Abstract
Exposure to estrogenic substances during a time window, the so-called “critical period,” in perinatal life causes an irregular development of the genital tract that leads to ovary-independent proliferation and cornification in the vaginal epithelium in mice. We have previously demonstrated that retinol inhibits the irreversible effects of estrogen on the vagina. Here, mice kept in a vitamin-A-deficient condition during perinatal life were shown to be more sensitive to the harmful effects of estrogen. In addition, expression of mRNA for retinol binding protein type 2 (CRBP2), a “small intestine-specific” cytosolic protein that captures intracellular retinal and retinol, was detected in the vaginal epithelium. Induction of increased expression of CRBP2 mRNA by estrogen was also evident in the uterus and epididymis. Both estradiol-17β and diethylstilbestrol markedly increased the tissue content of CRBP2 mRNA in the vagina and uterus during the neonatal “critical period” but not after 15 days of age. These results taken together imply that estrogen disrupts the local vitamin A balance by an induction of CRBP2 gene expression in the epithelium in the developing mouse genital tract, and that retinoid imbalance may contribute to the genesis of irreversible effects of estrogen on the vagina.
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Atanassova N, McKinnell C, Williams K, Turner KJ, Fisher JS, Saunders PT, Millar MR, Sharpe RM (2001) Age-, cell- and region-specific immunoexpression of estrogen receptor alpha (but not estrogen receptor beta) during postnatal development of the epididymis and vas deferens of the rat and disruption of this pattern by neonatal treatment with diethylstilbestrol. Endocrinology 142:874–886
Bern HA, Talamantes F (1981) Neonatal mouse models and their relation to disease in the human female. In: Herbst AL, Bern HA (eds) Developmental effects of diethylstilbestrol (DES) in pregnancy. Thieme Stratton, New York, pp 129–147
Block K, Kardana A, Igarashi P, Taylor HS (2000) In utero diethylstilbestrol (DES) exposure alters Hox gene expression in the developing mullerian system. FASEB J 14:1101–1108
Colborn T, von Saal FS, Soto AM (1993) Developmental effects of endocrine-disrupting chemicals in wildlife and humans. Environ Health Perspect 101:378–384
Conlon RA (1995) Retinoic acid and pattern formation in vertebrates. Trends Genet 11:314–319
Couse JF, Dixon D, Yates M, Moore AB, Ma L, Maas R, Korach KS (2001) Estrogen receptor-alpha knockout mice exhibit resistance to the developmental effects of neonatal diethylstilbestrol exposure on the female reproductive tract. Dev Biol 238:224–238
Crow JA, Ong DE (1985) Cell-specific immunohistochemical localization of a cellular retinol-binding protein (type two) in the small intestine of rat. Proc Natl Acad Sci U S A 82:4707–4711
Cunha GR, Lung B, Kato K (1977) Role of the epithelial-stromal interaction during the development and expression of ovary-independent vaginal hyperplasia. Dev Biol 56:52–67
Cunha GR, Wang YZ, Hayward SW, Risbridger GP (2001) Estrogenic effects on prostatic differentiation and carcinogenesis. Reprod Fertil Dev 13:285–296
Dalterio S, Bartke A, Steger R, Mayfield D (1985) Neonatal exposure to DES in BALB/c male mice: effects on pituitary-gonadal function. Pharmacol Biochem Behav 22:1019–1024
Evans TR, Kaye SB (1999) Retinoids: present role and future potential. Br J Cancer 80:1–8
Folli C, Calderone V, Ottonello S, Bolchi A, Zanotti G, Stoppini M, Berni R (2001) Identification, retinoid binding, and x-ray analysis of a human retinol-binding protein. Proc Natl Acad Sci U S A 98:3710–3715
Franz O, Bruchhaus II, Roeder T (1999) Verification of differential gene transcription using virtual northern blotting. Nucleic Acids Res 27:e3
Golden RJ, Noller KL, Titus-Ernstoff L, Kaufman RH, Mittendorf R, Stillman R, Reese EA (1998) Environmental endocrine modulators and human health: an assessment of the biological evidence. Crit Rev Toxicol 28:109–227
Green JB (1990) Retinoic acid: the morphogen of the main body axis? Bioessays 12:437–439
Harrison EH, Hussain MM (2001) Mechanisms involved in the intestinal digestion and absorption of dietary vitamin A. J Nutr 131:1405–1408
Herbst AL, Ulfelder H, Poskanzer DC (1971) Adenocarcinoma of the vagina. Association of maternal stilboestrol therapy with tumor appearance in young women. N Engl J Med 284:878–881
