From Oct. 1997 to Sept. 1998, we continued efforts to understand the molecular and cell signaling pathways involved in chemically- mediated ovarian dysfunction to focus on defining the roles that prostaglandins play in ovarian toxicity and cancer. One major research focus has been to define the roles of the isoforms of cyclooxygenases and related prostaglandins in ovarian and reproductive function using the cyclooxygenase-1 (COX-1)- and cyclooxygenase-2 (COX-2)-deficient mice. These studes show that COX-2 and not COX-1 is required for the gonadotropin-related surge in ovarian prostaglandin levels and that COX-2-induced prostaglandins is necessary for cumulus activation and ovulation. These are the first studies to show that ovulation can be restored in COX-2 (-/-) mice by simultaneous treatment with gonadotropins and PGE2 or the cytokine IL1b, and that IL1b can function independently of COX-2. In contrast, the COX-1 isoform is necessary for normal parturition and we show that both prostaglandins and estradiol are necessary for normal parturition in the COX-1 deficient mouse. Based on these studies the hypothesis is that the final pathway for parturition is COX-1-related prostaglandins are necessary to support an enhanced production of ovarian estradiol, and estradiol is necessary and required to up-regulate COX-2- related prostaglandins.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Intramural Research (Z01)
Project #
1Z01ES021197-05
Application #
6106590
Study Section
Special Emphasis Panel (LEP)
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
1998
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
Davis, B J; Price, H C; O'Connor, R W et al. (2001) Mercury vapor and female reproductive toxicity. Toxicol Sci 59:291-6
Davis, B J; Travlos, G; McShane, T (2001) Reproductive endocrinology and toxicological pathology over the life span of the female rodent. Toxicol Pathol 29:77-83
Bennett, L M; McAllister, K A; Ward, T et al. (2001) Mammary tumor induction and premature ovarian failure in ApcMin mice are not enhanced by Brca2 deficiency. Toxicol Pathol 29:117-25
Lovekamp, T N; Davis, B J (2001) Mono-(2-ethylhexyl) phthalate suppresses aromatase transcript levels and estradiol production in cultured rat granulosa cells. Toxicol Appl Pharmacol 172:217-24

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