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PubMed1985

Covalent binding of diethylstilbestrol to microsomal protein in vitro correlates with the organotropism of its carcinogenicity.

[14C]Diethylstilbestrol (DES) was incubated in vitro with liver and kidney microsomes from male and female hamsters and rats, and the extent of non-extractable binding of radioactivity to microsomal protein was determined. Binding to microsomes from male hamster kidney, which is a target organ for DES carcinogenicity in vivo, was found to be 5-10 times higher than binding to microsomes from non-target tissues. Pretreatment with phenobarbital led to a marked increase in binding of DES to kidney microsomes but not to liver microsomes from female hamsters and male and female rats. The correlations of in vitro covalent binding with organ susceptibility implies a role for metabolic activation of DES in the mechanism of its carcinogenicity.

Animals↗

PubMed1985

Target organ-specific covalent DNA damage preceding diethylstilbestrol-induced carcinogenesis.

The synthetic estrogen diethylstilbestrol (DES), a known human carcinogen, induces renal carcinoma in male Syrian hamsters within 6 months after s.c. implantation. Tumor formation could be evoked by its hormonal properties or by a reactive genotoxic metabolite binding to DNA, but previous attempts to detect adducts have failed. In the present study, kidney DNA of male Syrian hamsters, treated with s.c. DES implants to induce renal carcinoma, was analyzed for the presence of DES-induced adducts using 32P-postlabeling assay. Covalently-modified DNA nucleotides were detected in the kidneys after chronic DES treatment, but not in kidneys of untreated hamsters, or in liver or tumor tissue of DES-treated animals. This report demonstrates for the first time the ability of an estrogen to give rise to covalent DNA modification in vivo specifically in the target organ of carcinogenesis. DES-induced covalent DNA adducts are taken as evidence for tumor initiation by DES via damage to cellular macromolecules, in addition to tumor-promotional effects described previously.

Adenosine Triphosphate↗

PubMed1986

Co-oxidation of diethylstilbestrol and structural analogs by prostaglandin synthase.

Structural analogs of diethylstilbestrol (DES) with at least one phenolic hydroxyl group are metabolized by prostaglandin H synthase (PHS) from ram seminal vesicle microsomes (RSVM) in vitro in the presence of arachidonic acid (20:4). U.v. spectroscopy revealed the formation of p-quinoid intermediates in incubations of DES, tetrafluoro-DES and dimethylstilbestrol, and tautomerization of the quinones to the respective dien-compounds which were characterized by h.p.l.c. and GC/MS. Indomethacin inhibits the formation of these metabolites which are identical to the major metabolites formed in incubations with horseradish peroxidase/hydrogen peroxide. Covalent binding to protein was observed in incubations of PHS co-substrates. Notably, formation of reactive intermediates which bind to protein is not limited to DES-analogs which form quinone intermediates: radiolabeled hexestrol and E,E-dienestrol yield protein-bound radioactive products upon incubation with RSVM and 20:4, probably via one electron-oxidation to a phenoxy radical. PHS-catalyzed metabolism of structural analogs of DES is accompanied by a concentration-dependent increase in cyclo-oxygenase activity. The measurement of the 20:4-dependent oxygen uptake rates in vitro can serve as a convenient assay for estrogenic compounds which undergo co-oxidation. At high concentrations, however, DES structural analogs can inhibit rather than stimulate PHS. The PHS-catalyzed formation of reactive intermediates from DES structural analogs and their effect on PHS may be of importance for their biological activity in estrogen target tissues with low mono-oxygenase activity.

Animals↗

PubMed1986

Possible role of oxygen radicals in cell transformation by diethylstilbestrol and related compounds.

Diethylstilbestrol (DES) and four derivatives, viz. tetrafluoro-DES, 3'-hydroxy-DES, Z,Z-dienestrol and hexestrol, were examined for their abilities to form superoxide radicals and to induce DNA strand breaks in the presence of horseradish peroxidase/hydrogen peroxide metabolism in a cell-free system. Furthermore, the induction of strand breaks by these compounds was tested in Syrian hamster embryo (SHE) cells in vitro. Formation of superoxide radicals could be demonstrated by reduction of nitro blue tetrazolium for DES but not for its derivatives. With isolated superhelical DNA, induction of strand breaks in the presence of Fe3+ was observed for DES, tetrafluoro-DES and 3'-hydroxy-DES, while hexestrol and Z,Z-dienestrol were ineffective. In SHE cells, alkaline elution technique showed that DNA strand breaks were induced by DES and all derivatives tested, although only at cytotoxic concentrations. It is concluded that DES, under conditions of peroxidative metabolism, can give rise to superoxide generation and DNA strand breaks, and that these events may play a role in the process of DES-induced cell transformation.

