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diethylstilbestrol diethylstilbestrol [keywords]
- Timing and recovery of postweaning exposure to diethylstilbestrol on early pregnancy in CD-1 mice. [JOURNAL ARTICLE]
- Reprod Toxicol 2014 Jul 22.
Exposure timing could play an important role in the effects of estrogenic endocrine disrupting chemicals (EEDCs) on early pregnancy. This study examined the sensitivity of different exposure periods from weaning to gestation day 4.5 (D4.5) to 50 ppb diethylstilbestrol (DES, a test EEDC) diet on embryo implantation and potential recovery upon temporary cession of DES exposure in CD-1 mice. Peripubertal (3-5 weeks old) DES exposure reduced the numbers of corpora lutea and implantation sites. Postpubertal (5-7 weeks old) DES exposure did not have significant effects on early pregnancy. Postmating (D0.5-D4.5) DES exposure affected postovulation events leading to impaired embryo implantation. A 5-day premating rest from 5-week DES exposure (3-8 weeks old) resulted in recovery of early pregnancy rate. These data demonstrate that peripubertal and postmating periods are sensitive windows to endocrine disruption of early pregnancy and temporary cession of exposure could partially alleviate adverse effects of DES on early pregnancy.
- Structural insights into selective agonist actions of tamoxifen on human estrogen receptor alpha. [Journal Article]
- J Mol Model 2014 Aug; 20(8):2338.
Tamoxifen-an anti-estrogenic ligand in breast tissues used as a first-line treatment in estrogen receptor (ER)-positive breast cancers-is associated with the development of resistance followed by resumption of tumor growth in about 30 % of cases. Whether tamoxifen assists in proliferation in such cases or whether any ligand-independent pathway to transcription exists is not fully understood; also, no ERα mutants have been detected so far that could lead to tamoxifen resistance. Using in silico conformational analysis of the ERα ligand binding domain (LBD), in the absence and presence of selective agonist (diethylstilbestrol; DES), antagonist (Faslodex; ICI), and selective estrogen receptor modulator (SERM; 4-hydroxy tamoxifen; 4-OHT) ligands, we have elucidated ligand-responsive structural modulations of the ERα-LBD dimer in its agonist and antagonist complexes to address the issue of "tamoxifen resistance". DES and ICI were found to stabilize the dimer in their agonist and antagonist conformations, respectively. The ERα-LBD dimer without the presence of any bound ligand also led to a stable structure in agonist conformation. However, binding of 4-OHT to the antagonist structure led to a flexible conformation allowing the protein to visit conformations populated by agonists as was evident from principal component analysis and radius of gyration plots. Further, the relaxed conformations of the 4-OHT bound protein exhibited a diminished size of the co-repressor binding pocket in the LBD, thus signaling a partial blockage of the co-repressor binding motif. Thus, the ability of 4-OHT-bound ERα-LBD to assume flexible conformations visited by agonists and reduced co-repressor binding surface at the LBD provide crucial structural insights into tamoxifen-resistance that complement our existing understanding.
- Efficacy of kidney-tonifying traditional Chinese medicine prescriptions in hypoplastic uterus treatment: A systematic review and meta-analysis. [Journal Article]
- J Obstet Gynaecol Res 2014 Jul; 40(7):1913-24.
