Evidence of Combinatorial Effects of Bisphenol-A, Genistein, and 17beta-Estradiol in Reproductive Tissues and Liver in an Adult Ovariectomized Mouse Model

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: MON 338-354-Physiological Impacts of Endocrine Disrupting Chemicals
Basic/Translational
Monday, June 17, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board MON-348
Louise A Russo*, Abigail LeGendre, Chelsey Ciambella and Jessica Esernio
Villanova University, Villanova, PA
The goal of this study was to broaden understanding of the impacts of endocrine disrupting compounds (EDCs) bisphenol A (BPA) and genistein (GEN) by assessing effects in combination with 17beta-estradiol (E2) on estrogen responsive tissues in an ovariectomized adult mouse model.  Daily oral dosing with 50mg/kg BPA and 50mg/kg GEN or oil vehicle (control) was completed in conjunction with daily i.p. administration of saline (control) or E2 at low (0.04µg/kg), medium (0.4µg/kg) or high (4µg/kg) dose levels for a period of 7 days.  Following treatment, multiple estrogen-regulated morphological and gene expression endpoints were examined via light microscopy and real-time qPCR to assess EDC synergism or antagonism of the E2 dose response in uterine, mammary, and liver tissues.  BPA in combination with GEN decreased E2 up-regulation of uterine C3 mRNA at low and medium E2 levels and decreased E2 up-regulation of mammary INDO mRNA at all E2 levels. Morphological analyses showed that BPA in combination with GEN decreased E2- induced expansion of endometrial volume and luminal epithelial cell height but acted synergistically on E2 induced mammary terminal end bud formation.  Synergism was also observed in the liver where BPA in combination with GEN increased E2-induced up-regulation of IGFBP-1 mRNA at all E2 dose levels.  However BPA alone significantly decreased IGFBP-1 mRNA at all E2 dose levels. These data indicate that the synergism of BPA + GEN on IGFBP-1 mRNA up-regulation reflects a potent induction by GEN whereas in the absence of GEN, BPA alone produces a robust inhibition of the typical E2-induced dose response on IGFBP-1 mRNA. BPA-induced down-regulation of IGFBP-1 levels indicates that circulating levels of free IGF-1 would be elevated and therefore sustained exposure to BPA may have long-term implications with respect to development of insulin resistance, diabetes, and obesity.  Collectively these data show that the combinatorial activity of EDCs and E2 in adult animals produces a complex tissue selective responsiveness. Both synergistic (uterus and mammary tissue) and antagonistic (liver) effects suggest that enhanced reproductive tissue growth potential and altered glucose metabolism are potentiated through extended exposure to mixtures of EDCs in adult females in the presence of estrogen.

Nothing to Disclose: LAR, AL, CC, JE

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