Disruption of Glucocorticoid and Mineralocorticoid Receptor-Mediated Responses by Environmental Chemicals

Abstract

Glucocorticoids and mineralocorticoids are key endocrine hormones modulating essential physiological processes such as energy metabolism, cell growth and differentiation, maintenance of blood pressure and immune responses. Despite their importance and the fact that their impaired function has been associated with various diseases, there are only few studies on the potential disruption of glucocorticoid and mineralocorticoid action by xenobiotics. To facilitate the identification and characterization of such chemicals, we established cell-based assays to determine the impact of xenobiotics on different steps of corticosteroid hormone action. Screening of a small library of chemicals led to the identification of several compounds inhibiting the 11?-hydroxysteroid dehydrogenase (11?-HSD) prereceptor enzymes 11?-HSD1 and/or 11?-HSD2 and of chemicals blocking the function of glucocorticoid receptors (GR) and mineralocorticoid receptors (MR). These findings build a basis to extend the search for chemicals acting on additional targets of the corticosteroid hormone pathway and to apply in silico prediction tools in combination with biological testing to screen large numbers of chemicals. The identification of chemicals interfering with corticosteroid action and the elucidation of the underlying molecular mechanisms are relevant with respect to the potential contribution to common diseases such as metabolic syndrome, immune diseases, brain disorders and cancer.