Superfund Research Program
Arsenic as an Endocrine Disrupter
Dr. Joshua Hamilton and his team of researchers first discovered that arsenic can act as a potent endocrine disruptor, and the current research 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 (Aims 1 and 2). The second goal (Aim 3) 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.
The research group has 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 (Aim 1) while at slightly higher but still relatively low doses, arsenic has the opposite effect and suppresses hormone signaling (Aim 2). The researchers hypothesize that these opposite effects involve separate mechanisms and distinct targets.
Current work is focused on developing model systems where the researchers can separate these two mechanisms to better understand them. As part of Aims 1 and 2 the research group previously 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, they hypothesized as part of Aim 3 that this innate immune suppression would compromise the immune response to a viral or bacterial challenge in the lung, and this turns out to be the case, as they also previously 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. Current research is focusing on three related projects from these observations.
First, as part of Aim 1, the researchers have developed a cell culture model system that allows them to determine whether arsenic alters the kinetics or function of nuclear hormone receptors using a photo-activatible GFP-tagged glucocorticoid receptor stably expressed in a human cell line (paGFP-GR-HEK cells), and have seen effects of very low dose arsenic to enhance receptor signaling via changes in receptor activation (FJ Zandbergen et al., manuscript in preparation 2010a). Second, as part of Aims 1 and 2, they have observed profound effects of arsenic on cell differentiation and lipid metabolism in cultured cells (FJ Zandbergen et al., manuscript in preparation 2010b) and on growth and lipid homeostasis in newborn mice exposed to arsenic in vivo via the mother (CD Kozul-Horvath et al., manuscript in preparation, 2010a). Third, as part of Aim 3, the research group has observed effects of arsenic on native immunity in these newborn mice (CD Kozul-Horvath et al., manuscript in preparation, 2010b). As part of a collaboration with Dr. Margaret Karagas and another laboratory previously at Dartmouth (D Robbins and colleagues, now at U. Miami), and stemming from an initial observation made in this research group from transcriptome profiling regarding changes in the hedgehog pathway following exposure of mice to arsenic in vivo, the researchers collaborated to investigate the effects of arsenic on hedgehog signaling and saw effects in a cell culture model as well as a correlation between altered hedgehog signaling and arsenic-induced tumors in New Hampshire residents that were part of an ongoing epidemiology study (DL Fei et al., Cancer Res 70:1981-1988, 2010). Dr. Hamilton also helped organize, and participated in, a NIEHS-sponsored workshop on the use of phenotypic anchoring to investigate arsenic health effects (JC States et al., manuscript in preparation, 2010).