To review and evaluate the efficacy of kidney-tonifying traditional Chinese medicine prescriptions (KT-TCMP) in hypoplastic uterus (HU) treatment.We searched MEDLINE, the Cochrane Library, CNKI (China National Knowledge Infrastructure), WANFANG and VIP databases until 14 December 2013 independently with two investigators. Randomized controlled trials (RCT) involving KT-TCMP as a combined or monotherapy in the treatment of HU were reviewed and analyzed. Meta-analysis was performed by Review Manager (version 5.2).Nine RCT of 1745 patients were eligible for this review and meta-analysis, of which eight RCT described the primary outcome of clinical efficacy and three RCT drew the secondary outcome of uterine size. Meta-analyzed 'recovery' clinical efficacy of KT-TCMP in seven RCT was conducted which considered diethylstilbestrol therapy alone as control, as well as three RCT that meta-analyzed the effect of KT-TCMP on uterine diameter enlargement. As a result, KT-TCMP therapy had a significantly improved difference in increasing 'recovery' clinical efficacy (risk ratio, 2.34; 95% confidence interval [CI], 1.90-2.89) and enlarging the uterine diameter (standardized mean difference, 1.62; 95% CI, 1.39-1.84). One study reported adverse reactions as an important outcome and found it was safe during KT-TCMP therapy.The therapy of applying KT-TCMP as a combined or monotherapy in the treatment of HU may be more efficacious. However, these RCT were of moderate methodological quality and small sample size; thus, the results should be confirmed with more rigorously controlled further studies.
- Endocrine Disruption Screening by Protein and Gene Expression of Vitellogenin in Freshly Isolated and Cryopreserved Rainbow Trout Hepatocytes. [JOURNAL ARTICLE]
- Chem Res Toxicol 2014 Jul 23.
Xenobiotics may activate the estrogen receptor, resulting in alteration of normal endocrine functions in animals and humans. Consequently, this necessitates development of assay end points capable of identifying estrogenic xenobiotics. In the present study, we screened the potential estrogenicity of chemicals via their ability to induce vitellogenin (VTG) expression in cultured primary hepatocytes from male trout. A routine method for VTG detection measures the secretion of the protein by enzyme-linked immunosorbent assay (ELISA) in freshly isolated trout hepatocytes. However, this lengthy (6 days) culturing procedure requires that hepatocyte isolation is performed each time the assay is run. We optimized this methodology by investigating the utility of cryopreserved hepatocytes, shortening the incubation time, performing a quantitative real-time PCR (qPCR) method for VTG quantification, and verifying the model system with reference chemicals 17β-estradiol, estrone, diethylstilbestrol, hexestrol, genistein, and a negative control, corticosterone. To test the performance of both freshly isolated and cryopreserved hepatocytes, mRNA was collected from hepatocytes following 24 h treatment for VTG gene expression analysis, whereas cell culture media was collected for a VTG ELISA 96 h post-treatment. EC50 values were obtained for each reference chemical except for corticosterone, which exhibited no induction of VTG gene or protein level. Our results show linear concordance between ELISA and qPCR detection methods. Although there was approximately 50% reduction in VTG inducibility following cryopreservation, linear concordance of EC50 values was found between freshly isolated and cryopreserved hepatocytes, indicating that cryopreservation does not alter the functional assessment of estrogen receptor activation and therefore VTG expression. These studies demonstrate that qPCR is a sensitive and specific method for detecting VTG gene expression that can be used together with cryopreserved trout hepatocytes for screening estrogenic chemicals, resulting in a reduction of the time required to perform the assay and enabling greater access to the model system through the approach of cryopreservation.
- Vitellogenin of the northern leopard frog (Rana pipiens): Development of an ELISA assay and evaluation of induction after immersion in xenobiotic estrogens. [Journal Article]
- Chemosphere 2014 Oct.:348-54.
An immunoassay for leopard frog (Rana pipiens) vitellogenin was developed for studying endocrine disruption. Male frogs were injected with estradiol-17β to stimulate vitellogenin for purification. SDS-PAGE revealed high amounts of a 170-180kDa protein, which was confirmed to be vitellogenin by Western blotting. Vitellogenin was purified by DEAE chromatography and used to generate a polyclonal antibody. A competitive ELISA was developed for leopard frog vitellogenin with a detection limit of 6.0ngmL(-1) and a working range of 20-1000ngmL(-1). The intra-assay coefficient of variation averaged 5.47% for control sera and 9.71% for estrogen-treated sera. The inter-assay coefficient of variation averaged 8.21% for control sera and 9.93% for estrogen-treated sera. Recovery of purified vitellogenin averaged 95.2%. Vitellogenin was measured in male frogs immersed in the estrogenic compound diethylstilbestrol (DES) for various times and doses. Serum vitellogenin was detected within five days after immersion in 1.0mgL(-1) DES and levels continued to increase through 20d. In a 20-day dose-response experiment, serum vitellogenin was detected in frogs immersed in 0.01mgL(-1) DES and vitellogenin concentration increased with dose. Immersion of frogs in one of several xenobiotic estrogens (nonylphenol, octylphenol, bisphenol-A) for 20d did not increase vitellogenin for any treatment, suggesting that this frog may be less sensitive than fish to endocrine disruptors. Vitellogenin induction in R.pipiens may be a useful amphibian model system for field studies of endocrine disruption, due to its broad geographic range.
