In 1995, we defined the in-vivo and in-vitro ovarian toxicity of ethylene glycol monomethyl ether (EGME), a commonly used solvent in the chemical and food industries. Until our studies, the site of reproductive toxicity in the female had been unknown. We have found that EGME (300 mg/kg) specifically stimulates luteal cell progesterone production in cycling Sprague-Dawley rats in-vivo resulting in corpora lutea hypertrophy and physiological pseudopregnancy. Similarly, the active metabolite of EGME stimulates progesterone production in a dose- and time-dependent manner in cultured rat luteal cells. We are currently testing the hypothesis that the progesterone-stimulation is mediated through increases in receptor-mediated cAMP, and exploring the related cAMP-stimulated cell-signaling pathways in-vitro in rat luteal cells and then in human luteal cells. Our previous work has shown that chemically-mediated decreases in receptor-stimulated cAMP induce granulosa cell apoptosis, the results with EGME support the conclusion that cAMP levels appear to be critical in determining whether granulosa cells differentiate or undergo apoptosis. Other ongoing work relates to development of in-situ hybridization procedures for aromatase and BRCA1 message in tissue sections. These techniques should help tease out the mechanisms of ovarian cancer. In addition, an ovarian cancer study utilizing nitrofurazone is underway. Results of histology, endocrinology, and molecular analysis from this nitrofurazone study should help establish mechanisms of tumorigenesis and lead to the development of a model for ovarian cancer.
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