Our research seeks to determine molecular mechanisms by which environmental toxins and stresses contribute to reproductive diseases of significant impact to women's health. Our approach is to identify key genes and signaling molecules in cell growth, differentiation, and reproductive physiology that are disrupted by environmental factors, and to understand how these pathways may be protected to reduce the burden of disease in women. We recently demonstrated the role of peroxisome proliferator activated receptors (PPARs) in regulating estrogen synthesis and mediating the ovarian toxicity of the ubiquitous environmental contaminant di-2-ethylhexyl phthalate (DEHP). Phthalates are high production volume synthetic chemicals with ubiquitous human exposures because of their use in plastics and other common consumer products. Globally, over 18 billion pounds of phthalates are used each year, primarily as plasticizers in flexible polyvinyl chloride (PVC) products. Because DEHP is a peroxisome proliferator and that the metabolite of DEHP, MEHP, alters gene expression by activating PPARs, we hypothesized that MEHP decreased aromatase through activation of PPARalpha and PPARgamma in the rat granulosa cell. To test this hypothesis, we compared MEHP (50 mM), the PPARa specific and PPARg specific ligands in primary cultures of rat ovarian granulosa cells. We found that all decrease estradiol production and RNA message levels of aromatase to 50-70% of control. A PPARgamma antagonist, GR 259662, partially blocked the effect of MEHP on aromatase mRNA and completely blocked the effect of the PPARgamma-selective agonist.There was no effect on PPARalpha pathways. MEHP also stimulated genes that were induced by PPARalpha specific ligands but not PPARgamma-specific ligands. This data suggests that MEHP activates both PPARalpha and gamma in the regulation of aromatase and production of ovarian estradiol. We also examine the role of prostaglandin signalling pathways in ovarian function and demonstrate the absolute requirement of cyclooxygenase (COX)-2 enzyme, but not COX-1, in cumulus expansion and ovulation through evaluation of COX deficient mice. These studies also reveal a critical relationship between COX-1 and estrogen production in the ovary. We extend our understanding of the physiological and pathological processes mediated by cyclooxygenases to significant cancers of women including ovarian cancer. Ovarian cancer is the most fatal of the gynecological cancers, with about 28,000 new cases reported yearly in the U.S. We find that COX-2 expression is associated with increasing malignancy of human epithelial ovarian cancers. However, we also found the importance of COX-1 expression which appears in preneoplastic lesions and primary cancers. We are developing transgenic mice that over-express COX-1 or COX-2 in the ovary to address the role these enzymes play in ovarian dysfunction and cancer in an animal model.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Intramural Research (Z01)
Project #
1Z01ES021197-10
Application #
6837389
Study Section
(LWH)
Project Start
Project End
Budget Start
Budget End
Support Year
10
Fiscal Year
2003
Total Cost
Indirect Cost
Name
U.S. National Inst of Environ Hlth Scis
Department
Type
DUNS #
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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