This Article Full Text Full Text (PDF) Supplemental Data File All Versions of this Article: 19/3/669    most recent Author Manuscript (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager NURSA Molecule Pages Link Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Huang, W.-W. Articles by Ma, L. Search for Related Content PubMed PubMed Citation Articles by Huang, W.-W. Articles by Ma, L.

Developmental Diethylstilbestrol Exposure Alters Genetic Pathways of Uterine Cytodifferentiation

Tulane/Xavier Center for Bioenvironmental Research (W.-W.H., T.-C.C., N.G., J.A.M.) and Center for Gene Therapy (J.V.), Tulane University Medical Center, New Orleans, Louisiana 70112; and Department of Cell and Molecular Biology (Y.Y., Q.B., L.M.), Tulane University, New Orleans, Louisiana 70118

Address all correspondence and requests for reprints to: Liang Ma, Division of Dermatology, Department of Medicine, Washington University, Campus Box 8123, 660 South Euclid Avenue, St. Louis, Missouri 63110. E-mail: lima{at}im.wustl edu.

The formation of a simple columnar epithelium in the uterus is essential for implantation. Perturbation of this developmental process by exogenous estrogen, such as diethylstilbestrol (DES), results in uterine metaplasia that contributes to infertility. The cellular and molecular mechanism underlying this transformation event is not well understood. Here we use a combination of global gene expression analysis and a knockout mouse model to delineate genetic pathways affected by DES. Global gene expression profiling experiment revealed that neonatal DES treatment alters uterine cell fate, particularly in the luminal epithelium by inducing abnormal differentiation, characterized by the induction of stratified epithelial markers including members of the small proline-rich protein family and epidermal keratins. We show that Msx2, a homeodomain transcription factor, functions downstream of DES and is required for the proper expression of several genes in the uterine epithelium including Wnt7a, PLAP, and K2.16. Finally, Msx2–/– uteri were found to exhibit abnormal water trafficking upon DES exposure, demonstrating the importance of Msx2 in tissue responsiveness to estrogen exposure. Together, these results indicate that developmental exposure to DES can perturb normal uterine development by affecting genetic pathways governing uterine differentiation.

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα  |  ERRβ

Ligands:   Diethylstilbestrol

This article has been cited by other articles:

				Y. Yin, W.-W. Huang, C. Lin, H. Chen, A. MacKenzie, and L. Ma Estrogen Suppresses Uterine Epithelial Apoptosis by Inducing Birc1 Expression Mol. Endocrinol., January 1, 2008; 22(1): 113 - 125. [Abstract] [Full Text] [PDF]

				A. Suzuki, H. Urushitani, T. Sato, T. Kobayashi, H. Watanabe, Y. Ohta, and T. Iguchi Gene Expression Change in the Mullerian Duct of the Mouse Fetus Exposed to Diethylstilbestrol In Utero Experimental Biology and Medicine, April 1, 2007; 232(4): 503 - 514. [Abstract] [Full Text] [PDF]

				Y. Yin, C. Lin, and L. Ma Msx2 Promotes Vaginal Epithelial Differentiation and Wolffian Duct Regression and Dampens the Vaginal Response to Diethylstilbestrol Mol. Endocrinol., July 1, 2006; 20(7): 1535 - 1546. [Abstract] [Full Text] [PDF]

				D. Crews and J. A. McLachlan Epigenetics, Evolution, Endocrine Disruption, Health, and Disease Endocrinology, June 1, 2006; 147(6): s4 - s10. [Abstract] [Full Text] [PDF]

				A. Suzuki, H. Watanabe, T. Mizutani, T. Sato, Y. Ohta, and T. Iguchi Global Gene Expression in Mouse Vaginae Exposed to Diethylstilbestrol at Different Ages. Experimental Biology and Medicine, May 1, 2006; 231(5): 632 - 640. [Abstract] [Full Text] [PDF]

				K. Hayashi and T. E. Spencer WNT Pathways in the Neonatal Ovine Uterus: Potential Specification of Endometrial Gland Morphogenesis by SFRP2 Biol Reprod, April 1, 2006; 74(4): 721 - 733. [Abstract] [Full Text] [PDF]