Many industrial and environmental chemicals mimic, antagonize, or indirectly alter the activity of hormones, particularly steroid hormones. It is commonly thought that these chemicals bind to the estrogen receptor or androgen receptor, either imitating the action of the hormones or blocking their activity. However, it is also possible that some of these compounds may act in an indirect fashion by either inhibiting aromatase activity or inducing aromatase expression, resulting in a change in the level of estrogen in women. Aromatase is a cytochrome P450 enzyme that converts androgen to estrogen. During the previous grant period, this laboratory has made important accomplishments in three areas. It has been demonstrated that computer modeling, aromatase site-directed mutagenesis, and inhibition profile analyses are useful tools for evaluating the molecular basis of the inhibition of aromatase by endocrine disrupters such as flavone and isoflavone phytoestrogens. Furthermore, the laboratory has developed a yeast screen system that can be adapted for use as a high throughput method to screen endocrine disrupters with anti- aromatase activity. In addition, the orphan receptor ERRalpha-1 was identified as a target of endocrine disrupters.
The specific aims for this grant period are: (1) to refine the yeast screening system as a high throughput approach to identify endocrine disrupters for aromatase inhibitors and ligands for androgen receptors; (2) determine the binding nature of endocrine disrupters that have anti-aromatase activity; and (3) to investigate the molecular basis of the interaction of endocrine disrupters with ERRalpha-1.
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