ENDOCRINE DISRUPTING CHEMICALS AND AROMATASE

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DESCRIPTION: (adapted from the applicant's description) Many industrial and environmental chemicals mimic, antagonize, or indirectly alter the activity of hormones, particularly steroid hormones. In women, these chemicals mainly affect the activity of estrogens. It is commonly thought that these chemicals bind to the estrogen receptor, either imitating the action of the hormone or blocking its 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 synthesizes estrogen. Preliminary results have been obtained to indicate that phytoestrogens and organochlorine compounds can act as endocrine disrupters in women by modifying the level of estrogen through altering either the activity of aromatase or the expression of the enzyme. Experiments will be carried out to provide a molecular and mechanistic basis as to how phytoestrogens and organochlorine compounds affect estrogen biosynthesis (i.e., aromatase function) in women. The structural requirement for the compounds to modify the catalytic properties of aromatase will be determined by computer modeling and by evaluation of their interactions with aromatase mutants. In addition, the effects of phytoestrogens and organochlorine compounds on aromatase expression throughout critical periods of exposure (neonatal, premenopausal, pregnant, and postmenopausal) will be investigated using cell culture studies with cell lines that utilize different promoters for aromatase expression.