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diethylstilbestrol diethylstilbestrol [keywords]
- Neonatal exposure to low doses of endosulfan induces implantation failure and disrupts uterine functional differentiation at the pre-implantation period in rats. [JOURNAL ARTICLE]
- Mol Cell Endocrinol 2014 Dec 5.
We investigated whether neonatal exposure to low doses of endosulfan affects fertility and uterine functional differentiation at pre-implantation in rats. Newborn female rats received the vehicle, 0.2 µg/kg/d of diethylstilbestrol (DES), 6 µg/kg/d of endosulfan (Endo6) or 600 µg/kg/d of endosulfan (Endo600) on postnatal days (PND) 1, 3, 5, and 7. On PND90, the rats were mated to evaluate their reproductive performance on gestational day (GD) 19 and their ovarian steroid serum levels, endometrial proliferation and implantation-associated proteins on GD5. DES and endosulfan decreased the pregnancy rate and the number of implantation sites. On GD5, DES and endosulfan did not change the serum levels of 17β-estradiol (E2) and progesterone (P); the endometrial proliferation decreased, which was associated with silencing of Hoxa10 in the Endo600-treated rats. Both doses of endosulfan increased the progesterone receptor (PR) expression, whereas the higher dose led additionally to an increase in estrogen receptor alpha (ERα). In the Endo600-treated rats, the down-regulation of Hoxa10 was associated with a deregulation of the steroid receptor coregulators. Alterations in endometrial proliferation and the endocrine pathway of Hoxa10/steroid receptors/coregulators might be the mechanism of endosulfan-induced implantation failure.
- Pituitary gene expression differs in D-galactose-induced cell senescence and steroid-induced prolactinomas. [JOURNAL ARTICLE]
- Mol Med Rep 2014 Dec 8.
In general, pituitary tumors are benign with low mitotic activity. Premature senescence has been considered to be a significant mechanism underlying this uniquely benign pituitary tumor. The present study aims to compare the expression of the associated proteins involved in premature senescence pathways among normal, aging and pituitary adenoma cells. We successfully induced the aging pituitary using continuous D‑galactose (D‑gal) injection as well as a prolactin‑secreting pituitary tumor via diethylstilbestrol implants. Compared with normal pituitary cells, the aging pituitary tissues revealed increased expression of IL‑6, C/EBPβ, p53, p21 and p16 and decreased expression of pituitary tumor transforming gene. In contrast, the expression of IL‑6, p21 and p16 was decreased in pituitary tumor cells compared with normal pituitary tissues. Taken together, multiple pathways including IL‑6/C/EBPβ, p53/p21 and p16 were activated in aging pituitary cells in response to D‑gal treatment. However, all these pathways were immune to pituitary tumors treated by chronic estrogen. The findings and the involvement of cytokines in a highly prevalent natural disease model (pituitary adenomas) indicate a potential use of this pathway as a target for effective therapy for tumor silencing and prevention of adenoma progression towards malignancy.
- Prostaglandin D2 synthase related to estrogen in the female reproductive tract. [JOURNAL ARTICLE]
- Biochem Biophys Res Commun 2014 Dec 2.
Prostaglandin D2 synthase (PTGDS), also known as a glutathione-independent prostaglandin D synthase, catalyzes prostaglandin H2 to prostaglandin D2 that exhibits functions that include regulation of the central nervous system, contraction/relaxation of smooth muscle and inhibition of platelet aggregation. Gene profiling data based on our previous study indicated that PTGDS is significantly increased during development, differentiation and remodeling of the oviduct in chickens in response to estrogen. Therefore, the aims of the present study were to investigate expression of PTGDS in the oviduct and examine if the relationship between PTGDS and estrogen is conserved during development and remodeling of the oviduct. Results of our study indicate d that PTGDS expression is specifically localized to the luminal (LE) and glandular epithelial (GE) cells of the chicken oviduct in response to diethylstilbestrol, a synthetic estrogen. In addition, PTGDS expression increased during the regeneration phase of the oviduct in concert with increasing concentrations of estrogen in the circulation of laying hens during induced molting. Moreover, PTGDS mRNA and protein were expressed abundantly in GE of ovarian carcinoma, but not in normal ovaries. These results provide the first evidence that PTGDS is a novel estrogen-stimulated gene in oviductal epithelial cells, as well as a candidate biomarker for diagnosis of ovarian carcinoma.
