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Department of Cell Biology, Neurobiology and Anatomy, University of Cincinnati Medical School (N.G.B., D.L.A., N.B.J.), Cincinnati, Ohio 45267; and the Department of Obstetrics and Gynecology, Indiana University School of Medicine (R.S., R.M.B.), Indianapolis, Indiana 46202
Address all correspondence and requests for reprints to: Dr. Nira Ben-Jonathan, Department of Cell Biology, University of Cincinnati Medical School, 231 Bethesda Avenue, Cincinnati, Ohio 45267-0521.
Environmental estrogens (xenoestrogens) are a diverse group of chemicals that mimic estrogenic actions. Bisphenol A (BPA), a monomer of plastics used in many consumer products, has estrogenic activity in vitro. The pituitary lactotroph is a well established estrogen-responsive cell. The overall objective was to examine the effects of BPA on PRL release and explore its mechanism of action. The specific aims were to: 1) compare the potency of estradiol and BPA in stimulating PRL gene expression and release in vitro; 2) determine whether BPA increases PRL release in vivo; 3) examine if the in vivo estrogenic effects are mediated by PRL regulating factor from the posterior pituitary; and 4) examine if BPA regulates transcription through the estrogen response element (ERE).
BPA increased PRL gene expression, release, and cell proliferation in anterior pituitary cells albeit at a 1000- to 5000-fold lower potency than estradiol. On the other hand, BPA had similar efficacy to estradiol in inducing hyperprolactinemia in estrogen-sensitive Fischer 344 (F344) rats; Sprague Dawley (SD) rats did not respond to BPA. Posterior pituitary cells from estradiol- or BPA-treated F344 rats strongly increased PRL gene expression upon coculture with GH3 cells stably transfected with a reporter gene. Similar to estradiol, BPA induced ERE activation in transiently transfected anterior and posterior pituitary cells.
We conclude that: a) BPA mimics estradiol in inducing hyperprolactinemia in genetically predisposed rats; b) the in vivo action of estradiol and BPA in F344 rats is mediated, at least in part, by increasing PRL regulating factor activity in the posterior pituitary; c) BPA appears to regulate transcription through an ERE, suggesting that it binds to estrogen receptors in both the anterior and posterior pituitaries. The possibility that BPA and other xenoestrogens have adverse effects on the neuroendocrine axis in susceptible human subpopulations is discussed.
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T. E. Stoker, C. L. Robinette, B. H. Britt, S. C. Laws, and R. L. Cooper Prepubertal Exposure to Compounds That Increase Prolactin Secretion in the Male Rat: Effects on the Adult Prostate Biol Reprod, December 1, 1999; 61(6): 1636 - 1643. [Abstract] [Full Text]
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N. A. Mitchner, C. Garlick, R. W. Steinmetz, and N. Ben-Jonathan Differential Regulation and Action of Estrogen Receptors {alpha} and {beta} in GH3 Cells Endocrinology, June 1, 1999; 140(6): 2651 - 2658. [Abstract] [Full Text]
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F. Olea-Serrano, P. Lardelli-Claret, A. Rivas, A. Barba-Navarro, and N. Olea Inadvertent exposure to xenoestrogens in children Toxicology and Industrial Health, February 1, 1999; 15(1-2): 152 - 159. [Abstract] [PDF]
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T. Colborn and P. Short Pesticide use in the U.S. and policy implications: A focus on herbicides Toxicology and Industrial Health, February 1, 1999; 15(1-2): 241 - 276. [Abstract] [PDF]
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G. G. J. M. Kuiper, J. G. Lemmen, B. Carlsson, J. C. Corton, S. H. Safe, P. T. van der Saag, B. van der Burg, and J.-A. Gustafsson Interaction of Estrogenic Chemicals and Phytoestrogens with Estrogen Receptor {beta} Endocrinology, October 1, 1998; 139(10): 4252 - 4263. [Abstract] [Full Text] [PDF]
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 F. J. M. Verhagen, H. J. Swarts, J. B. P. A. Wijnberg, and J. A. Field Biotransformation of the Major Fungal Metabolite 3,5-Dichloro- p-Anisyl Alcohol under Anaerobic Conditions and Its Role in Formation of Bis(3,5-Dichloro-4-Hydroxyphenyl)methane Appl. Envir. Microbiol., September 1, 1998; 64(9): 3225 - 3231. [Abstract] [Full Text]
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N. A. Mitchner, C. Garlick, and N. Ben-Jonathan Cellular Distribution and Gene Regulation of Estrogen Receptors {alpha} and {beta} in the Rat Pituitary Gland Endocrinology, September 1, 1998; 139(9): 3976 - 3983. [Abstract] [Full Text] [PDF]
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R. Steinmetz, N. A. Mitchner, A. Grant, D. L. Allen, R. M. Bigsby, and N. Ben-Jonathan The Xenoestrogen Bisphenol A Induces Growth, Differentiation, and c-fos Gene Expression in the Female Reproductive Tract Endocrinology, June 1, 1998; 139(6): 2741 - 2747. [Abstract] [Full Text] [PDF]
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 J. I. Macgregor and V. C. Jordan Basic Guide to the Mechanisms of Antiestrogen Action Pharmacol. Rev., June 1, 1998; 50(2): 151 - 196. [Abstract] [Full Text] [PDF]
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F. S. Vom Saal, P. S. Cooke, D. L. Buchanan, P. Palanza, K. A. Thayer, S. C. Nagel, S. Parmigiani, and W. V. Welshons A Physiologically Based Approach To the Study of Bisphenol a and Other Estrogenic Chemicals On the Size of Reproductive Organs, Daily Sperm Production, and Behavior Toxicology and Industrial Health, January 1, 1998; 14(1-2): 239 - 260. [Abstract] [PDF]
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R. Hnasko, S. Khurana, N. Shackleford, R. Steinmetz, M. J. Low, and N. Ben-Jonathan Two Distinct Pituitary Cell Lines from Mouse Intermediate Lobe Tumors: A Cell that Produces Prolactin-Regulating Factor and a Melanotroph Endocrinology, December 1, 1997; 138(12): 5589 - 5596. [Abstract] [Full Text] [PDF]
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D. Feldman M.D. Editorial: Estrogens from Plastic--Are We Being Exposed? Endocrinology, May 1, 1997; 138(5): 1777 - 1779. [Full Text] [PDF]
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D. L. Allen, N. A. Mitchner, T. E. Uveges, K. P. Nephew, S. Khan, and N. B. Jonathan Cell-Specific Induction of c-fos Expression in the Pituitary Gland by Estrogen Endocrinology, May 1, 1997; 138(5): 2128 - 2135. [Abstract] [Full Text]
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