Pilot Project 1: The Effects of Endocrine Disruption on the Developing Human Fetal Ovary

Reproductive health is a major concern for healthcare. Since the etiology of infertility goes undetermined in 60% of cases (1,2), the number of cases whose problems arise from environmental exposures is unknown. Exposures to xenobiotics have been linked to early reproductive failure or ovotoxicity, including cigarette smoke (3), solvents (4-7), radio/chemotherapy (8-11), and pollutants (12,13). To date, few molecular mechanisms of ovotoxicity have been determined. A growing body of evidence suggests that exposure of the developing fetus to estrogen mimicking compounds also known as xenoestrogens plays a role in the adult onset of primary ovarian insufficiency and infertility (14, 15). It is well known that estrogen plays an essential role in the growth and maturation of the mammalian ovary and oocyte. Both Bisphenol A (BPA), an ubiquitous environmental xenoestrogen, and genistein, a phytoestrogen in soy products, have been shown at environmentally relevant physiological doses to target the mammalian ovary in rodents (16, 17). Based on this information, we hypothesize that exposure of the developing ovary to estrogenic chemicals leads to accelerated follicle loss resulting in primary ovarian insufficiency and infertility. The objective of this study will be 1.) To examine at the molecular level the effects of BPA and genistein on germ cell nest breakdown in the human fetal ovary in vitro; and 2.) To characterize the effects of maternal exposure to the estrogenic chemicals, BPA and Genistein, at levels comparable to human exposure on development of the human fetal ovary in an in vivo xenotransplant model.

Specific Aims

• Determine if xenoestrogens like BPA and genistein target the oocyte and/or alter germ cell nest breakdown leading to a decrease in number of the primordial follicle pool. Utilizing in vitro culture methods of human fetal ovary, we will examine the response of the primordial follicle pool in vitro following exposure to the xenoestrogens, BPA or genistein. We hypothesize that xenoestrogens target the primordial follicle pool leading to primary ovarian insufficiency.
• Characterize the growth parameters of the human fetal ovary in vivo following estrogenic exposures to BPA or genistein. We will examine the effect of exposure to either BPA or genistein in the human fetal ovary in a nude rat xenotransplantation model. We hypothesize that xenoestrogens target the human fetal oocyte leading to primary ovarian insufficiency in the adult.

Personnel

Richard Freiman, PhD
Project Leader
Richard_Freiman@brown.edu
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Mary L. Hixon, PhD
Project Co-Leader
Mary_Hixon@brown.edu
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