Commentary: Prenatal exposure to diethylstilbestrol (DES): a continuing story (original) (raw)
Related papers
Cancer Research, 1997
Alteration of DNA demethylation in five CpG sites (â€"547, â€"533, â€"475, â€"464, and â€"454) immediately upstream from the estrogen response ele ment of lactofemn promoter was determined in the uteri of immature (17-day-old) and mature (21-and 30-day-old) mice treated neonatally with DES. Only the CpG/â€"464 was found to be abnormally demethylated by diethylstilbestrol (DES) treatment in the mature uteri. This abnormal demethylation occurred in specific response to DES in neonatal mice, because DES injected into the 30-day-old mature mice did not demethy late CpG/â€"464. This site, however, remained methylated in the neonatally DES-treated/ovariectomized mice, indicating that this DES-elicited de methylation is under hormonal controL Thus, neonatal DES treatment appeared to imprint an abnormal, site•specific demethylation of CpGI â€"464, whichrequiresovarianhormones to occurin adultmice.Moreover, the demethylation was maintained in uterine tumors of the neonatafiy DES-treated mice. This mode of demethylation is reminiscent of uterine tumor formation, which also depends on both neonatal DES exposure and ovarian hormone stimulation in adulthood. Thus, neonatal DES treatment may induce tumor formation as well as demethylation through a common cellular process.
PubMed, 1994
Exposure to estrogens during critical periods of development induces teratogenic and carcinogenic lesions in the reproductive tracts of humans and experimental animals. It is important to determine the molecular and cellular targets of estrogenic chemicals and to establish the mechanisms by which interactions of estrogens with the developing genital tract results in permanent lesions of growth and differentiation. The experiments presented here were designed to examined the effects of neonatal estrogen exposure on the expression of two genes, lactoferrin and epidermal growth factor, that are subject to steroid hormone regulation. Using in situ and Northern RNA hybridization, immunoblotting, and immunohistochemistry, our data demonstrate that exposure to the synthetic estrogen, diethylstilbestrol, during a critical neonatal period results in the persistent ovary-independent induction of mRNA and protein encoded by these two genes in the mouse uterus and vagina. The constitutive expression of lactoferrin and EGF, and probably other estrogen-regulated genes, may contribute to the establishment of a permanently "estrogenized" phenotype which is then instrumental in the development of abnormal tissue morphogenesis, function, and neoplasia in the rodent reproductive tract.
Developmental Biology, 2001
Data indicate that estrogen-dependent and -independent pathways are involved in the teratogenic/carcinogenic syndrome that follows developmental exposure to 17-estradiol or diethylstilbestrol (DES), a synthetic estrogen. However, the exact role and extent to which each pathway contributes to the resulting pathology remain unknown. We employed the ␣ERKO mouse, which lacks estrogen receptor-␣ (ER␣), to discern the role of ER␣ and estrogen signaling in mediating the effects of neonatal DES exposure. The ␣ERKO provides the potential to expose DES actions mediated by the second known ER, ER, and those that are ER-independent. Wild-type and ␣ERKO females were treated with vehicle or DES (2 g/pup/day for Days 1-5) and terminated after 5 days and 2, 4, 8, 12, and 20 months for biochemical and histomorphological analyses. Assays for uterine expression of the genes Hoxa10, Hoxa11, and Wnt7a shortly after treatment indicated significant decreases in DES-treated wild-type but no effect in the ␣ERKO. In contrast, the DES effect on uterine expression of Wnt4 and Wnt5a was preserved in both genotypes, suggesting a developmental role for ER. Adult ␣ERKO mice exhibited complete resistance to the chronic effects of neonatal DES exposure exhibited in treated wild-type animals, including atrophy, decreased weight, smooth muscle disorganization, and epithelial squamous metaplasia in the uterus; proliferative lesions of the oviduct; and persistent vaginal cornification. Therefore, the lack of DES effects on gene expression and tissue differentiation in the ␣ERKO provides unequivocal evidence of an obligatory role for ER␣ in mediating the detrimental actions of neonatal DES exposure in the murine reproductive tract.
