Superfund Research Program
Arsenic as an Endocrine Disrupter
This project first discovered that arsenic can act as potent endocrine disruptor, and the current project continues to focus on two aspects of this effect. The first goal is to determine the mechanism(s) for these effects, focusing on the cellular and molecular level. The second goal is to determine the adverse consequences of low dose arsenic exposure and how arsenic ultimately increases disease risk via endocrine disruption and other mechanisms at the physiological level. Researchers have previously shown that arsenic profoundly affects the function of a wide variety of nuclear hormone receptors, making it a unique endocrine disruptor. It is likely, based on these results, that the mechanism for these arsenic effects involves a shared pathway or regulatory machinery given the diverse structures and functions of these receptors. Current work is focusing specifically on identifying the specific target(s) for these effects. Interestingly, at extremely low doses arsenic enhances hormone signaling while at slightly higher but still relatively low doses, arsenic has the opposite effect and suppresses hormone signaling. Researchers hypothesize that these opposite effects involve separate mechanisms and distinct targets. Currently work is focused on developing model systems where they can separate these two mechanisms to better understand them. Researchers recently reported that arsenic has a significant effect on the ability of an activated hormone receptor to interact with and modify nuclear DNA-chromatin to regulate gene expression in a cell culture model (FD Barr et al., PLoS ONE 4:e6766, 2009). As part of Aims 1 and 2 the researchers also recently reported that low level drinking water arsenic has profound and tissue-specific effects on expression of genes and proteins involved in the innate immune response in mouse lung (CD Kozul et al., Environ Hlth Perspect 117:1108-1115, 2009). Based on this discovery, researchers hypothesized that this innate immune suppression would compromise the immune response to a viral or bacterial challenge in lung, and this turns out to be the case, as they recently reported (CD Kozul et al., Environ Hlth Perspect 117:1441-1447, 2009). Mice that were exposed to arsenic in drinking water at 100 ppb for five weeks had a significantly compromised response to H1N1 influenza infection, leading to increased morbidity and, ultimately, death. This has profound implications for human health, since some 25 million people in the U.S. are exposed to excess arsenic in drinking water and some 25-30% of the population contracts the flu each year. In a follow-up study, they demonstrated that arsenic directly affects the migration of immune cells called dendritic cells that are critical to the innate immune response to influenza, suggesting that this may be one of the major mechanisms underlying this effect (CD Kozul et al., manuscript submitted 2009). This immune modulation may also explain why arsenic is able to affect long-term risk of various lung diseases in exposed populations, even decades after cessation of exposure.