Involvement of keratinocyte growth factor (KGF)-KGF receptor signaling in developmental estrogenization syndrome of mouse vagina

Masui, Fujiko; Matsuda, Manabu; Mori, Taketoshi

doi:10.1007/s00441-004-0980-9

Cited by 11 publications

(13 citation statements)

References 21 publications

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“…In fact, vitamin A (retinol) and a FGF receptor 2 (IIIb) blocker attenuated the estrogen effects on the neonatal mouse vagina in our previous studies, which provided insights on the mechanisms by which estrogens misleads the developmental processes of the genital tracts [12, 13]. In the present study, the influence of vitamin D and its active derivates on the estrogen effects was explored for the first time.…”

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confidence: 77%

Activated Vitamin D3 and Pro-activated Vitamin D3 Attenuate Induction of Permanent Changes Caused by Neonatal Estrogen Exposure in the Mouse Vagina

Matsuda

Kurosaki

Okamura

2014

Journal of Reproduction and Development

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Exposure of mice to a high dose of estrogens including diethylstilbestrol (DES) during the neonatal period modifies the developmental plan of the genital tract, which leads to various permanent changes in physiology, morphology and gene expression. These changes include development of an abnormal vaginal epithelium lined with hyperplastic mucinous cells accompanied by Tff1 gene expression in mice. Here, the influence of vitamin D on the direct effect of estrogen on the developing mouse vagina was examined. The mid-vagina of neonatal mice was cultured in a serum-free medium containing estradiol-17β (E2) and various concentrations of 1,25-dihydroxyvitamin D3 (1,25(OH)2D) ex vivo and then was transplanted under the renal capsule of ovariectomized host mice for 35 days. Exposure to E2 alone caused the vaginal tissue to develop estrogen-independent epithelial hyperplasia and to express TFF1 mRNA, while addition of a low nanomolar amount of 1,25(OH)2D added at the same time as E2 to the culture medium attenuated the effects of estrogen. Expression of vitamin D receptor was also evident in the neonatal mouse vagina. Interestingly, addition of 25-hydroxyvitamin D3, a pro-activated form of vitamin D, at the micromolar level was found to be potent in disrupting the developmental effects of E2, while cholecalciferol was not at least at the dose examined. Correspondingly, expression of Cyp27B1, a kidney-specific 25-hydroxyvitamin D hydroxylase, was evident in the neonatal mouse vagina when examined by RT-PCR. In addition, simultaneous administration of 1,25(OH)2D successfully attenuated DES-induced ovary-independent hyperplasia in the vagina in neonatal mice in vivo. Thus, manipulation of vitamin D influenced the harmful effects of estrogens on mouse vaginal development.

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confidence: 77%

Activated Vitamin D3 and Pro-activated Vitamin D3 Attenuate Induction of Permanent Changes Caused by Neonatal Estrogen Exposure in the Mouse Vagina

Matsuda

Kurosaki

Okamura

2014

Journal of Reproduction and Development

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“…At the first step, exposure of the vagina to estrogen during the neonatal "critical" period induces persistent changes in the epithelium. This epithelial differentiation step (ED step) is completed within 5 days of estrogenization after birth, possibly being mediated by keratinocyte growth factor receptor signaling (Hom et al 1998;Masui et al 2004). Consequently, at the second step, the abnormally differentiated epithelium in turn induces irreversible changes in stromal development within a later, but longer, period of 30 days (stromal differentiation, SD step), so that, at the third step, the stroma assures permanent proliferation of the epithelium regardless of the presence of estrogen (epithelial proliferation, EP step).…”

