Acute and permanent growth effects in the mouse uterus after neonatal treatment with estrogens

Halling, Anders; Forsberg, John‐Gunnar

doi:10.1016/0890-6238(93)90248-6

Cited by 19 publications

(11 citation statements)

References 45 publications

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“…The uterotrophic response to DES was evidenced in many studies, uterine weight being doubled even after a short period of postnatal exposure (PND 20-22 or 23-26, 0.2-7 µg/kg day). Uterine abnormalities were also observed when 0.01-100 µg/kg day of DES were given prenatally (McLachlan et al, 1982;Newbold et al, 1983Newbold et al, , 1984 and after a PND 1-5 exposure to 0.01 µg/kg day, resulting in permanent disorders of the reproductive ability (Branham et al, 1988;Hailing and Forsberg, 1993).…”

Section: Two Synthetic Estrogens: Diethylstilbestrol (Des) and Ethynymentioning

confidence: 95%

Female sexual maturation and reproduction after prepubertal exposure to estrogens and endocrine disrupting chemicals: A review of rodent and human data

Rasier

Toppari

Parent

et al. 2006

Molecular and Cellular Endocrinology

144

108

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Natural hormones and some synthetic chemicals spread into our surrounding environment share the capacity to interact with hormone action and metabolism. Exposure to such compounds can cause a variety of developmental and reproductive detrimental abnormalities in wildlife species and, potentially, in human. Many experimental and epidemiological data have reported that exposure of the developing fetus or neonate to environmentally relevant concentrations of some among these endocrine disrupters induces morphological, biochemical and/or physiological disorders in brain and reproductive organs, by interfering with the hormone actions. The impact of such exposures on the hypothalamic-pituitary-gonadal axis and subsequent sexual maturation is the subject of the present review. We will highlight epidemiological human studies and the effects of early exposure during gestational, perinatal or postnatal life in female rodents.

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Section: Two Synthetic Estrogens: Diethylstilbestrol (Des) and Ethynymentioning

confidence: 95%

Female sexual maturation and reproduction after prepubertal exposure to estrogens and endocrine disrupting chemicals: A review of rodent and human data

Rasier

Toppari

Parent

et al. 2006

Molecular and Cellular Endocrinology

144

108

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“…1986; Haining et al, 1991;Nelson et al, 1991;Halling and Forsberg, 1993). EGF and its receptor have been demonstrated in the mouse genital tract as early as on day 12 of gestation (Nexo et al, 1980;Lingham et al, 1988;Bossert et al, 19901, and in the adult animal these factors are said to occur in all major uterine cell types (Lin et al, 1988).…”

mentioning

confidence: 99%

“…The aim of this immunohistochemical study was to compare the distribution and estrogen response of EGF, its receptor (EGF-r), and the c-fos protein in uterus and vagina from neonatal and adult mice. The adult females include such treated with estrogen neonatally because this treatment results in life-long aberrations in the genital epithelium (Forsberg, 1979;Forsberg and Kalland, 1981) and disturbed growth control mechanisms in the uterus (Halling and Forsberg, 1993). Thus a further reason for this study was to investigate if these estrogen-induced changes could be linked to changes in immunodetectable growth factors and proto-oncogenes.…”

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confidence: 99%

“…As a result of estrogen exposure in neonatal life, the cells in the basal zone may be affected resulting in an ovary-independent, noncycling squamous epithelium (cornified or parakeratotic) in adult life (Takasugi and Bern, 1964). The columnar paramesonephric epithelium responds to estrogen in opposite ways in different regions: the proliferative activity is increased in the uterine horns, whereas it is inhibited in the uterine cervix and vagina (Forsberg, 1970;Halling and Forsberg, 1993). The latter results in nontransformation in the uterine cervix and vagina, the columnar epithelium remains and after puberty it may develop into adenosis and even morphological malignancy (Forsberg, 1979;Forsberg and Kalland, 1981).…”

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confidence: 99%

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Immunohistochemical studies on the expression and estrogen dependency of EGF and its receptor and C-fos proto-oncogene in the uterus and vagina of normal and neonatally estrogen-treated mice

Falck

Forsberg

1996

Anat. Rec.