- Novel molecularly imprinted stir bar sorptive extraction based on an 8-electrode array for preconcentration of trace exogenous estrogens in meat. [Journal Article]
- Anal Chim Acta 2015 Jan 1.:342-50.
A novel 8-electrode array as stir bar was designed for selective extraction of trace level exogenous estrogens from food samples, followed by liquid desorption and HPLC-photodiode array detection. The array consisted of 8 screen-printed electrodes and each electrode was modified with Fe3O4@meso-/macroporous TiO2 microspheres and molecularly imprinted film (m-TiMIF). The fabrication of the imprinted film coating was very simple without organic solvents and chemical grafting. Both bisphenol A (BPA) and diethylstilbestrol (DES) were employed as templates in m-TiMIF fabrication in order to enrich both targets simultaneously. Interestingly, the imprinted stir bar array showed higher extraction capacity and selectivity for BPA and DES than the non-imprinted counterpart. Meanwhile, it exhibited fast adsorption and desorption kinetics due to increased mass transport in the ultra-thin film. Importantly, the m-TiMIF coating was robust enough for at least 20 uses without obvious alteration in extraction performance. The main parameters affecting the extraction efficiency, including stir speeding, sample pH, ionic strength, extraction time, desorption solvent and time, were optimized. Under optimal experimental conditions, the limits of detection (S/N=3) of the developed method were 0.28 and 0.47μgL(-1) for BPA and DES respectively, with enrichment factors of 32.6 and 52.8-fold. The linear ranges were 3.0-1500μgL(-1) and 4.0-1500μgL(-1) for BPA and DES, respectively. The m-TiMIF-coating conferred better recovery and selectivity, compared with the commercial stir bar coating. The new method was successfully applied to assess BPA and DES in pork and chicken samples with satisfactory recovery.
- Comparison of two thin-film microextractions for the analysis of estrogens in aqueous tea extract and environmental water samples by high performance liquid chromatography-ultraviolet detection. [Journal Article]
- Food Chem 2015 Apr 15.:1158-66.
Two thin-film microextractions (TFME), octadecylsilane (ODS)-polyacrylonitrile (PAN)-TFME and polar enhanced phase (PEP)-PAN-TFME have been proposed for the analysis of bisphenol-A, diethylstilbestrol and 17β-estradiol in aqueous tea extract and environmental water samples followed by high performance liquid chromatography-ultraviolet detection. Both thin-films were prepared by spraying. The influencing factors including pH, extraction time, desorption solvent, desorption volume, desorption time, ion strength and reusability were investigated. Under the optimal conditions, the two TFME methods are similar in terms of the analytical performance evaluated by standard addition method. The limits of detection for three estrogens in environmental water and aqueous tea extract matrix ranged from 1.3 to 1.6 and 2.8 to 7.1ngmL(-1) by the two TFME methods, respectively. Both approaches were applied for the analysis of analytes in real aqueous tea extract and environmental water samples, presenting satisfactory recoveries ranged from 87.3% to 109.4% for the spiked samples.
- Simultaneous determination of resorcylic acid lactones, β and α trenbolone and stilbenes in bovine urine by UHPLC/MS/MS. [JOURNAL ARTICLE]
- J Chromatogr B Analyt Technol Biomed Life Sci 2014 Oct 12.:89-96.