Section: Discussionmentioning

confidence: 99%

Persistent trefoil factor 1 expression imprinted on mouse vaginal epithelium by neonatal estrogenization

et al. 2005

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Exposure of female mice to estrogenic substances during the neonatal period induces developmental defects in the reproductive tract such as estrogen-independent persistent proliferation of the vaginal epithelium, which often leads to carcinogenesis in adulthood. In this study, several estrogen-regulated genes have been identified in the neonatal mouse vagina by DNA microarray hybridization analysis. Among the genes up-regulated in the developing vagina by a high dose of estrogen, trefoil factor 1 (TFF1), a mucin-associated gastrointestinal growth factor, showed a unique expression pattern in accordance with the irreversible changes induced by neonatal estrogenization in the vagina. Vaginal expression of TFF1 mRNA was markedly increased by estrogen in neonatal mice but not in adults, and pronouncedly intensified expression of the gastrointestinal gene was observed in the vagina of neonatally estrogenized mice even at adulthood. The specific localization of TFF1 protein in the epithelium of neonatally estrogenized vagina was confirmed by immunohistochemistry. Moreover, without any obvious alteration in the expression of gel-forming mucin genes, the lumen of the neonatally estrogenized vagina became filled with periodic-acid-Schiff-stained mucinous gel, which was possibly caused by the overexpression of TFF1. Thus, estrogen acts directly on the developing vagina in the permanent induction of TFF1 gene expression, and the gene induction does not appear to be related to hypermethylation of the cis-promoter of the TFF1 gene. TFF1 may be a useful marker for developmental estrogenization syndrome of the mouse vagina.

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“…Vet Pathol 45:6, 2008 extent, cows, thickens and keratinizes in response to the estrogen wave of estrus. 36 The epithelium of prepubertal animals and animals in diestrus is usually thin, with only a scant keratin layer, whereas animals under the influence of estrogen have a very thick epithelium. No explanation for the requirement for estrogen for T. foetus infection in some mouse strains has been offered, but it may be that excess keratin protects the organisms from the immune response, provides nutrients for the parasites, or alters the vaginal flora to enhance infection.…”

Section: Discussionmentioning

confidence: 99%

A Pregnant Mouse Model for BovineTritrichomonas foetusInfection

et al. 2008

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Abstract. The economically important effects of Tritrichomonas foetus infection in cattle are abortion and infertility, yet there has not been an animal model to examine the parasite-host interactions during gestation. In this study, 5-and 7-to 8-week-old BALB/cAnNCr, BALB/cJ, and SCID/NCr mice on a BALB/c background were intravaginally infected with T. foetus. All BALB/ cAnNCr and BALB/cJ mice, and 89% of SCID/NCr mice sustained infections for 13 weeks, if inoculated before 5 weeks of age. Infection rates were lower in all mouse strains inoculated at 7 weeks of age, although BALB/cAnNCr mice were significantly more susceptible than BALB/cJ or SCID/ NCr mice. Vaginal bacterial flora did not account for the variation in mouse-strain susceptibility, although coagulase-negative staphylococci in vaginal flora were associated with failure of T. foetus to infect. As with infected cattle, T. foetus-specific vaginal immunoglobulin (Ig) G and IgA antibodies were elevated after infection. The number and viability of day-10 fetuses were reduced in mice infected at 5 weeks of age and bred 12 weeks after infection. Lesions in pregnant and nonpregnant infected mice, including suppurative and eosinophilic vaginitis; cervicitis; endometritis with distension of the uterine lumen; endometrial ulceration; and glandular ectasia, with neutrophils in the glandular lumen and loss of gland epithelium, were similar to those in cattle. The decidua and placenta were multifocally necrotic. Immunohistochemistry demonstrated trichomonads in vaginal folds and uterine glands, and adjacent to fetal tissues. In summary, experimentally infected BALB/cAnNCr mice showed many pathologic similarities to cattle and may serve as a model to study host-trichomonad interactions.

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Involvement of keratinocyte growth factor (KGF)-KGF receptor signaling in developmental estrogenization syndrome of mouse vagina

Cited by 11 publications

References 21 publications

Activated Vitamin D<sub>3</sub> and Pro-activated Vitamin D<sub>3</sub> Attenuate Induction of Permanent Changes Caused by Neonatal Estrogen Exposure in the Mouse Vagina

Activated Vitamin D<sub>3</sub> and Pro-activated Vitamin D<sub>3</sub> Attenuate Induction of Permanent Changes Caused by Neonatal Estrogen Exposure in the Mouse Vagina

Persistent trefoil factor 1 expression imprinted on mouse vaginal epithelium by neonatal estrogenization

A Pregnant Mouse Model for BovineTritrichomonas foetusInfection

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