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Title:Mechanism of Bisphenol A toxicity in adult mouse ovarian antral follicles
Author(s):Peretz, Jackye
Director of Research:Flaws, Jodi A.
Doctoral Committee Chair(s):Flaws, Jodi A.
Doctoral Committee Member(s):Bagchi, Indrani C.; Dirikolu, Levent; Mahoney, Megan M.; Nardulli, Ann M.; Nowak, Romana A.
Department / Program:Comparative Biosciences
Discipline:VMS - Comparative Biosciences
Degree Granting Institution:University of Illinois at Urbana-Champaign
Subject(s):Antral follicle
follicle growth
Bisphenol A
Abstract:Bisphenol A (BPA) is an endocrine disrupting chemical widely used in the manufacturing of commonly used consumer products containing polycarbonate plastics, epoxy resins, dental sealants, and receipt paper. During a process called leaching, the ester bonds maintaining BPA polymers can break, releasing BPA into food and beverages, onto skin, into the air, or into the environment. Studies indicate that BPA, with a half-life of at least 4-6 hours, is present in 95% of random urine samples, indicating that humans are constantly exposed to this chemical. Once in the body, BPA can readily mimic, enhance, or inhibit normal endocrine responsive processes such as ovarian follicle growth and steroidogenesis. Follicles are the functional units of the ovary, responsible for ovulating an oocyte and producing sex steroid hormones during steroidogenesis. Follicles grow and develop from primordial, primary, pre-antral, and finally, to antral follicles over the course of the female reproductive life. Further, over time, follicles not marked for ovulation undergo atresia, a normal process of follicular cell death. Disturbances in follicle growth or atresia could impair healthy oocyte development and ovulation, ultimately affecting fertility. Steroidogenesis is required for healthy development and functioning of various physiological systems such as the neural, cardiovascular, and reproductive systems. Steroidogenesis occurs in pre- and antral follicles, though the majority of hormone production occurs in antral follicles. Cholesterol is metabolized into sex steroid hormones such as progesterone, testosterone, and estradiol in the theca and granulosa cell layers. Disturbances in steroidogenesis could impair overall female physiological health, as well as impair reproduction. Though many studies have investigated the adverse effects of BPA, few studies have evaluated the effects of BPA on antral follicles. Thus, the goal of my dissertation work was to determine the toxicity of BPA on adult antral follicles. Specifically, I examined whether and how BPA affects follicle growth, atresia, and steroidogenesis in adult antral follicles. First, I tested the hypothesis that postnatal BPA exposure inhibits antral follicle growth and steroidogenesis. I found that BPA inhibited follicle growth and steroidogenesis independently of each other. Additionally, I found that co-culturing follicles with the hormone precursor, pregnenolone, partially protected the follicles from BPA-inhibited hormone production, indicating that BPA may be targeting rate-limiting enzymes in the estradiol biosynthesis pathway. Next, I tested the hypothesis that BPA alters cell cycle regulators and induces atresia in antral follicles via the genomic estrogenic pathway, inhibiting follicle growth. I found that BPA up-regulated the pro-atresia factor Bax, inducing atresia in antral follicles. Further, I found that BPA did not inhibit follicle growth or induce atresia through the genomic estrogenic pathway, though BPA altered expression of estrogen receptors 1 and 2 over time. Finally, I tested the hypothesis that BPA reversibly targets cytochrome P450 side chain cleavage (Cyp11a1) and steroidogenic acute regulatory protein (StAR), leading to a decrease in hormone levels. I found that BPA initially targets and decreases expression of Cyp11a1, leading to a decrease in the expression of StAR and hormone production. Further, removal of BPA restored expression of Cyp11a1 to control levels and prevented down-regulation of StAR and decreases in hormone production. Collectively, these data indicate that BPA inhibits follicle growth, induces atresia, and reversibly decreases steroidogenesis by targeting rate-limiting enzymes in the estradiol biosynthesis pathway of adult antral follicles.
Issue Date:2013-05-24
Rights Information:Copyright 2010 Jackye Peretz; Copyright 2012 Jackye Peretz
Date Available in IDEALS:2013-05-24
Date Deposited:2013-05

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