The overall objective of this research is to determine the mechanism by which inorganic arsenic (As)increases human disease risks. The specific goal is to determine the mechanism by which As acts as anendocrine disrupter, which our laboratory first reported and has now demonstrated occurs with severalnuclear hormone receptors via a unique mechanism distinct from that of other known endocrine disrupters.We hypothesize that As-induced endocrine disruption is one of the principal means by which it is able toinfluence the wide array of disease risks including various cancers, diabetes, cardiovascular disease anddevelopmental problems to which it has been linked in epidemiology studies, and that these effects are aresult of As targeting one or more critical regulatory steps that are shared by these receptors, leading in turnto a variety of patho-physiological consequences. We will examine As effects on glucocorticoid receptor(GR)-mediated gene expression in H4IIE and EDR3 rat hepatoma cells as our principal model system,focusing on the differential effects of As on GR signaling at low and intermediate As doses.
Our SpecificAims are to: 1) Determine the effects of very low dose As (0.01-1 u.M, 0.75-75 ppb) to enhance GR-mediatedgene regulation. We hypothesize that these effects are a result of As targeting the early steps in receptoractivation between binding of hormone and activation of transcription. 2) Determine the effects ofintermediate dose As (1-3 |aM, 75-225 ppb) to suppress hormone receptor-mediated gene regulation. Wehypothesize that these effects are distinct from the enhancement seen at lower doses, and involve theintermediate to later steps of receptor-mediated transcription. 3) Determine the effects of endocrinedisruption by As on two hormone-regulated and As-affected genes, TAT and GREB1, that are likely to beinvolved in As-associated disease processes. We will use a combination of confocal microscopy, molecularbiology, biochemistry, and proteomics approaches to investigate these questions. The long-term goals of thisproject are to provide mechanistic insights that can be used for more effective science-based riskassessments, for predicting the specific patho-physiological consequences of As exposure, for assessinggene-environment, agent-agent and other interactions, for assessing specifically sensitive sub-populations atelevated risk, and for developing effective interventions for these As-exposed populations.
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