Environmental Health Perspectives, 1995
Concerns have been raised regarding the role of environmental and dietary estrogens as possible contributors to an increased incidence of various abnormalities in estrogen-target tissues of both sexes. These abnormalities include breast cancer, endometriosis, fibroids, and uterine adenocarcinoma in females, as well as alterations in sex differentiation, decreased sperm concentrations, benign prostatic hyperplasia, prostatic cancer, testicular cancer, and reproductive problems in males. Whether these concerns are valid remains to be determined; however, studies with the potent synthetic estrogen diethylstilbestrol (DES) suggest that exogenous estrogen exposure during critical stages of development can result in permanent cellular and molecular alterations in the exposed organism. These alterations manifest themselves in the female and male as structural, functional, or long-term pathological changes including neoplasia. Although DES has potent estrogenic activity, it may be used as a model compound to study the effects of weaker environmental estrogens, many of which may fit into the category of endocrine disruptors.-Environ Health
Toxicology, 2004
It is generally believed that estrogen receptor-dependent and -independent pathways are involved in mediating the developmental effects of the synthetic estrogen, diethylstilbestrol (DES). However, the precise role and extent to which each pathway contributes to the resulting pathologies remains unknown. We have employed the estrogen receptor knockout (ERKO) mice, which lack either estrogen receptor-␣ (␣ERKO or estrogen receptor- (ERKO), to gain insight into the contribution of each ER-dependent pathway in mediating the effects of neonatal DES exposure in the female and male reproductive tract tissues of the mouse. Estrogen receptor-␣ female mice exhibited complete resistance to the chronic effects of neonatal DES exposure that were obvious in exposed wild-type animals, including atrophy and epithelial squamous metaplasia in the uterus; proliferative lesions of the oviduct; and persistent cornification of the vaginal epithelium. DES-mediated reduction in uterine Hoxa10, Hoxa11 and Wnt7a expression that occurs wild-type females during the time of exposure was also absent in ␣ERKO females. In the male, ␣ERKO mice exhibited complete resistance to the chronic effects of neonatal DES exposure on the prostate, including decreased androgen receptor levels, epithelial hyperplasia, and increased basal cell proliferation. Although ER is highly expressed in the prostate epithelium, DES-exposed ERKO males exhibited all of the effects of neonatal DES exposure that were observed in similarly exposed wild-type males. Therefore, the lack of DES-effects on gene expression and tissue differentiation in the ␣ERKO uterus and prostate provides unequivocal evidence of an obligatory role for ER␣ in mediating the detrimental actions of neonatal DES exposure in the murine reproductive tract.
Reproductive Toxicology, 2008
The synthetic estrogen diethylstilbestrol (DES) is a model to study the effects on female reproductive tract of endocrine disrupting chemicals interacting with estrogen receptors. Pregnant CD-1 mice were given daily by gavage 10 g/kg bw of DES (the lower range of therapeutic exposure) during gestational days 9-16, critical period for reproductive tract development. Parameters of sexual development were recorded after weaning and at sexual maturation. No signs of general toxicity were observed in dams. In DES-treated group, reduced litter weight during lactation and earlier vaginal patency was observed. Uterus weight was increased in F1 treated females at weaning. Histological analysis showed reduced endometrium thickness and increased polyovular follicles, irregular and oocytes with condensed chromatin in the ovary at sexual maturity. Prenatal DES oral administration induces subtle but significant effects on puberty onset, uterine and ovary morphology.
The Journal of Steroid Biochemistry and Molecular Biology, 2013
The exposure to endocrine disrupters and female reproductive tract disorders has not been totally clarified. The present study assessed the long-term effect of perinatal (gestation + lactation) exposure to diethylstilbestrol (DES) on the rat uterus and the effect of estrogen replacement therapy. DES (5 g/kg bw/day) was administered in the drinking water from gestational day 9 until weaning and we studied the uterus of young adult (PND90) and adult (PND360) females. To investigate whether perinatal exposure to DES modified the uterine response to a long-lasting estrogen treatment, 12-month-old rats exposed to DES were ovariectomized and treated with 17-estradiol for 3 months (PND460). In young adult rats (PND90), the DES treatment decreased both the proliferation of glandular epithelial cells and the percentage of glandular perimeter occupied by ␣-smooth muscle actin-positive cells. The other tissue compartments remained unchanged. Cell apoptosis was not altered in DES-exposed females. In control adult rats (PND360), there were some morphologically abnormal uterine glands. In adult rats exposed to DES, the incidence of glands with cellular anomalies increased. In response to estrogens (PND460), the incidence of cystic glands increased in the DES group. We observed glands with daughter glands and conglomerates of glands only on PND460 and in response to estrogen replacement therapy, independently of DES exposure. The p63 isoforms were expressed without changes on PND460. Estrogen receptors ␣ and  showed no changes, while the progesterone receptor decreased in the subepithelial stroma of DESexposed animals with estrogen treatment. The long-lasting effects of perinatal exposure to DES included the induction of abnormalities in uterine tissues of aged female rats and an altered response of the adult uterus to estradiol.
