Superfund Research Program
Arsenic as an Endocrine Disrupter
This project is examining the mechanisms by which exposure to arsenic and chromium contribute to human disease risk. Dr. Hamilton's team had previously shown that arsenic can act as an endocrine disruptor, blocking the ability of glucocorticoid hormone to signal through its hormone receptor, the glucocorticoid receptor (GR). Project investigators subsequently demonstrated similar effects of arsenic on signaling by each of the other steroid hormones, i.e., the estrogen, progesterone, testosterone and mineralocorticoid hormones - acting through their respective hormone receptors - both in cell culture and whole animal models. The receptors themselves appear to be the target for these effects. These steroid hormone receptors are all part of the nuclear receptor superfamily, and arsenic may also disrupt other members of this critical family of regulatory proteins. The researchers are currently investigating whether there are similar effects of arsenic on signaling through the retinoid and thyroid hormone receptors. The most significant progress this year was in beginning to determine the specific regions or amino acid residues within these receptors that mediate these arsenic effects. Specific experimental mutations generated within the GR molecule have demonstrated that the central DNA binding domain (DBD) of GR is the critical region for mediating these arsenic effects, since the entire amino or carboxy terminal portions of GR can be removed without altering the arsenic effect on GR signaling. Point mutations within the DBD region that changed the amino acids at the two DBD cysteines that are outside the zinc finger region (see Project 5) indicate that, while cysteines are not obligatory at these sites (and therefore not likely to be direct binding sites for arsenic), there are qualitative changes in the arsenic response. Comparison of these effects with other mutational data previously obtained with GR suggest that arsenic is altering the three-dimensional conformation of GR as one of the principal mechanisms by which it affects GR signaling. The strong effects of arsenic on hormone receptor signaling at very low doses - which are comparable to those that might typically be encountered by the U.S. population in areas of high drinking water arsenic contamination - suggest that such effects on endocrine signaling may be a major contributor to the processes by which long term arsenic exposure increases the risk of vascular disease, diabetes and many different arsenic-associated cancers.