In vivo Imaging Analysis of Steroid-Nuclear Receptor Function

Division Of Basic Sciences - Nci

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Abstract

1 Globally, contaminant exposure in unregulated water sources is a recognized public-health data gap and an obstacle to both risk-management. To address contaminant exposures in hydrologically-vulnerable aquifers, rivers, and tap water, samples were collected from multiple sources. We assessed EDCs activity (aryl hydrocarbon [AhR], androgenic [AR], thyroid [Ty], estrogenic [ER], corticosteroid [CS]) with novel mammalian cell-based assays that express nuclear steroid receptors. Results demonstrate that AR and AhR activities are commonly detected in water supplies, and that bioactivity varies by season and utility/sample characteristics. Screening EDCs with bioassays holds promise for characterizing population exposure to diverse EDCs mixtures. Continued assessment of unmonitored and unregulated private supply TW is needed to model contaminant exposures and human-health risks. 2. The glucocorticoid receptor (GR) is widely believed to bind DNA as a dimer to regulate gene responses related to its anti-inflammatory effects. This model has been built upon widely reported studies that focus on dead cell genomics. We reported earlier that GR adopts a tetramers conformation on response elements in living cells. Recent reports from the Barcelona group identified crystal structures for AR GR consistent with tetramer formation. We analyzed a variety of GR DBD and LBD mutations and their effect on multimerization. We report preliminary evidence that the GR can also form crystal structures with tetrameric conformations. Results do support a physiological role for tetrameric GR and are consistent with a common mode of receptor binding via higher order structures that drives both the activating and repressive actions of glucocorticoids.