The primary emphasis of the group is ovarian function and disease, and through major collaborations we also study uterine leiomyoma and breast cancer. Using ovarian toxicants such as the phthalates and glycol ethers, and ovarian carcinogens such as dioxins and other furans, we have defined cellular and molecular pathologies that contribute to fundamental lesions in ovarian function and towards the development of cancer. For example, these studies are the first to show that the most common environmental contaminant, di-2-ethylhexyl phthalate (DEHP) and its active metabolite (MEHP) suppresses estradiol production in ovarian granulosa cells by decreasing transcription of aromatase through the PPARalpha and gamma receptors. Research efforts continue to determine how prostaglandins function in reproductive health and disease. Specially, we have examined expression of cyclooxygenase 1 and 2 in human ovarian cancers and ovarain cancer cell lines. Prostaglandins and specificially COX-2 regulated prostaglandins may play a role in uterine leiomyoma. Current evidence suggest that this tumor has characteristics of well-differentiated uterine smooth muscle cells of pregnancy. Data from our laboratory using animal models (Eker Rat) and cell culture experiments (Eker rat-derived uterine leiomyoma cells and human leiomyoma and normal myometiral cells) suggest further that these tumor cells have features of smooth muscle just prior to the onset of parturition. However, the tumor cells may lack the ability to induce COX-2 necessary to induce either apoptosis or dedifferentiation as occurs in parturition. Thus, leiomyoma cells are unresponsive to this signaling pathway and thereby persist in a cancerous phenotype. The growth of uterine leiomyoma is under further investigation using magnetic resonance imaging (MRI) in a clinically relevant population of women. We test the hypotheses that uterine leiomyomas are heterogeneous in terms of their growth characteristics and in their clinical symptoms or outcomes and that differences in leiomyoma growth dynamics can be discriminated by molecular markers and cellular phenotypes.
The specific aims are to: (1) compare leiomyoma growth as a function of multiplicity and location by MRI analysis in women with high risk for surgical intervention (i.e., hysterectomy/myomectomy); (2) examine the relationship between leiomyoma growth and clinical symptoms or outcome; (3) identify molecular, cellular, and pathological characteristics of the leiomyomas with differing growth dynamics; and (4) examine endocrinological parameters and lifestyle factors related to differential growth dynamics of uterine leiomyomas. Participants will include 300 ethnically diverse women of reproductive age (18-45 years) with uterine leiomyoma.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Intramural Research (Z01)
Project #
1Z01ES021197-08
Application #
6553189
Study Section
(LWH)
Project Start
Project End
Budget Start
Budget End
Support Year
8
Fiscal Year
2001
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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