Skip to main content

Vitamin A prevents the irreversible proliferation of vaginal epithelium induced by neonatal injection of keratinocyte growth factor in mice

Cell and Tissue Research volume 311, pages 251–258 (2003)Cite this article

Abstract.

Exposure of female mice to estrogen during the perinatal period results in estrogen-independent persistent proliferation and cornification of the vaginal epithelium when the animals become adults. However, the occurrence of such irreversible vaginal changes is blocked by concurrent vitamin A treatment. Neonatal exposure to keratinocyte growth factor (KGF), which is a paracrine mediator of epithelial-mesenchymal interactions, also induces the persistent proliferation and cornification of the vaginal epithelium in adult mice. This study was designed to examine whether concurrent administration of vitamin A inhibits the development of the irreversible vaginal changes in mice exposed neonatally to KGF. The vaginal epithelium in ovariectomized 35-day-old mice given 5 µg of KGF for 3 days after birth possessed a significantly larger number of layers and increased thickness as compared to that in control mice. Concurrent injections of 100 IU of vitamin A acetate inhibited the occurrence of the irreversible proliferation of the vaginal epithelium. These changes were equal to the results observed when 20 µg of estrogen with or without vitamin A acetate was administered for 5 days after birth. Unlike the case of estrogen treatment, the effect of neonatal treatment with KGF seemed to appear after a latent period, since the vaginal epithelium did not show proliferation soon after the treatment. We discuss the inhibitory effect of VA on the irreversible vaginal changes induced by neonatal KGF treatment with reference to endocrine disruption by neonatal estrogen exposure.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

Fig. 1A–D.
Fig. 2A–I.
Fig. 3.
Fig. 4.
Fig. 5A–E.

References

  • Alarid ET, Rubin JS, Young P, Chedid M, Ron D, Aaronson SA, Cunha GR (1994) Keratinocyte growth factor functions in epithelial induction during seminal vesicle development. Proc Natl Acad Sci U S A 91:1074–1078

    CAS  PubMed  Google Scholar 

  • Boyd J, Takahashi H, Waggoner SE, Jones LA, Hajek RA, Wharton JT, Liu FS, Fujino T, Barrett JC, McLachlan JA (1996) Molecular genetic analysis of clear cell adenocarcinomas of the vagina and cervix associated and unassociated with diethylstilbestrol exposure in utero. Cancer 77:507–513

    Article  CAS  PubMed  Google Scholar 

  • Chateau D, Boehm N (1996) Regulation of differentiation and keratin 10 expression by all-trans retinoic acid during the estrous cycle in the rat vaginal epithelium. Cell Tissue Res 284:373–381

    Article  CAS  PubMed  Google Scholar 

  • Cooke PS, Buchanan DL, Kurita T, Lubahn DB, Cunha GR (1998) Stromal-epithelial cell communication in the female reproductive tract. In: Bazer FW (ed) The endocrinology of pregnancy. Humana Press, Totowa, pp 491–506

  • Elias PM, Williams ML (1981) Retinoids, cancer and the skin. Arch Dermatol 117:160–180

    CAS  PubMed  Google Scholar 

  • Herbst AL, Bern HA (eds) (1981) Developmental effects of diethylstilbestrol (DES) in pregnancy. Thieme Stratton Inc., New York

  • Hom YK, Young P, Thomson AA, Cunha GR (1998) Keratinocyte growth factor injected into female mouse neonates stimulates uterine and vaginal epithelial growth. Endocrinology 139:3772–3779

    CAS  PubMed  Google Scholar 

  • Ka H, Jaeger LA, Johnson GA, Spencer TE, Bazer FW (2001) Keratinocyte growth factor is up-regulated by estrogen in the porcine uterine endometrium and functions in trophectoderm cell proliferation and differentiation. Endocrinology 142:2303–2310

    CAS  PubMed  Google Scholar 

  • Mackenzie IC, Gao Z (2001) Keratinocyte growth factor expression in human gingival fibroblasts and stimulation of in vitro gene expression by retinoic acid. J Periodontol 72:445–453

    CAS  PubMed  Google Scholar 

  • Masui F, Matsuda M, Akazome Y, Imaoka T, Mori T (2001) Prevention of neonatal estrogen imprinting by vitamin A as indicated by estrogen receptor expression in the mouse vagina. Cell Tissue Res 306:441–447

    Article  CAS  PubMed  Google Scholar 

  • McCullough FS, Northrop-Clewes CA, Thurnham DI (1999) The effect of vitamin A on epithelial integrity. Proc Nutr Soc 58:289–293

    CAS  PubMed  Google Scholar 

  • McLachlan JA (2001) Environmental signaling: what embryos and evolution teach us about endocrine disrupting chemicals. Endocr Rev 22:319–341

    CAS  PubMed  Google Scholar 

  • McLachlan JA, Newbold RR, Shah HC, Hogan MD, Dixon RL (1982) Reduced fertility in female mice exposed transplacentally to diethylstilbestrol (DES). Fertil Steril 38:364–371

    CAS  PubMed  Google Scholar 

  • Mori T (1968) Effects of neonatal injections of estrogen in combination with vitamin A on the vaginal epithelium of adult mice. Annot Zool Jpn 41:113–118

    CAS  Google Scholar 

  • Mori T, Nagasawa H (eds) (1988) Toxicity of hormones in perinatal life. CRC Press, Boca Raton, FL

  • Morriss-Kay GM, Ward SJ (1999) Retinoids and mammalian development. Int Rev Cytol 188:73–131

