Arsenic and Endocrines: New Study Suggests Disruption.

Chronic low-level human exposure to arsenic is associated with increased cancer risk. Epidemiologic studies of exposed populations in Asia and South America have shown a significant increase in the risk of skin, lung, liver, and bladder cancers, yet arsenic's carcinogenic mechanism remains unknown. Chronic exposure to arsenic also is associated with elevated risks of type 2 diabetes mellitus and vascular disease. In this issue, Ronald Kaltreider, Joshua Hamilton, and colleagues from Dartmouth Medical School in Hanover, New Hampshire, may have uncovered a clue to a central mechanism behind arsenic's myriad adverse health effects [EHP 109:245-251].

Low-level exposure to arsenic in drinking water is widespread in the United States and elsewhere. In New Hampshire, for instance, where 40% of the population's water supply comes from private wells, as much as 8% of the state (one-fifth of all private well users) may be exposed to arsenic concentrations between the U.S. Environmental Protection Agency's proposed standard of 10 parts per billion and the current standard of 50 parts per billion. At industrial sites and toxic waste sites--including over 70% of all Superfund waste sites--arsenic is usually found in combination with many other toxic chemicals, and it can leach into groundwater and find its way into drinking water.

The current study follows up on previous research that found that arsenic affects expression of the well-characterized phosphoenolpyruvate carboxykinase gene in rat liver cancer cells, reducing its responsiveness to hormone signals. Working in Hamilton's laboratory, which studies the effects of toxic metals on gene expression, Kaltreider and colleagues studied three sets of rat liver cancer cells. The first set was treated with various noncytotoxic concentrations of arsenite solution. The second was treated with a synthetic glucocorticoid hormone called dexamethasone (Dex). The third was treated with both arsenite and Dex. Glucocorticoids mediate a large array of effects. Among them are blood glucose regulation, vascular function, cell differentiation, and apoptosis, all of which are key functions in systems affected by arsenic exposure.

The researchers found that low doses of arsenic blocked the glucocorticoid receptor (GR) from responding to its normal hormone signal. More specifically, the researchers found that arsenic selectively disrupted the ability of GR in exposed cells to regulate the expression of its target genes in the nucleus, with the highest arsenite dose causing a greater than 50% suppression in Dex-inducible expression. Arsenite did not appear to interfere with the binding of Dex to GR or with the ability of Dex to activate GR and cause it to migrate to the nucleus. However, once inside the nucleus GR was unable to stimulate gene expression, even though it was fully activated by Dex.

Arsenic thus appears to act as a new class of endocrine disruptor by altering certain aspects of receptor function, even in nontoxic doses. GR is a critical player in mediating blood glucose regulation, so disrupting that function could be a part of how arsenic affects diabetes. GR is also an important regulator of normal vascular function, so disrupting GR in these tissues may contribute to how arsenic causes vascular disease. Finally, GR has been shown in animal and cell culture studies to play a crucial role in the cancer process in both the skin and the lung--both of which are targets for arsenic-induced carcinogenesis--and loss of GR function in animal tumor models has been shown to promote the cancer process in both tissues. The researchers therefore theorize that arsenic's action as an endocrine disruptor, although perhaps not the only mechanism, may be an important contributing factor in several different arsenic-related diseases.

Arsenic's effects also seem to be highly specific for GR-induced gene expression. Kaltreider and colleagues are currently' investigating whether binding of arsenic to GR directly causes the alterations in GR function. They suggest that possible effects of arsenic on other steroid receptors such as those for estrogen and progesterone should be investigated to determine whether arsenic's effects are specific to GR or a general effect on this family of hormone receptors.