Teratogenesis, Carcinogenesis, and Mutagenesis, 1985
Structural malformation of the oviduct has been reported in experimental animal models and women following prenatal exposure to diethylstilbestrol (DES). To study histological changes in the oviduct in the absence of gross structural rnalformation, neonatal CD-1 mice were treated with DES (2 pg/pup/day) on days 1-5 of age. Focal epithelial hyperplasia was present at 1 month of age in 16 out of 18 (89%) of the DES-treated mice. At 4 months of age, general epithelial hyperplasia with multiple gland-like structures into and through the muscle wall of the oviduct was observed in 90% of the treated mice; by 12 months of age, epithelial hyperplasia and pseudogland formation were seen in 100% of the DES-exposed animals. Epithelial hyperplasia and gland formation were not observed in control mice. The alteration induced by DES in the differentiation and proliferation of mouse oviductal epithelium suggests that the oviduct is a target for DES toxic effects. In addition, there was a progression of the epithelial changes with age. The histological changes described in this study may be partially responsible for the decreased fertility previously reported in this mouse model. Similar changes in the oviduct of DES-exposed women remain to be determined.
Molecular Carcinogenesis, 2007
Previously, we described a mouse model where the well-known reproductive carcinogen with estrogenic activity, diethylstilbestrol (DES), caused uterine adenocarcinoma following neonatal treatment. Tumor incidence was dose-dependent reaching >90% by 18 mo following neonatal treatment with 1000 μg/kg/d of DES. These tumors followed the initiation/promotion model of hormonal carcinogenesis with developmental exposure as initiator, and exposure to ovarian hormones at puberty as the promoter. To identify molecular pathways involved in DES-initiation events, uterine gene expression profiles were examined in prepubertal mice exposed to DES (1, 10, or 1000 μg/kg/d) on days 1-5 and compared to controls. Of more than 20 000 transcripts, approximately 3% were differentially expressed in at least one DES treatment group compared to controls; some transcripts demonstrated dose-responsiveness. Assessment of gene ontology annotation revealed alterations in genes associated with cell growth, differentiation, and adhesion. When expression profiles were compared to published studies of uteri from 5-d-old DES-treated mice, or adult mice treated with 17β estradiol, similarities were seen suggesting persistent differential expression of estrogen responsive genes following developmental DES exposure. Moreover, several altered genes were identified in human uterine adenocarcinomas. Four altered genes [lactotransferrin (Ltf), transforming growth factor beta inducible (Tgfb1), cyclin D1 (Ccnd1), and secreted frizzledrelated protein 4 (Sfrp4)], selected for real-time RT-PCR analysis, correlated well with the directionality of the microarray data. These data suggested altered gene expression profiles observed 2 wk after treatment ceased, were established at the time of developmental exposure and maybe related to the initiation events resulting in carcinogenesis.
Cancer research, 1980
The association between treatment of pregnant women with diethylstilbestrol (DES) and reproductive tract abnormalities in their female offspring is well known. Reports of comparable in utero exposure in animals are few. In this paper, pregnant outbred mice were treated s.c. with daily doses of DES ranging from 0.01 to 100 jug/kg on Days 9 to 16 of gestation. This period corresponds with major organogénesis of the reproduc tive tract in the mouse. Additional groups of pregnant mice were treated during the same time interval with 100-/ig/kg doses of either dimethylstilbestrol (DMS), a weakly estrogenic structural analog of DES, or 17/?-estradiol, a potent steroidal estrogen. When female offspring of mice gestationally exposed to DES were sacrificed at 12 to 18 months of age, lesions were found throughout their reproductive tracts. The vagina was characterized by excess keratinization and female hypo-1To whom requests for reprints should be addressed, at