help button home button Endocrine Society Endocrinology
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Steinmetz, R.
Right arrow Articles by Ben-Jonathan, N.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Steinmetz, R.
Right arrow Articles by Ben-Jonathan, N.
Endocrinology Vol. 139, No. 6 2741-2747
Copyright © 1998 by The Endocrine Society

ARTICLES

The Xenoestrogen Bisphenol A Induces Growth, Differentiation, and c-fos Gene Expression in the Female Reproductive Tract1

Rosemary Steinmetz, Natasha A. Mitchner, Andrea Grant, Donald L. Allen, Robert M. Bigsby and Nira Ben-Jonathan

Department of Cell Biology, University of Cincinnati College of Medicine (N.A.M., D.L.A., N.B.J.), Cincinnati, Ohio 45267; and the Department of Obstetrics and Gynecology, Indiana University School of Medicine (R.S., A.G., 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 Ave, Cincinnati, Ohio 45267-0521.

The xenoestrogen bisphenol A (BPA) has been shown to mimic estrogen both in vivo and in vitro. BPA stimulates PRL secretion and the expression of a PRL regulating factor from the posterior pituitary in the estrogen-sensitive Fischer 344 rat (F344), but not in Sprague-Dawley (SD) rats. The goal of the present studies was to examine the in vivo actions of BPA on the reproductive tract. The specific objectives were 1) to characterize the short term effects of BPA on cell proliferation and c-fos expression in the uterus and vagina, and 2) to compare the effects of prolonged exposure to low doses of BPA on the reproductive tract of F344 and SD rats.

Treatment with single high doses of BPA induced cell proliferation in the uterus and vagina of ovariectomized F344 rats, as determined by bromodeoxyuridine immunostaining. This proliferation was dose dependent (from 37.5–150 mg/kg) and followed a time course similar to that of estradiol (E2). Quantitative RT-PCR revealed that both BPA and E2 increased c-fos messenger RNA levels in the uterus 14- to 16-fold within 2 h, which returned to basal levels after 6 h. In the vagina, BPA-induced c-fos expression remained elevated for up to 6 h, compared with the transient increase caused by E2. Treatment of F344 rats for 3 days with continuous release capsules that supplied a much lower dose of BPA (~0.3 mg/kg·day) resulted in hypertrophy, hyperplasia, and mucus secretion in the uterus and hyperplasia and cornification of the vaginal epithelium. The reproductive tract of SD rats did not respond to this treatment paradigm with BPA.

These studies demonstrate that 1) the molecular and morphological alterations induced by BPA in the uterus and vagina are nearly identical to those induced by estradiol; 2) the vagina appears to be especially sensitive to the estrogenic actions of BPA; 3) the reproductive tract of the inbred F344 rat appears more sensitive to BPA than that of the outbred SD rat; and 4) continuous exposure to microgram levels of BPA is sufficient for exerting estrogenic actions.




This article has been cited by other articles:


Home page
 Endocr. Rev.Home page
L. N. Vandenberg, M. V. Maffini, C. Sonnenschein, B. S. Rubin, and A. M. Soto
Bisphenol-A and the Great Divide: A Review of Controversies in the Field of Endocrine Disruption
Endocr. Rev., February 1, 2009; 30(1): 75 - 95.
[Abstract] [Full Text] [PDF]

Home page
 Toxicol SciHome page
J. Matsumoto, H. Iwano, H. Inoue, N. Iwano, N. Yamashiki, and H. Yokota
Metabolic Barrier against Bisphenol A in Rat Uterine Endometrium
Toxicol. Sci., September 1, 2007; 99(1): 118 - 125.
[Abstract] [Full Text] [PDF]

Home page
 FASEB J.Home page
C. C. Smith and H. S. Taylor
Xenoestrogen exposure imprints expression of genes (Hoxa10) required for normal uterine development
FASEB J, January 1, 2007; 21(1): 239 - 246.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Cell. ProteomicsHome page
I. Apraiz, J. Mi, and S. Cristobal
Identification of Proteomic Signatures of Exposure to Marine Pollutants in Mussels (Mytilus edulis)
Mol. Cell. Proteomics, July 1, 2006; 5(7): 1274 - 1285.
[Abstract] [Full Text] [PDF]