- A novel ERα-mediated reporter gene assay for screening estrogenic/antiestrogenic chemicals based on LLC-MK2 cells. [JOURNAL ARTICLE]
- Toxicol Mech Methods 2014 Jul 21.:1-14.
Abstract Low concentration of endocrine disrupting chemicals (EDCs) may lead to serious consequences in animals and human, so it is essential to develop an effective assay for EDCs detection. In this study, we developed a novel ERα-mediated reporter gene assay based on LLC-MK2 cells by co-transfecting pERE-sv40-Luc, hERα-pcDNA3.1 and pRL-tk. Then we determined 17β-estradiol (E2) and some estrogenic/antiestrogenic chemicals to verify the validity of this assay. Data showed that the assay possess a concentration-dependent responses to E2, diethylstilbestrol (DES) from 10(-12)M to 10(-8)M with EC50 3.4×10(-10)M and 5.9×10(-10)M respectively and ICI 182,780 completely block the luciferase activity induced by 10(-9)M E2. Bisphenol A (BPA), nonylphenol (NP), genistein (GS) and tamoxifen (TAM) also showed corresponding estrogenic or antiestrogenic activity at test concentrations. All evidences proved that the LLC-MK2 reporter gene assay was specific and sensitive to estrogen receptor (ER) agonistic and antagonistic chemicals.
- Atypical McMurry Cross-Coupling Reactions Leading to a New Series of Potent Antiproliferative Compounds Bearing the Key [Ferrocenyl-Ene-Phenol] Motif. [JOURNAL ARTICLE]
- Molecules 2014; 19(7):10350-10369.
In the course of the preparation of a series of ferrocenyl derivatives of diethylstilbestrol (DES), in which one of the 4-hydroxyphenyl moieties was replaced by a ferrocenyl group, the McMurry reaction of chloropropionylferrocene with a number of mono-aryl ketones unexpectedly yielded the hydroxylated ferrocenyl DES derivatives, 5a-c, in poor yields (10%-16%). These compounds showed high activity on the hormone-independent breast cancer cell line MDA-MB-231 with IC50 values ranging from 0.14 to 0.36 µM. Surprisingly, non-hydroxylated ferrocenyl DES, 4, showed only an IC50 value of 1.14 µM, illustrating the importance of the hydroxyethyl function in this promising new series. For comparison, McMurry reactions of the shorter chain analogue chloroacetylferrocene were carried out to see the difference in behaviour with mono-aryl ketones versus a diaryl ketone. The effect of changing the length of the alkyl chain adjacent to the phenolic substituent of the hydroxylated ferrocenyl DES was studied, a mechanistic rationale to account for the unexpected products is proposed, and the antiproliferative activities of all of these compounds on MDA-MB-231 cells lines were measured and compared. X-ray crystal structures of cross-coupled products and of pinacol-pinacolone rearrangements are reported.
- Maternal exposure to diethylstilbestrol during pregnancy and increased breast cancer risk in daughters. [Journal Article, Research Support, N.I.H., Extramural]
- Breast Cancer Res 2014; 16(2):208.