    CAS  PubMed  Google Scholar 

  • Nagasawa H, Yanai R, Taniguchi H, Tokuzen R, Nakahara W (1976) Two-way selection of a stock of Swiss albino mice for mammary tumorigenesis; establishment of two new strains (SHN and SLN). J Natl Cancer Inst 57:425–430

    CAS  PubMed  Google Scholar 

  • Nakahashi K, Matsuda M, Mori T (2001) Vitamin A insufficiency accelerates the decrease in the number of sperm induced by an environmental disruptor, bisphenol A, in neonatal mice. Zool Sci 18:819–821

    CAS  Google Scholar 

  • Niles RM (2000) Vitamin A and cancer. Nutrition 16:573–576

    Article  CAS  PubMed  Google Scholar 

  • Oshika E, Liu S, Singh G, Michalopoulos GK, Shinozuka H, Katyal SL (1998) Antagonistic effects of dexamethasone and retinoic acid on rat lung morphogenesis. Pediatr Res 43:315–324

    CAS  PubMed  Google Scholar 

  • Parrott JA, Kim G, Mosher R, Skinner MK (2000) Expression and action of keratinocyte growth factor (KGF) in normal ovarian surface epithelium and ovarian cancer. Mol Cell Endocrinol 167:77–87

    Article  CAS  PubMed  Google Scholar 

  • Peehl DM, Wong ST, Rubin JS (1996) KGF and EGF differentially regulate the phenotype of prostatic epithelial cells. Growth Regul 6:22–31

    CAS  PubMed  Google Scholar 

  • Ross SA, McCaffery PJ, Drager UC, DeLuca LM (2000) Retinoids in embryonal development. Physiol Rev 80:1021–1054

    PubMed  Google Scholar 

  • Rubin JS, Bottaro DP, Chedid M, Miki T, Ron D, Cheon HG, Taylor WG, Fortney E, Sakata H, Finch PW, LaRochelle WJ (1995) Keratinocyte growth factor. Cell Biol Int 19:399–411

    Article  CAS  PubMed  Google Scholar 

  • Sah JF, Eckert RL, Chandraratna RA, Rorke EA (2002) Retinoids suppress epidermal growth factor-associated cell proliferation by inhibiting epidermal growth factor receptor-dependent ERK1/2 activation. J Biol Chem 277:9728–9735

    Article  CAS  PubMed  Google Scholar 

  • Sato T, Ohta Y, Okamura H, Hayashi S, Iguchi T (1996) Estrogen receptor (ER) and its messenger ribonucleic acid expression in the genital tract of female mice exposed neonatally to tamoxifen and diethylstilbestrol. Anat Rec 244:374–385

    Article  CAS  PubMed  Google Scholar 

  • Sugimura Y, Foster BA, Hom YK, Lipschutz JH, Rubin JS, Finch PW, Aaronson SA, Hayashi N, Kawamura J, Cunha GR (1996) Keratinocyte growth factor (KGF) can replace testosterone in the ductal branching morphogenesis of the rat ventral prostate. Int J Dev Biol 40:941–951

    CAS  PubMed  Google Scholar 

  • Sun SY, Lotan R (2002) Retinoids and their receptors in cancer development and chemoprevention. Crit Rev Oncol Hematol 41:41–55

    Article  PubMed  Google Scholar 

  • Suzuki A, Enari M, Iguchi T (1996) Effect of neonatal exposure to DES in Fas and Bcl-2 expression in the adult mouse vagina and approach to the DES syndrome. Reprod Toxicol 10:465–470

    Article  CAS  PubMed  Google Scholar 

  • Takasugi N (1976) Cytological basis for permanent vaginal changes in mice treated neonatally with steroid hormones. Int Rev Cytol 44:193–224

    CAS  PubMed  Google Scholar 

  • Takasugi N, Bern HA, DeOme KB (1962) Persistent vaginal cornification in mice. Science 138:438–439

    CAS  Google Scholar 

  • Ulich TR, Yi ES, Cardiff R, Yin S, Bikhazi N, Biltz R, Morris CF, Pierce GF (1994) Keratinocyte growth factor is a growth factor for mammary epithelium in vivo. The mammary epithelium of lactating rats is resistant to the proliferative action of keratinocyte growth factor. Am J Pathol 144:862–868

    CAS  PubMed  Google Scholar 

  • Yasui T, Takasugi N (1977) Prevention by vitamin A of the occurrence of permanent vaginal changes in neonatally estrogen-treated mice. An electron microscopic study. Cell Tissue Res 179:475–482

    CAS  PubMed  Google Scholar 

Download references

Author information

Affiliations

  1. Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Bunkyo-ku, Tokyo, 113–0033, Japan

    Fujiko Masui, Manabu Matsuda & Takao Mori

Authors
  1. Fujiko Masui
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Manabu Matsuda
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Takao Mori
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Fujiko Masui.

Additional information

This work was supported by the Sasakawa Scientific Research Grant from the Japan Science Society and Grants-in-Aid for Scientific Research (C), Scientific Research on Priority Areas (A) and Encouragement of Young Scientists from the Ministry of Education, Science, Sports and Culture, Japan

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Masui, F., Matsuda, M. & Mori, T. Vitamin A prevents the irreversible proliferation of vaginal epithelium induced by neonatal injection of keratinocyte growth factor in mice. Cell Tissue Res 311, 251–258 (2003). https://doi.org/10.1007/s00441-002-0667-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00441-002-0667-z

Keywords

  • Keratinocyte growth factor (KGF)
  • Vitamin A
  • Estrogen
  • Vagina
  • Mouse (SHN)