). Chromium(III) was shown to stimulate production of a cell signaling molecule, cyclic AMP (cAMP), which in turn caused the effects on GR regulation we had previously observed (Hamilton et al., 2001). This effect was modest with chromium alone, but chromium also increased the signaling of other cell surface receptors, notably the glucagon receptor, which signaled at a much higher level in the presence of chromium than in the absence, and led to higher cAMP levels and greater gene expression effects by the combination. This is the first demonstration of chromium affecting this cAMP pathway. The other known effect of chromium(III) is to enhance the signaling of insulin at the cell surface. Thus, it appears that chromium can alter these two pathways. Interestingly, insulin and glucagon are the primary signaling molecules on opposite sides of the glucose regulation "seesaw," and normally balance each other out to allow our bodies to maintain constant glucose levels. Project investigators are now investigating how these effects contribute to the overall effects of chromium on gene expression, and the beneficial or detrimental biological effects that follow, when cells or animals are exposed to chromium(VI) or chromium(III).