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 (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. Dr. Joshua W. Hamilton’s research team 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. The current project 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 in Aims 1 and 2 is focused on two areas: the first is using a cell culture model system the group developed 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). The second area is extending their work with specific receptors to focus on the PPAR receptor system and its regulation of lipid metabolism and adipocyte differentiation. The researchers have observed profound effects of low-dose arsenic on PPAR regulation of gene expression in response to hormone stimulation, and this results in changes in PPAR-mediated cell differentiation and lipid metabolism in cultured cells (FJ Zandbergen et al., manuscript in preparation 2011). Regarding Aim 3, the group recently observed effects of low-dose arsenic on growth and lipid homeostasis in the mothers and their newborn mice exposed to arsenic in vivo via drinking water to the mother (CD Kozul Horvath et al., manuscript submitted, 2011). The researchers have also seen profound effects of low-dose arsenic in drinking water on lipid regulation in adult male mice. Collectively, these results suggest that the broad endocrine disrupting abilities of arsenic in vivo result in specific patho-physiological effects at low doses as a consequence. These results are concordant with recent epidemiology studies indicating a link between arsenic exposure and metabolic disorders in human populations, and the group’s results with the pregnant female mice suggest that in utero and early childhood exposures may also result in metabolic disorders in the offspring.