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Fetal exposure to DES results in de-regulation of Wnt7a during uterine morphogenesis

Nature Genetics volume 20, pages 228–230 (1998)Cite this article

Diethylstilbestrol (DES) was used in the United States from 1947 to 1971 to prevent miscarriage. Approximately one-million women were exposed in utero to DES (ref. 1). Women prenatally exposed to DES commonly display epithelial and/or structural changes in the uterus, cervix, or vagina, and can develop clear cell adenocarcinoma of the vagina or cervix at an early age2,3,4,5. The frequency of DES-associated reproductive tract anomalies6 and cancer7 appears temporally related to the time of exposure, with most abnormal findings occurring in women exposed to DES in the first trimester. The specific molecular response to DES that fully accounts for the DES syndrome remains unknown. We recently reported that mice lacking Wnt7a have malformed female reproductive tracts8 (FRTs). The observed phenotype closely resembles the reproductive tract morphologies observed in female mice prenatally exposed to DES (ref. 9), and indicates that Wnt7a may have a role in the DES response in the developing FRT.

Previous studies have shown that cytodifferentiation of the female reproductive tract in mice is determined 5–7 days after birth and is dependent on mesenchymal-epithelial interactions14. After this time period, the uterine epithelium is no longer responsive to inductive signals from vaginal stroma15. Thus, the FRT has a critical temporal window during which key patterning events occur. We propose that the observed downregulation of Wnt7a during this critical window is sufficient to account for the mouse DES syndrome. DES-like substances such as tamoxifen have recently been shown to be effective in decreasing the incidence of breast cancer in premenopausal women, although uterine cancer increases twofold (NCI clinical trials web site, http://cancertrials.nci.nih.gov). Understanding the molecular responses in breast and uterine tissues to steroidal pharmacological agents will be of high importance should their use increase in clinical applications.

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Figure 1: Prenatal DES treatment mimics the phenotype of the Wnt7a–/– female reproductive tract.
Figure 2: Wnt7a expression is downregulated in DES-exposed mice at the time of birth.

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Acknowledgements

We gratefully acknowledge A.P. McMahon and B. Parr for Wnt7a mutant mice. We thank J. Miano for the SMMHC plasmid and E. Yang for valuable discussion. This work was supported by NIHNIA-AG13784, NIDR RO1DE11953, a Hirschl Award to D.S. and NIH-T32GM08553 to C.M.

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  1. The Mount Sinai School of Medicine, Brookdale Center of Developmental and Molecular Biology, One Gustave Levy Place, Box 1126, New York, 10029, New York, USA

    Cary Miller, Karl Degenhardt & David A. Sassoon

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Correspondence to David A. Sassoon.

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Miller, C., Degenhardt, K. & Sassoon, D. Fetal exposure to DES results in de-regulation of Wnt7a during uterine morphogenesis . Nat Genet 20, 228–230 (1998). https://doi.org/10.1038/3027

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