Home page
 J EndocrinolHome page
A Glover and S J Assinder
Acute exposure of adult male rats to dietary phytoestrogens reduces fecundity and alters epididymal steroid hormone receptor expression.
J. Endocrinol., June 1, 2006; 189(3): 565 - 573.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
W. V. Welshons, S. C. Nagel, and F. S. vom Saal
Large Effects from Small Exposures. III. Endocrine Mechanisms Mediating Effects of Bisphenol A at Levels of Human Exposure
Endocrinology, June 1, 2006; 147(6): s56 - s69.
[Abstract] [Full Text] [PDF]

Home page
 Toxicol SciHome page
H. Masuno, J. Iwanami, T. Kidani, K. Sakayama, and K. Honda
Bisphenol A Accelerates Terminal Differentiation of 3T3-L1 Cells into Adipocytes through the Phosphatidylinositol 3-Kinase Pathway
Toxicol. Sci., April 1, 2005; 84(2): 319 - 327.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
H. Inoue, A. Tsuruta, S. Kudo, T. Ishii, Y. Fukushima, H. Iwano, H. Yokota, and S. Kato
BISPHENOL A GLUCURONIDATION AND EXCRETION IN LIVER OF PREGNANT AND NONPREGNANT FEMALE RATS
Drug Metab. Dispos., January 1, 2005; 33(1): 55 - 59.
[Abstract] [Full Text] [PDF]

Home page
 Toxicol SciHome page
H. Kurebayashi, H. Betsui, and Y. Ohno
Disposition of a Low Dose of 14C-Bisphenol A in Male Rats and Its Main Biliary Excretion as BPA Glucuronide
Toxicol. Sci., May 1, 2003; 73(1): 17 - 25.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
H. Inoue, G. Yuki, H. Yokota, and S. Kato
Bisphenol A Glucuronidation and Absorption in Rat Intestine
Drug Metab. Dispos., January 1, 2003; 31(1): 140 - 144.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
K.-H. Song, K. Lee, and H.-S. Choi
Endocrine Disrupter Bisphenol A Induces Orphan Nuclear Receptor Nur77 Gene Expression and Steroidogenesis in Mouse Testicular Leydig Cells
Endocrinology, June 1, 2002; 143(6): 2208 - 2215.
[Abstract] [Full Text] [PDF]

Home page
 J. Lipid Res.Home page
H. Masuno, T. Kidani, K. Sekiya, K. Sakayama, T. Shiosaka, H. Yamamoto, and K. Honda
Bisphenol A in combination with insulin can accelerate the conversion of 3T3-L1 fibroblasts to adipocytes
J. Lipid Res., May 1, 2002; 43(5): 676 - 684.
[Abstract] [Full Text] [PDF]

Home page
 Biol. Reprod.Home page
O. Putz, C. B. Schwartz, S. Kim, G. A. LeBlanc, R. L. Cooper, and G. S. Prins
Neonatal Low- and High-Dose Exposure to Estradiol Benzoate in the Male Rat: I. Effects on the Prostate Gland
Biol Reprod, November 1, 2001; 65(5): 1496 - 1505.
[Abstract] [Full Text] [PDF]

Home page
 Biol. Reprod.Home page
O. Putz, C. B. Schwartz, G. A. LeBlanc, R. L. Cooper, and G. S. Prins
Neonatal Low- and High-Dose Exposure to Estradiol Benzoate in the Male Rat: II. Effects on Male Puberty and the Reproductive Tract
Biol Reprod, November 1, 2001; 65(5): 1506 - 1517.
[Abstract] [Full Text] [PDF]

Home page
 Toxicol SciHome page
A. D. Papaconstantinou, B. R. Fisher, T. H. Umbreit, P. L. Goering, N. T. Lappas, and K. M. Brown
Effects of {beta}-Estradiol and Bisphenol A on Heat Shock Protein Levels and Localization in the Mouse Uterus Are Antagonized by the Antiestrogen ICI 182,780
Toxicol. Sci., October 1, 2001; 63(2): 173 - 180.
[Abstract] [Full Text] [PDF]

Home page
 Biol. Reprod.Home page
J. G. Ramos, J. Varayoud, C. Sonnenschein, A. M. Soto, M. Munoz de Toro, and E. H. Luque
Prenatal Exposure to Low Doses of Bisphenol A Alters the Periductal Stroma and Glandular Cell Function in the Rat Ventral Prostate
Biol Reprod, October 1, 2001; 65(4): 1271 - 1277.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
H. Inoue, H. Yokota, T. Makino, A. Yuasa, and S. Kato
Bisphenol A Glucuronide, a Major Metabolite in Rat Bile after Liver Perfusion
Drug Metab. Dispos., August 1, 2001; 29(8): 1084 - 1087.
[Abstract] [Full Text] [PDF]

