Superfund Research Program
Arsenic as an Endocrine Disrupter
Dr. Joshua Hamilton’s research group first reported in 2001 that arsenic acts as potent endocrine disruptor, and work continues to focus on two aspects of this effect. The first research goal is to determine the mechanistic basis for these effects, focusing on the cellular and molecular levels. The second is to determine the patho-physiological 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 group has shown that arsenic profoundly affects the function of all five steroid hormone receptors, i.e., those for glucocorticoids, mineralocorticoids, androgen, estrogen and progesterone, in a very similar manner; as well as the type 2 nuclear hormone receptors for thyroid hormone and retinoic acid. It is likely, based on these results to date, that the mechanism for these arsenic 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. Current work is focusing specifically on identifying the target(s) for these effects at the cellular and molecular level. The researchers have also examined the consequences of such disruption in several model in vivo systems, and previously demonstrated that arsenic at very low levels disrupts thyroid hormone-mediated metamorphosis in a frog tadpole model (JC Davey et al., Environ Hlth Perspect 116:165-172, 2008), and that it 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. Toxicogenomics studies in mice revealed new understanding of patterns of altered gene expression by low-level drinking water arsenic in lung and liver (CD Kozul et al. Chem-Biol Interact 173:129-140, 2008; CD Kozul et al. manuscript submitted 2008; JC Davey et al., manuscript in preparation 2008). Further, project researchers recently discovered that low level drinking water arsenic has profound and tissue-specific effects on innate immune response in mouse lung (CD Kozul et al., manuscript submitted 2008; CD Kozul et al., manuscript in preparation 2008) which may explain why arsenic is able to affect long-term of various lung diseases in exposed populations even decades after cessation of exposure. The long-term goal is to understand and prevent or ameliorate arsenic-induced human health impacts.