The primary emphasis of this research group is to understand environmental influences on ovarian function and disease. Using ovarian toxicants such as the phthalates and glycol ethers, and ovarian carcinogens such as dioxins and other furans, the cellular and molecular pathologies are defined that contribute to fundamental lesions in ovarian function and towards the development of cancer. Using genetically altered animal models, the roles of genes and signaling molecules in ovarian, breast and uterine function and disease are also determined. Previous studies demonstrated that MEHP suppresses granulosa cell estradiol production independent of an effect on FSH-stimulated cAMP by affecting the amount of aromatase, the rate-limiting enzyme that converts testosterone to estradiol. The hypothesis was tested that MEHP affects aromatase trasncription, and MEHP was compared to several structurally related phthalates (0-200 microM) and Wy-14,643 (0-100 microM) in rat granulosa cell cultures. RNA was measured by fluorescent RT-PCR, and protein by western analysis. MEHP (0-200 mM) was unique among the phthalates in its ability to decrease estradiol production and was also found to significantly decrease aromatase RNA levels. The decrease in transcription was paralleled by a decrease in aromatase protein. Wy-14,643 had effects similar to MEHP at 100 microM. MEHP decreased transcription of aromatase specifically, and did not alter levels of P450scc. Treatment with a cAMP analogue increased expression of P450scc, while the decrease in aromatase remained. Thus, these studies are the first to show that MEHP decreases estradiol production in ovarian granulosa cells by decreasing transcription of aromatase specifically. Research efforts also continue to determine how prostaglandins function in reproductive health and disease. Specically, the expression of cyclooxygenase 1 and 2 in human ovarian cancers and ovarain cancer cell lines were examined. COX-2 is up-redulated in metastatic tumors, but not seen expressed in primary ovarian cancers (40 cases examined by immunohistochemistry). We are also confirming preliminary data that COX-1 is inhibited and COX-2 is up-regulated in nitrofurazone-induced ovarian tumors in mice. COX-2 is also overexpressed in mammary gland tumors of wnt-1 transgenics however, indomethacin does not seem to inhibit the development of tumors in these mice.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Intramural Research (Z01)
Project #
1Z01ES021197-07
Application #
6432246
Study Section
(LWH)
Project Start
Project End
Budget Start
Budget End
Support Year
7
Fiscal Year
2000
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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