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

Abstract

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 age [2][3][4][5] . The frequency of DES-associated reproductive tract anomalies 6 and cancer 7 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 tracts 8 (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.To directly compare the effects of loss of Wnt7a with the effects of DES in the FRT, we generated mice with DES-induced malformed FRTs using an established protocol 9,10 . DESexposed mice had shallow vaginal fornices, malformed oviducts that lacked coils, Wolffian duct remnants (Fig. 1a), vaginal concretions and adenotic lesions in the vagina 9,11,12 . Wnt7a −/− mice also had shallow vaginal fornices (data not shown) and malformed oviducts 8 . Similarly, Wnt7a −/− FRTs contained Wolffian duct remnants (Fig. 1b), vaginal concretions ( Fig. 1c) and epithelial inclusions in the vaginal stroma (Fig. 1d). Control FRTs (oil treated) had normal morphology and tissue cytoarchitecture (Fig. 1e). DES-exposed and Wnt7a −/− FRTs displayed stratified epithelium with reduced stroma and glands (Fig. 1f,g). DESexposed women were reported to display uterine abnormalities which were attributed to abnormal smooth muscle proliferation 13 . Both Wnt7a −/− and DES-exposed mice had a disorganized and thickened inner layer of smooth muscle (Fig. 1i-k).Wnt7a is normally expressed perinatally in the luminal epithelium of the uterus 8 . As expected, Wnt7a was found to be expressed in the epithelium of the control uterus (Fig.2 b,d). In the DES-exposed uteri, however, low levels of Wnt7a transcripts were detected at birth (Fig. 2f). Wnt7a expression in the DES-exposed uteri returned to high levels five days after birth (Fig. 2h) and was maintained at later stages (data not shown).Correspondence should be addressed to D.A.S. (dsassoo@smtplink.mssm.edu). HHS Public AccessAuthor manuscript Nat Genet. Author manuscript; available in PMC 2016 February 11. Published in final edited form as:Nat Genet. 1998 November ; 20(3): 228-230. doi:10.1038/3027. Author ManuscriptAuthor Manuscript Author Manuscript Author ManuscriptPrevious 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 interactions 14 . After this time period, the uterine epithelium ...

Interaction between genetic susceptibility and early-life environmental exposure determines tumor-suppressor-gene penetrance

“…However, in the presence of a tumor-suppressor-gene defect, the combined effect of a genetic susceptibility and developmental programming can result in enhanced tumor-suppressor-gene penetrance. Supporting our observations, the CD-1 strain of mice exposed to DES develop uterine adenocarcinomas, whereas C57BL͞6 mice are resistant to tumor induction by DES, pointing to the importance of genetic background as a determinant of response to xenoestrogen exposure (18,40). A previous report by Couse et al (18) proposed that developmental exposure to DES functions as a promoter rather than as an initiator of tumorigenesis.…”

Postnatal Deletion of Wnt7a Inhibits Uterine Gland Morphogenesis and Compromises Adult Fertility in Mice.

“…A stratified type of LE is characteristic of the vagina but not of normal uterus or oviduct. The myometrium appears to be hyperplastic and disorganized by 3 mo of postnatal development, and by 6 mo, the endometrial stroma is displaced by the myometrium [23,27]. Although to our knowledge it has not been investigated in the uterus, WNT7A signals through the canonical WNT/ catenin, beta 1 signaling pathway in other cells and organs [28][29][30][31].…”

Environmental signaling: from environmental estrogens to endocrine‐disrupting chemicals and beyond

“…This is one of the first demonstrations of epigenetic reprogramming by an environmental estrogen during development. Subsequent studies on the mechanisms of epigenetic change following perinatal treatment with DES in the laboratories of Hugh Taylor (Bromer et al, 2009), David Sassoon (Miller et al, 1998), Cheryl Walker and Shuk-Mei Ho (Walker & Ho, 2012), Gail Prins (Prins & Korach, 2007), and others have provided elegant evidence of mechanisms for developmental reprogramming or misprogramming because of DES and estrogenic environmental chemicals.…”