Projects
09: Disruption of glucocorticoid- and mineralocorticoid receptor-mediated responses by environmental chemicals.
Activation of hormonal receptors by environmental chemicals.
The inappropriate activation of glucocorticoid and mineralocorticoid receptors can lead to adverse metabolic effects. Here, the disruption caused by environmental chemicals to these receptors is under investigation.
Odermatt Alex, Institute of Molecular and Systemic Toxicology Department of Pharmaceutical Sciences University of Basel
e-mail: alex.odermatt@unibas.ch
Background
Cumulative exposure to environmental chemicals poses serious health problems. Assessment of the risk associated with such chemicals has so far focused on their ability to interfere with the action of sex hormones such as estrogens and androgens. Whether disturbance of other hormones, including the glucocorticoid cortisol and the mineralocorticoid aldosterone, occurs remains largely unknown.
The inappropriate action of cortisol, acting on glucocortoid receptors, induces an array of metabolic effects including osteoporosis, weight gain, diabetes and cataracts, whereas the inappropriate action of the hormone aldosterone, acting on mineralocorticoid receptors, causes renal salt retention with hypertension, hypokalaemia and heart failure.
Aim
This project intends to investigate whether environmental chemicals disrupt the action of the hormones cortisol and aldosterone.
Significance
We identified organotin and dithiocarbamate compounds as potent inhibitors of a pre-receptor enzyme (11β-HSD2) which converts biologically active cortisol to inactive cortisone. Enhanced cortisol concentrations cause sodium retention and hypertension. The same compounds block the activation of both mineralocorticoid and glucocorticoid receptors. Thus, these compounds cause severely disturbed responses to both cortisol and aldosterone.
The enzyme 11β-HSD1 converts cortisone to cortisol. Enhanced cortisol activity is associated with an increased risk for the development of type 2 diabetes mellitus. 11β-HSD1 is therefore considered a promising target for the therapeutic treatment of type 2 diabetes mellitus. We identified flavanone as a selective inhibitor of 11β-HSD1 and are now testing it for beneficial effects in diabetic animal models.
7-ketocholesterol is most abundant in processed food. 7-ketocholesterol activates the mineralocorticoid receptor, which may contribute to sodium retention and hypertension or to the development of cardiac fibrosis. We found that 11β-HSD1 efficiently metabolizes 7-ketocholesterol in the liver, preventing accumulation.
Further studies are required to understand the molecular mechanisms and to assess the impact of environmental compounds on animal and human health.