Superfund Research Program
Arsenic as an Endocrine Disrupter
Chronic exposure to arsenic in drinking water is associated with increased risk of various cancers, type 2 diabetes, vascular and cardiovascular disease, and developmental and reproductive problems. The mechanisms by which arsenic contributes to these various disease processes is unknown. This project is primarily examining potential mechanisms, focusing in particular on the ability of low-level arsenic to selectively alter the pattern of gene expression in specific cells. Project 2 investigators also collaborate with investigators in Projects 1, 4 and 7 to develop and apply genomics and proteomics tools in these studies.
Dr. Hamilton's team has previously shown that arsenic can act as a potent endocrine disruptor, blocking the ability of glucocorticoid hormone to signal through its hormone receptor, the glucocorticoid receptor (GR). They 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, or the proteins with which they must interact to elicit altered gene expression, appear to be the direct target for these effects, presumably by binding of arsenic to critical sites on these proteins. 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 focus of this year's research was four-fold. The first objective was to examine in more detail the mechanism for these effects, using specific mutations in GR to examine structural and functional features of GR that may be the target. These studies indicate that the central DNA binding domain is critical for these effects, and that individual amino acid residues modulate these effects. However, the researchers were unable to ablate the arsenic effect with any mutations, suggesting that while GR structure is important, the GR molecule itself may not be the actual binding target. The second goal was to examine the role of DNA-chromatin structure in these effects. They recently demonstrated that arsenic substantially alters the pattern of changes in chromatin that are critical for hormone receptor signaling. The third goal was to examine other critical nuclear receptors. They have evidence that both thyroid hormone receptor and the retinoid receptor family are affected by arsenic in a similar manner as the steroid receptors. Fourth, Dr. Hamilton's team has used genomics approaches to investigate the global patterns of gene expression changes in specific using mice exposed to arsenic in drinking water, in collaboration with Aaron Barchowsky of Project 1 and with Drs. Jay Gandolfi and Clark Lantz of the Arizona Superfund Basic Research Program. The investigators recently completed the first of these studies and have shown that there is a small number of very specific changes that occur in lung and heart, and that these changes are tissue-, dose-, and time-point specific. They have worked with Project 4 to examine effects of arsenic on expression of DNA repair genes in the New Hampshire population and have also worked with Project 7 to use genomics tools to develop potential biomarkers of toxic metal exposure and effect in the aquatic sentinel species, Daphnia pulex. The strong and very specific effects of arsenic on nuclear 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 reproductive and developmental problems, vascular disease, diabetes and many different arsenic-associated cancers.