The idea that susceptibility to breast cancer is determined not only through inherited germline mutations but also by epigenetic changes induced by alterations in hormonal environment during fetal development is gaining increasing support. Using findings obtained in human and animal studies, this review addresses the mechanisms that may explain why daughters of mothers who took synthetic estrogen diethylstilbestrol (DES) during pregnancy have two times higher breast cancer risk than women who were not exposed to it. The mechanisms likely involve epigenetic alterations, such as increased DNA methylation and modifications in histones and microRNA expression.Further, these alterations may target genes that regulate stem cells and prevent differentiation of their daughter cells. Recent findings in a preclinical model suggest that not only are women exposed to DES in utero at an increased risk of developing breast cancer, but this risk may extend to their daughters and granddaughters as well. It is critical, therefore, to determine if the increased risk is driven by epigenetic alterations in genes that increase susceptibility to breast cancer and if these alterations are reversible.
- A birth cohort analysis of the incidence of adenocarcinoma of the uterine cervix in the USA. [JOURNAL ARTICLE]
- Eur J Cancer Prev 2014 Jul 14.
We investigated the incidence trends for adenocarcinoma (AC) of the cervix among individuals belonging to the 20-44-year age group in the USA and compared the observed birth cohort incidence patterns with the changing patterns of exposure to potential risk factors associated with AC of the cervix, such as infection with human papillomavirus, use of diethylstilbestrol (DES), obesity, and use of oral contraceptives. Using data from the National Cancer Institute's Surveillance, Epidemiology, and End Results program for 1973-2010, we conducted age-period-cohort modeling to evaluate birth cohort patterns on incidence trends of AC of the cervix over time. The increase in the incidence of AC of the cervix started among those born around the mid 1940s and accelerated up until around the mid 1960s birth cohort in both whites and all races combined, regardless of the assumed period slope. There was a suggestion that the incidence rates of AC of the cervix slowed down after the 1975 birth cohort in both whites and all races combined. DES was used by millions of women in the USA as a synthetic estrogen between the years 1940 and 1971. This time period of DES use among pregnant women parallels the observed birth cohort trends in our study, whereby a notable acceleration in the incidence rates of AC of the cervix was observed among those born in the mid 1940s through the mid 1975s. Thus, our results appear to suggest that in-utero exposure to DES might be at least partly responsible for the observed incidence pattern of AC of the cervix as observed in this study.
- Evaluation of mesoporous silicas functionalized with C18 groups as stationary phases for the solid-phase extraction of steroid hormones in milk. [Journal Article, Research Support, Non-U.S. Gov't]
- Electrophoresis 2014 Jun; 35(11):1666-76.
In this work, two mesoporous silicas functionalized with C18 groups (SM-C18 and SBA-15-C18) have been synthesized for their evaluation as stationary phases in SPE for the extraction and preconcentration of seven steroid hormones (estrone, estradiol, estriol, ethinyl estradiol, diethylstilbestrol, testosterone, and progesterone ) from milk. The characterization of both materials by diverse techniques such as transmission electron microscopy, SEM, thermogravimetric analysis, X-ray diffraction, and adsorption-desorption isotherms showed that the mesoporous silicas had a high surface area, high pore volume, and a homogeneous distribution of the pores and that both silicas presented a similar degree of functionalization. An analytical methodology for the simultaneous separation of the seven selected steroids by HPLC-DAD was developed. Both silicas were evaluated as stationary phases in SPE for the extraction of the steroid hormones from milk. This HPLC-DAD method was applied to the analysis of all extracts obtained in the SPE experiments, showing that from the two synthesized mesoporus silicas, SBA-15-C18 silica enabled the extraction of the seven compounds with recoveries between 88 and 108% for all except for estriol, for which a recovery of 62% was obtained. The analytical characteristics of this methodology were evaluated, showing good precision and linearity (R2 > 0.994) for all analytes. The comparison of the results obtained with this silica and those obtained with commercial C18 particles and with some other commercial cartridges usually employed in the extraction of steroids showed that SBA-15-C18 silica was able to extract the seven steroids with higher recovery values.