p21 and Notch Signalings in the Persistently Altered Vagina Induced by Neonatal Diethylstilbestrol Exposure in Mice

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  • NAKAMURA Takeshi
    Department of Basic Biology, Faculty of Life Science, The Graduate School for Advanced Studies (SOKENDAI), and Okazaki Institute for Integrative Bioscience, National Institute for Basic Biology, National Institutes of Natural Sciences, 5–1 Higashiyama, Myodaiji, Okazaki 444–8787, Japan Department of Material and Biological Chemistry, Faculty of Science, Yamagata University, Kojirakawa-machi, Yamagata 990–8560, Japan
  • MIYAGAWA Shinichi
    Department of Basic Biology, Faculty of Life Science, The Graduate School for Advanced Studies (SOKENDAI), and Okazaki Institute for Integrative Bioscience, National Institute for Basic Biology, National Institutes of Natural Sciences, 5–1 Higashiyama, Myodaiji, Okazaki 444–8787, Japan
  • KATSU Yoshinao
    Department of Basic Biology, Faculty of Life Science, The Graduate School for Advanced Studies (SOKENDAI), and Okazaki Institute for Integrative Bioscience, National Institute for Basic Biology, National Institutes of Natural Sciences, 5–1 Higashiyama, Myodaiji, Okazaki 444–8787, Japan Graduate School of Life Science and Department of Biological Sciences, Hokkaido University, Sapporo 060–0810, Japan
  • MIZUTANI Takeshi
    Department of Basic Biology, Faculty of Life Science, The Graduate School for Advanced Studies (SOKENDAI), and Okazaki Institute for Integrative Bioscience, National Institute for Basic Biology, National Institutes of Natural Sciences, 5–1 Higashiyama, Myodaiji, Okazaki 444–8787, Japan
  • SATO Tomomi
    International Graduate School of Arts and Sciences, Yokohama City University, Yokohama 236–0027, Japan
  • TAKEUCHI Takashi
    Department of Veterinary Medicine, Faculty of Agriculture, Tottori University, Tottori 680–8553, Japan
  • IGUCHI Taisen
    Department of Basic Biology, Faculty of Life Science, The Graduate School for Advanced Studies (SOKENDAI), and Okazaki Institute for Integrative Bioscience, National Institute for Basic Biology, National Institutes of Natural Sciences, 5–1 Higashiyama, Myodaiji, Okazaki 444–8787, Japan
  • OHTA Yasuhiko
    Department of Veterinary Medicine, Faculty of Agriculture, Tottori University, Tottori 680–8553, Japan

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Abstract

Female reproductive organs show organ-specific morphological changes during estrous cycles. Perinatal exposure to natural and synthetic estrogens including diethylstilbestrol (DES) or estrogenic chemicals induces estrogen-independent persistent proliferation of vaginal epithelium in mice. To understand the underlying mechanism of the estrogen-independent persistent vaginal changes induced by perinatal DES exposure, we examined global gene expressions in the vaginae of ovariectomized adult mice exposed neonatally to DES using a microarray. The cell cycle-related gene, p21, a cyclin-dependent kinase inhibitor, showed upregulation in the vagina, and p21 protein was localized in the basal layer of the vaginal epithelium in mice exposed neonatally to DES and an estrogen receptor α agonist, propyl pyrazole triol (PPT). The expressions of Notch receptors and Notch ligands were unchanged; however, the mRNAs of hairy-related basic helix-loop-helix (bHLH) transcription factor genes, Hes1, Hey1 and Heyl were persistently downregulated in the vagina, indicating estrogen-independent epithelial cell proliferation in mice exposed neonatally to DES and PPT.

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