Treatment of cattle with α-zearalanol (zeranol, α-ZAL), a resorcylic acid lactone (RAL), is illegal in European Union countries. Zearalenone, a common contaminant of cattle feed, is also a RAL and there is evidence that it, or its metabolites, can be converted in vivo to α-ZAL (or to β-zearalanol, β-ZAL). To determine whether an animal has been treated with α-ZAL it is necessary to quantify separately all the RALs. This work presents the simultaneous determination in urine of RALs, β-trenbolone (β-TB) and its metabolite α-trenbolone (α-TB) and the stilbenes diethylstilbestrol (DES), dienestrol (DEN) and hexestrol (HEX) using Ultra High Performance Liquid Chromatography/Mass Spectrometry (UHPLC/MS/MS). Several chromatographic UHPLC columns were tested in order to achieve chromatographic separation of the analytes and the results are shown. Baseline separation of all compounds was not possible, so that careful consideration of the MRM transitions was necessary. The separation chosen for the validation work used a 100mm×2.1mm×1.7μm Phenyl column eluting with a gradient of acetonitrile/methanol/water. The method validation according to EU Decision 657/2002 included linearity, within laboratory reproducibility and trueness, decision limit (CCα) and detection capability (CCβ). For all compounds the method was linear in the range 2-12μg/l (1 and 6μg/l for DES) with determination coefficients greater than 0.97 and linear residuals below 20%. Within laboratory reproducibility was lower than 25% and trueness less than 11% for all compounds and concentration levels. CCα ranged from 0.6μg/l (DES) to 1.6 (α-TB) and CCβ was 0.8μg/l (α-zearalenol) to 1.9μg/l (α-TB).
- Differential expression of vitelline membrane outer layer protein 1: Hormonal regulation of expression in the oviduct and in ovarian carcinomas from laying hens. [Journal Article]
- Mol Cell Endocrinol 2015 Jan 5.:250-8.
Vitelline membrane outer layer protein 1 (VMO1), a basic protein present in the outer layer of the vitelline membrane of eggs, plays essential roles in separating the yolk from the egg white and preventing infection from bacteria by forming a barrier of fibrous layers in avian eggs. Although VMO1 is expressed in the oviduct of hens, little is known about endocrine regulation of transcription of VMO1 in the oviduct and its expression in cancerous ovaries of laying hens. Results of present study indicated that expression of VMO1 mRNA increased in the chick oviduct in response to diethylstilbestrol (DES, a synthetic non-steroidal estrogen). VMO1 mRNA and protein were particularly abundant in the glandular epithelium (GE) and luminal epithelium (LE) of the magnum of the oviducts of chicks treated with DES. Also, during the regression and recrudescence phases of the oviduct during induced molting with zinc feeding, VMO1 expression decreased as the oviduct regressed and increased with remodeling and recrudescence of the oviduct in laying hens. In addition, changes in relative expression of specific microRNAs (miR-1623, miR-1552-3p, miR-1573, miR-22-3p, miR-124a and miR-1764) regulating VMO1 gene were detected in the oviducts during the molting period. Moreover, abundant expression of VMO1 was found in GE of cancerous, but not normal ovaries of laying hens. Results of the present study suggest that VMO1 is regulated by estrogen and target microRNAs in the chicken oviduct and that it is a potential diagnostic marker of ovarian cancer in laying hens.
- Ovarian dysfunction, obesity and pituitary tumors in female mice following neonatal exposure to low-dose diethylstilbestrol. [Journal Article]
- Reprod Toxicol 2014 Dec.:145-51.
In a previous study, we found that early life exposure to low-dose diethylstilbestrol (DES) induced early onset of spontaneous abnormalities in estrus cycle and shortened survival in female Sprague-Dawley rats. In order to confirm the repeatability of the previous study, neonates of C57BL/6J mice were orally administered DES at doses of 0.005, 0.05, 0.5 and 5μg/kg/day, and the aging of their reproductive function was observed. As a result, delayed toxicity on ovarian function was found in females treated with 0.5μg/kg/day of DES. Concomitantly, the females in the 0.05μg/kg/day of DES, or greater, groups, had increased body weights and, in the 0.5μg/kg/day of DES, or greater, groups, had developed pituitary tumors, which were causal factors in their accelerated mortality. Thus, we found that early life exposure to low-dose DES induced early onset of spontaneous abnormalities in estrus cycle not only in female rats but also in female mice.
