Superfund Research Program
Arsenic as an Endocrine Disrupter
Dr. Hamilton and his research team first reported that arsenic acts as potent endocrine disruptor, and continue to focus on two aspects of this effect. The first goal is to determine the mechanistic basis for these effects, focusing on the cellular and molecular levels. The second is to determine the pathopysiological consequences of such endocrine disruption, and the overall role such effects play in the ability of arsenic to increase risk of the myriad of chronic and deadly diseases with which it has been associated in epidemiological studies. The project researchers initially reported that arsenic alters glucocorticoid receptor-mediated gene regulation both in vivo and in cell culture models. They have recently reported that arsenic also profoundly affects the function of the other four steroid hormone receptors, i.e., those for mineralocorticoids, androgen, estrogen and progesterone, in a very similar manner. These results were recently reported in a manuscript published in Chemical Research in Toxicology and a second manuscript recently submitted for publication. The researchers have also shown that arsenic alters in a similar manner the ability to regulate gene transcription by the type 2 nuclear hormone receptors for thyroid hormone and retinoic acid (manuscript submitted for publication). It is likely, based on these results to date, that the mechanism for these effects involves a shared pathway or regulatory machinery given the lack of absolute structural homology among these diverse proteins. In addition, these results suggest that many other nuclear hormone receptors may be affected similarly by arsenic. Given the myriad of functions that these receptors and their hormones modulate in normal human biology, as well as the many diseases in which they have been shown to play a fundamental role, it is hypothesized that this is one of the major pathways by which arsenic increases the risk of various cancers, heart and vascular disease, reproductive and developmental problems, diabetes, and the growing list of other diseases associated with arsenic exposure. These results also predict that there will be human health effects at drinking water levels of arsenic at or below the current U.S. drinking water standard of 10 ppb since these effects were observed at levels far below 10 ppb in cell culture and at or below this level in several in vivo models. The project researchers' current work is focusing on how arsenic perturbs the interaction of these receptors with the partner proteins that are required for modulating hormone-induced gene transcription. They have also examined the consequences of such disruption in several model in vivo systems. Project researchers recently demonstrated that arsenic at very low levels (2-10 ppb) disrupts thyroid hormone-mediated metamorphosis in a frog tadpole model (manuscript submitted for publication). Similarly, the researchers demonstrated, in collaboration with the Arsenic and ABC Transporters project, that arsenic profoundly alters glucocorticoid receptor-mediated regulation of the CFTR protein, a chloride channel that regulates salt balance in the model fish, killifish, and also in human lung. Mutations within the CFTR gene are responsible for the human disease, cystic fibrosis. Dysfunction of CFTR in killifish by low dose arsenic treatments led to the inability of these fish to adapt to their normal transition from freshwater to salt water, resulting in toxicity and lethality at doses that are otherwise not toxic. Finally, mice given arsenic in drinking water for five weeks at the current US drinking water standard, 10 ppb, showed profound alterations in patterns of gene expression in liver and lung, and many of these gene changes are consistent with the hypothesis that arsenic is acting principally as an endocrine disruptor in vivo at very low levels. Further work will explore in more detail the precise mechanism by which arsenic disrupts hormone receptor action, and also will examine the consequences of this disruption by focusing on key genes involved in specific disease processes such as carcinogenesis, diabetes and vascular disease. In addition to these primary objectives, Dr. Hamilton also collaborates with several other projects within the program to conduct toxicogenomics studies and other molecular investigations. Project researchers have worked with the Arsenic Epidemiology, Biomarkers and Exposure Assessment project to examine the effects of arsenic on DNA repair in lymphocytes of people exposed to arsenic in New Hampshire drinking water. They have also worked with the Trophic Transfer of Toxic Metals in Aquatic Food Webs project to develop and use genomics tools in Daphnia to examine effects of metals on gene expression. And they have worked with the Arsenic and ABC Transporters project to examine endocrine disruption by arsenic in killifish. These studies have enhanced the researchers' own understanding of arsenic effects while also providing powerful new tools and observations to these other projects.