Home page
 Biol. Reprod.Home page
H. Cardenas, K.A. Burke, R.M. Bigsby, W.F. Pope, and K.P. Nephew
Estrogen Receptor {beta} in the Sheep Ovary During the Estrous Cycle and Early Pregnancy
Biol Reprod, July 1, 2001; 65(1): 128 - 134.
[Abstract] [Full Text] [PDF]

Home page
 Exp. Biol. Med.Home page
X. Long, K. A. Burke, R. M. Bigsby, and K. P. Nephew
Effects of the Xenoestrogen Bisphenol A on Expression of Vascular Endothelial Growth Factor (VEGF) in the Rat
Experimental Biology and Medicine, May 1, 2001; 226(5): 477 - 482.
[Abstract] [Full Text]

Home page
 Hum ReprodHome page
J. L. Spearow and M. Barkley
Reassessment of models used to test xenobiotics for oestrogenic potency is overdue: Opinion
Hum. Reprod., May 1, 2001; 16(5): 1027 - 1029.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
R. Elsby, J. L. Maggs, J. Ashby, and B. K. Park
Comparison of the Modulatory Effects of Human and Rat Liver Microsomal Metabolism on the Estrogenicity of Bisphenol A: Implications for Extrapolation to Humans
J. Pharmacol. Exp. Ther., April 1, 2001; 297(1): 103 - 113.
[Abstract] [Full Text]

Home page
 EndocrinologyHome page
S. Khurana, S. Ranmal, and N. Ben-Jonathan
Exposure of Newborn Male and Female Rats to Environmental Estrogens: Delayed and Sustained Hyperprolactinemia and Alterations in Estrogen Receptor Expression
Endocrinology, December 1, 2000; 141(12): 4512 - 4517.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
A. Nadal, A. B. Ropero, O. Laribi, M. Maillet, E. Fuentes, and B. Soria
Nongenomic actions of estrogens and xenoestrogens by binding at a plasma membrane receptor unrelated to estrogen receptor alpha and estrogen receptor beta
PNAS, October 10, 2000; 97(21): 11603 - 11608.
[Abstract] [Full Text] [PDF]

Home page
 Toxicol SciHome page
A. D. Papaconstantinou, T. H. Umbreit, B. R. Fisher, P. L. Goering, N. T. Lappas, and K. M. Brown
Bisphenol A-Induced Increase in Uterine Weight and Alterations in Uterine Morphology in Ovariectomized B6C3F1 Mice: Role of the Estrogen Receptor
Toxicol. Sci., August 1, 2000; 56(2): 332 - 339.
[Abstract] [Full Text] [PDF]

Home page
 Toxicol SciHome page
J. Odum and J. Ashby
Neonatal Exposure of Male Rats to Nonylphenol Has No Effect on the Reproductive Tract
Toxicol. Sci., August 1, 2000; 56(2): 400 - 404.
[Abstract] [Full Text] [PDF]

Home page
 Integr. Comp. Biol.Home page
T. Iguchi and T. Sato
Endocrine Disruption and Developmental Abnormalities of Female Reproduction
Integr. Comp. Biol., June 1, 2000; 40(3): 402 - 411.
[Abstract] [Full Text] [PDF]

Home page
 Integr. Comp. Biol.Home page
K. L. Howdeshell and F. S. vom Saal
Developmental Exposure to Bisphenol A: Interaction with Endogenous Estradiol During Pregnancy in Mice
Integr. Comp. Biol., June 1, 2000; 40(3): 429 - 437.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
H. M. Wright, C. B. Clish, T. Mikami, S. Hauser, K. Yanagi, R. Hiramatsu, C. N. Serhan, and B. M. Spiegelman
A Synthetic Antagonist for the Peroxisome Proliferator-activated Receptor gamma Inhibits Adipocyte Differentiation
J. Biol. Chem., January 21, 2000; 275(3): 1873 - 1877.
[Abstract] [Full Text] [PDF]

Home page
 Biol. Reprod.Home page
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]

Home page
 Proc. Natl. Acad. Sci. USAHome page
B. Moosmann and C. Behl
The antioxidant neuroprotective effects of estrogens and phenolic compounds are independent from their estrogenic properties
PNAS, August 3, 1999; 96(16): 8867 - 8872.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
R. M. Bigsby, H. Cardenas, A. Caperell-Grant, and C. J. Grubbs
Protective effects of estrogen in a rat model of age-related cataracts
PNAS, August 3, 1999; 96(16): 9328 - 9332.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
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]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals
Copyright © 1998 by The Endocrine Society