- Comparative effects of neonatal diethylstilbestrol on external genitalia development in adult males of two mouse strains with differential estrogen sensitivity. [Journal Article]
- Differentiation 2014 Sep-Oct; 88(2-3):70-83.
The effect of neonatal exposure to diethylstilbestrol (DES), a potent synthetic estrogen, was examined to evaluate whether the CD-1 (estrogen insensitive, outbred) and C57 (estrogen sensitive, inbred) mouse strains differ in their response to estrogen disruption of male ExG differentiation. CD-1 and C57BL/6 litters were injected with sesame oil or DES (200ng/g/5μl in sesame oil vehicle) every other day from birth to day 10. Animals were sacrificed at the following time points: birth, 5, 10 and 60 days postnatal. Neonatally DES-treated mice from both strains had many ExG abnormalities that included the following: (a) severe truncation of the prepuce and glans penis, (b) an abnormal urethral meatus, (c) ventral tethering of the penis, (d) reduced os penis length and glans width, (e) impaired differentiation of cartilage, (f) absence of urethral flaps, and (g) impaired differentiation of erectile bodies. Adverse effects of DES correlated with the expression of estrogen receptors within the affected tissues. While the effects of DES were similar in the more estrogen-sensitive C57BL/6 mice versus the less estrogen-sensitive CD-1 mice, the severity of DES effects was consistently greater in C57BL/6 mice. We suggest that many of the effects of DES, including the induction of hypospadias, are due to impaired growth and tissue fusion events during development.
- Prenatal diethylstilbestrol induces malformation of the external genitalia of male and female mice and persistent second-generation developmental abnormalities of the external genitalia in two mouse strains. [Journal Article]
- Differentiation 2014 Sep-Oct; 88(2-3):51-69.
Potential trans-generational influence of diethylstilbestrol (DES) exposure emerged with reports of effects in grandchildren of DES-treated pregnant women and of reproductive tract tumors in offspring of mice exposed in utero to DES. Accordingly, we examined the trans-generational influence of DES on development of external genitalia (ExG) and compared effects of in utero DES exposure in CD-1 and C57BL/6 mice injected with oil or DES every other day from gestational days 12 to 18. Mice were examined at birth, and on 5-120 days postnatal to evaluate ExG malformations. Of 23 adult (>60 days) prenatally DES-exposed males, features indicative of urethral meatal hypospadias (see text for definitions) ranged from 18% to 100% in prenatally DES-exposed CD-1 males and 31% to 100% in prenatally DES-exposed C57BL/6 males. Thus, the strains differed only slightly in the incidence of male urethral hypospadias. Ninety-one percent of DES-exposed CD-1 females and 100% of DES-exposed C57BL/6 females had urethral-vaginal fistula. All DES-exposed CD-1 and C57BL/6 females lacked an os clitoris. None of the prenatally oil-treated CD-1 and C57BL/6 male and female mice had ExG malformations. For the second-generation study, 10 adult CD-1 males and females, from oil- and DES-exposed groups, respectively, were paired with untreated CD-1 mice for 30 days, and their offspring evaluated for ExG malformations. None of the F1 DES-treated females were fertile. Nine of 10 prenatally DES-exposed CD-1 males sired offspring with untreated females, producing 55 male and 42 female pups. Of the F2 DES-lineage adult males, 20% had exposed urethral flaps, a criterion of urethral meatal hypospadias. Five of 42 (11.9%) F2 DES lineage females had urethral-vaginal fistula. In contrast, all F2 oil-lineage males and all oil-lineage females were normal. Thus, prenatal DES exposure induces malformations of ExG in both sexes and strains of mice, and certain malformations are transmitted to the second-generation.