Herr FM, Ong DE (1992) Differential interaction of lecithin-retinol acyltransferase with cellular retinol binding proteins. Biochemistry 31:6748–6755
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
Iguchi T, Fukazawa Y, Bern HA (1995) Effects of sex hormones on oncogene expression in the vagina and on development of sexual dimorphism of the pelvis and anococcygeus muscle in the mouse. Environ Health Perspect 103 (Suppl 7):79–82
Imaoka T, Horseman ND, Lockefeer JA, Mori T, Matsuda M (2002) Cortactin-binding protein 90 (CBP90) expression in the mouse mammary glands during prolactin-induced lobuloalveolar development. Zool Sci 19:443–448
Kakkad BP, Ong DE (1988) Reduction of retinaldehyde bound to cellular retinol-binding protein (type II) by microsomes from rat small intestine. J Biol Chem 263:12916–12919
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
Masui F, Matsuda M, Mori T (2003) Inhibition of KGF-induced ovary-independent cornification of vaginal epithelium by vitamin A in neonatally estrogenized mice. Cell Tissue Res 311:251–258
Matsuda M, Mori T (1997) Effect of hormones on expression of prolactin receptor messenger ribonucleic acids in pancreatic islets of adult female mice in vitro. Zool Sci 14:159–165
Matsuda M, Mori T, Park MK, Yanaihara N, Kawashima S (1994) Enhanced cell proliferation by hyperprolactinemia in both exocrine and endocrine pancreas in mice. Eur J Endocrinol 130:187–194
McLachlan JA (1979) Transplacental effects of diethylstilbestrol in mice. Natl Cancer Inst Monogr 51:67–72
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
Mori T (1969) Further studies on the inhibitory effect of vitamin A on the development of ovary-independent vaginal cornification in neonatally estrogenized mice. Proc Jpn Acad 45:115–120
Mori T (1986) Abnormalities in the reproductive system of aged mice after neonatal estradiol exposure. J Endocrinol Invest 9:397–402
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
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
Noy N (2000) Retinoid-binding proteins: mediators of retinoid action. Biochem J 348:481–495
Prins GS, Birch L, Couse JF, Choi I, Katzenellenbogen B, Korach KS (2001) Estrogen imprinting of the developing prostate gland is mediated through stromal estrogen receptor alpha: studies with alphaERKO and betaERKO mice. Cancer Res 61:6089–6097
Santti R, Makela S, Strauss L, Korkman J, Kostian ML (1999) Phytoestrogens: potential endocrine disruptors in males. Toxicol Ind Health 14:223–237
Schaefer WH, Kakkad B, Crow JA, Blair IA, Ong DE (1989) Purification, primary structure characterization, and cellular distribution of two forms of cellular retinol-binding protein, type II from adult rat small intestine. J Biol Chem 264:4212–4221
Takasugi N (1963) Vaginal cornification in persistent-estrous mice. Endocrinology 72:607–619
Takasugi N (1979) Development of permanently proliferated and cornified vaginal epithelium in mice treated with steroid hormones and the implication in tumorigenesis. Natl Cancer Inst Monogr 51:57–66
Takasugi N, Bern HA (1964) Tissue changes in mice with persistent vaginal cornification induced by early postnatal treatment with estrogen. J Natl Cancer Inst 33:855–865
Takasugi N, Bern HA, DeOme KB (1962) Persistent vaginal cornification in mice. Science 138:438–439
Wardlaw SA, Bucco RA, Zheng WL, Ong DE (1997) Variable expression of cellular retinol- and cellular retinoic acid-binding proteins in the rat uterus and ovary during the estrous cycle. Biol Reprod 56:125–132
Yamashita M, Matsuda M, Mori T (1999) In situ detection of prolactin receptor mRNA and apoptotic cell death in mouse uterine tissues with adenomyosis. In Vivo 13:57–60
Zheng WL, Ong DE (1998) Spatial and temporal patterns of expression of cellular retinol-binding protein and cellular retinoic acid-binding proteins in rat uterus during early pregnancy. Biol Reprod 58:963–970
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This work was supported by Grants-in-Aid for Priority Area B (to T.M. and M.M.) and for Young Scientists (to M.M.) from the Ministry of Culture, Sports, Science and Technology, Japan
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Matsuda, M., Masui, F. & Mori, T. Neonatal estrogenization leads to increased expression of cellular retinol binding protein 2 in the mouse reproductive tract. Cell Tissue Res 316, 131–139 (2004). https://doi.org/10.1007/s00441-004-0852-3
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DOI: https://doi.org/10.1007/s00441-004-0852-3