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Involvement of activin signaling in abnormalities of mouse vagina exposed neonatally to diethylstilbestrol

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Abstract

Perinatal exposure to a synthetic estrogen, diethylstilbestrol (DES), causes cervicovaginal adenosis and permanent hyperplastic cornified vaginal epithelium with keratinization in mice. To investigate the mechanisms of the induction of vaginal abnormalities by DES, we have focused on activin A signaling. We have found that the βA-subunit mRNA is mainly expressed in the neonatal vaginal stroma, whereas activin A receptor type IB is localized in the neonatal vaginal epithelium. SMAD2, the intracellular signaling protein, is phosphorylated in the neonatal vagina. Cell proliferation in the vaginal epithelium grown in vitro is reduced by DES treatment or by activin signaling suppression through inhibin treatment. Thus, activin A (a homodimer of the βA-subunit) in the stroma stimulates epithelial cell proliferation in the neonatal vagina. DES treatment decreases the expression of the βA-subunit and activin receptor IIB but increases the expression of the βB-subunit and inhibin receptor. Neonatal DES treatment inhibits the phosphorylation of SMAD2 in the vaginal epithelium, indicating the inhibition of activin A signaling in the vaginal epithelium by neonatal DES treatment. Treatment with DES or inhibin, a native antagonist of activin, induces adenosis-like structures and keratinization in the vagina grown in vitro. These data suggest that the suppression of activin A signaling by DES is involved in the induction of cervicovaginal adenosis and keratinization in the neonatal mouse vaginal epithelium.

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Acknowledgements

We thank Dr. Raphael Guzman, Department of Molecular and Cell Biology and the Cancer Research Laboratory, University of California, Berkeley, USA, for his critical reading of the manuscript.

Disclosures

The authors declare no conflicts of interest.

Author information

Correspondence to Tomomi Sato.

Additional information

This work was partially supported by a Grant-in-Aid for Scientific Research (B) (T.I.) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, Grants for Strategic Research Projects at Yokohama City University (nos. K19020, K2109, G2201, and W18005 to T.S.), a Health Sciences Research Grant from the Ministry of Health, Labor, and Welfare, Japan (T.I.), and a grant for Support of the Collaborative Study at NIBB (T.S).

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Fig. S
figure8

The expression of inhibin α, βA-subunit, follistatin (Fst), activin receptor (Acvr) 1, Acvr1b, Acvr2a, Acvr2b and transforming growth factor, β receptor III (Tgfβr3) mRNAs in the uterine epithelium (UE), uterine stroma (US), vaginal epithelium (VE) and vaginal stroma (VS) at days 2 and 15 was analyzed by RT-PCR. Peptidylprolyl isomerase A (Ppia) was chosen as an internal standard (GIF 62 kb)

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Table S

(DOC 99 kb)

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Nakajima, T., Iguchi, T. & Sato, T. Involvement of activin signaling in abnormalities of mouse vagina exposed neonatally to diethylstilbestrol. Cell Tissue Res 344, 527 (2011). https://doi.org/10.1007/s00441-011-1161-2

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Keywords

  • Diethylstilbestrol
  • Activin
  • Uterus
  • Vagina
  • Cervicovaginal adenosis
  • Mouse