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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Intramural Research (Z01)
Project #
1Z01ES021197-02
Application #
5202135
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
1995
Total Cost
Indirect Cost
City
State
Country
United States
Zip Code
Pritchard, John B; French, John E; Davis, Barbara J et al. (2003) The role of transgenic mouse models in carcinogen identification. Environ Health Perspect 111:444-54
Lovekamp-Swan, Tara; Jetten, Anton M; Davis, Barbara J (2003) Dual activation of PPARalpha and PPARgamma by mono-(2-ethylhexyl) phthalate in rat ovarian granulosa cells. Mol Cell Endocrinol 201:133-41
McAllister, Kimberly A; Bennett, L Michelle; Houle, Chris D et al. (2002) Cancer susceptibility of mice with a homozygous deletion in the COOH-terminal domain of the Brca2 gene. Cancer Res 62:990-4
Houle, Christopher D; Ding, Xiao-Yu; Foley, Julie F et al. (2002) Loss of expression and altered localization of KAI1 and CD9 protein are associated with epithelial ovarian cancer progression. Gynecol Oncol 86:69-78
Bennett, L Michelle; Davis, Barbara J (2002) Identification of mammary carcinogens in rodent bioassays. Environ Mol Mutagen 39:150-7
Hoppin, Jane A; Brock, John W; Davis, Barbara J et al. (2002) Reproducibility of urinary phthalate metabolites in first morning urine samples. Environ Health Perspect 110:515-8
Moser, V C; Barone Jr, S; Smialowicz, R J et al. (2001) The effects of perinatal tebuconazole exposure on adult neurological, immunological, and reproductive function in rats. Toxicol Sci 62:339-52
Wagner, K U; McAllister, K; Ward, T et al. (2001) Spatial and temporal expression of the Cre gene under the control of the MMTV-LTR in different lines of transgenic mice. Transgenic Res 10:545-53
Miller, R T; Davis, B J (2001) Summary of panel discussion: past, present and future of toxicologic pathologists and the contributions to hazard identification and molecular mechanisms of action. Toxicol Pathol 29:156-7
Smialowicz, R J; Williams, W C; Copeland, C B et al. (2001) The effects of perinatal/juvenile heptachlor exposure on adult immune and reproductive system function in rats. Toxicol Sci 61:164-75

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