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Background The final target cell response to estrogen is dependent not only on the estrogen receptor, but also on autocrine/paracrine interactions with growth factors (e.g., EGF) and proto‐oncogenes (e.g., c‐fos). Because neonatal estrogen treatment results in permanent changes in the female mouse genital tract (permanent vaginal cornification, cervical adenosis and tumors, changed growth control mechanisms in uterus), it was of interest to study possible acute and permanent effects of such treatment on distribution and levels of EGF, its receptor (EGF‐r), and c‐fos and to relate such changes to morphological development and appearance of epithelial abnormalities. Methods Immunohistochemical techniques using frozen sections from the uterus and vagina of neonatal and adult (ovariectomized, estradiol‐treated) females, treated with olive oil or diethylstilbestrol in neonatal life. Results A difference in stromal‐epithelial distribution of EGF was demonstrated with respect to region studied (uterus, vagina) and age (neonatal, adult). EGF was localized mainly in the uterine stroma but in both vaginal epithelium and stroma (with a different pattern compared to uterus). In neonatal females, EGF occurred in both tissue components in both regions, and the distribution pattern was quite different from that in adult females. The EGF level was increased by estrogen in adult but not in neonatal females. EGF‐r and c‐fos occurred in both uterine epithelium and stroma and in the vaginal epithelium; levels and distribution pattern were affected by estrogen. Neonatal estrogen treatment increased the levels of uterine EGF and c‐fos in adult life. Conclusions There are distinct developmental changes in the distribution and estrogen sensitivity of EGF. Only further studies can prove or disprove the association between the earlier reported disturbed growth control mechanisms in the uterus of adult but neonatally estrogen‐treated females and the increased levels of uterine EGF and c‐fos. The present results do not seem to explain mechanisms involved in the origin of neonatally estrogen‐induced cervicovaginal epithelial abnormalities, nor do they explain the earlier described difference in estrogen‐induced proliferative response between the uterine cervix and uterus proper. © 1996 Wiley‐Liss, Inc.

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“…The perinatal DES-treated mouse model correlates remarkably well with the adverse effects observed in both male and female humans exposed in utero to DES. Tables 1 and 2 (25) and 0.01 pglkg/day for the neonatal mouse uterus (20,21,23 (50,51). The expression of lactoferrin is induced by DES in the uterus prenatally, neonatally, and in adult stages (52), thus making it a particularly attractive biomarker of DES action in the mouse.…”

Section: Animal Models Summary Ofthe Modelsmentioning

confidence: 99%

New approaches for estimating risk from exposure to diethylstilbestrol.

Cunha

Forsberg

Golden

et al. 1999

Environ Health Perspect

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A subgroup from a National Institute of Environmental Health Sciences, workshop concerned with characterizing the effects of endocrine disruptors on human health at environmental exposure levels considered the question, If diethylstilbestrol (DES) were introduced into the market for human use today and likely to result in low-dose exposure of the human fetus, what would be required to assess risk? On the basis of an analysis of the quality of data on human DES exposure, the critical times and doses for inducing genital tract malformations and cancer must be determined. This would be facilitated through analysis of the ontogeny of estrogen receptor expression in the developing human genital tract. Models of low-dose estrogenic effects will have to be developed for human and rodent genital tract development. Mouse models offer many advantages over other potential animal models because of the wealth of the earlier literature, the availability of sensitive end points, the availability of mutant lines, and the possibility of generating genetically engineered model systems. Through multidisciplinary approaches, it should be possible to elucidate the cellular and molecular mechanisms of endocrine disruption elicited by estrogens during development and facilitate an assessment of risk to humans. (4,5) and were thought to cross the placenta in humans (6,7), direct evidence of teratogenicity of estrogens in humans was unknown until after the association between DES and vaginal adenocarcinoma was reported. In any case, despite the tragedy of the DES episode, the human DES clinical data offer an unprecedented opportunity to learn about the consequences of in utero exposure to a potent estrogen and thus to infer potential risks following exposure to less potent environmental estrogens.If properly interpreted, lessons from the DES episode may prove invaluable for judging potential effects of compounds that have been or will be identified as potential endocrine disruptors. It will be important, however, to keep in mind the considerable differences in potency between such compounds when inferences are drawn concerning potential effects. For example, the carcinogenicity of DES was identified in a human study including only 8 cases and 32 controls (8). Normal sample size calculations would rule such a study as inadequate. However, because the cancer induced by DES (clear cell vaginal adenocarcinoma) was so rare in young women, the association between prenatal DES exposure and development of clear cell adenocarcinoma of the vagina was easily identified. Clearly, most chemicals with significantly less potent endocrine (e.g., estrogenic) effects will convey much-reduced risks, particularly at low doses. Thus, study designs for other endocrine disruptors will have to be more precise and more powerful, especially if the background incidence of a particular lesion is substantial. Given the history of the DES episode, we have considered this issue: If DES were introduced into the market for human use today and were likely to result in ...

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Acute and permanent growth effects in the mouse uterus after neonatal treatment with estrogens

Cited by 19 publications

References 45 publications

Female sexual maturation and reproduction after prepubertal exposure to estrogens and endocrine disrupting chemicals: A review of rodent and human data

Female sexual maturation and reproduction after prepubertal exposure to estrogens and endocrine disrupting chemicals: A review of rodent and human data

Immunohistochemical studies on the expression and estrogen dependency of EGF and its receptor and C-fos proto-oncogene in the uterus and vagina of normal and neonatally estrogen-treated mice

New approaches for estimating risk from exposure to diethylstilbestrol.

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