Animals↗

PubMed1986

Alteration in diethylstilbestrol-induced mutagenicity and cell transformation by exogenous metabolic activation.

It was shown previously that diethylstilbestrol (DES) can induce morphological and neoplastic transformation of Syrian hamster embryo cells in culture in the absence of detectable gene mutations or DNA damage. However, in the presence of exogenous metabolic activation with rat liver post-mitochondrial supernatant, DES can induce unscheduled DNA synthesis. In this report we have examined whether with exogenous metabolic activation DES can also induce biological effects possibly related to its carcinogenicity, i.e. specific locus mutations in Syrian hamster embryo cells and cell transformation. We observed that DES was mutagenic only in the presence of exogenous metabolic activation. DES induced morphological transformation both in the absence and presence of exogenous metabolic activation. Enhanced cell transformation was observed in the presence of exogenous metabolic activation. These results indicate that two pathways may exist for the induction of cell transformation by DES. One does not apparently involve direct DNA damage, and the other, which requires rat liver post-mitochondrial supernatant-mediated exogenous metabolic activation, is associated with DNA damage and mutagenicity. These results may provide an experimental model to elucidate the biological properties of DES metabolites.

Animals↗

PubMed1977

Trace analysis of diethylstilbestrol [DES] in animal chow by parallel high-speed liquid chromatography, electron-capture gas chromatography, and radioassays.

An analytical method is described for determining residues of the synthetic estrogen diethylstilbestrol (DES) in animal chow at levels as low as 1 ppb. A methanol extract of the chow is subjected to a 3-step cleanup procedure including a Sephadex LH-20 column, liquid-liquid partitioning at pH 14 and 10.2, and a silica gel column. Residues of DES in the cleaned-up extract are analyzed directly by high-speed liquid chromatography or derivatized to pentafluoropropionyl-DES and assayed by electron-capture gas chromatography. Tests with 14C-DES were used to develop and validate the procedure. Ancillary data concerning extraction efficiencies of various solvents, comparisons of various derivatizing reagents, rates of trans-cis isomerization in two solvents, P-values of DES in various solvent-systems and thin-layer chromatographic behavior i

Animal Feed↗

PubMed2005

Hypospadias: a transgenerational effect of diethylstilbestrol?

BACKGROUND: In 2002, an increased risk of hypospadias was reported for sons of women exposed to diethylstilbestrol (DES) in utero, suggesting transgenerational effects of DES. The aim of this study was to further assess the association between parental DES exposure and hypospadias in a case-referent study. METHODS: Cases with hypospadias were retrieved from the hospital information system. Referents were recruited via the parents of cases. Both parents completed postal questionnaires. Associations were estimated by odds ratios (OR) with 95% confidence intervals (CI). Additionally, conditional logistic regression analyses were performed for a matched subset of parents. RESULTS: The final database included 583 cases and 251 referents. In the initial analyses, an indication was found for an increased risk of hypospadias when mothers were exposed to DES in utero: OR=2.3 (95% CI 0.7-7.9). Conditional logistic regression resulted in a stronger risk estimate: OR=4.9 (95% CI 1.1-22.3). Paternal exposure to DES did not increase the risk. CONCLUSIONS: The results confirm an increased risk of hypospadias when mothers were exposed to DES in utero. However, the excess risk appears to be of much smaller magnitude than in the 2002 study. Further research on the potential health risks for the third generation is of great importance.

Diethylstilbestrol↗

PubMed2006

Menstrual and reproductive characteristics of women whose mothers were exposed in utero to diethylstilbestrol (DES).

BACKGROUND: In women, prenatal exposure to diethylstilbestrol (DES) is associated with adult reproductive dysfunction. The mouse model, which replicates many DES outcomes, suggests DES causes epigenetic alterations, which are transmissable to daughters of prenatally exposed animals. We report menstrual and reproductive characteristics in a unique cohort comprising daughters of women exposed prenatally to DES. METHODS: Menstrual and reproductive outcomes and baseline characteristics were assessed by mailed questionnaire in 793 women whose mothers had documented information regarding in utero DES exposure. RESULTS: Mean age at menarche was 12.6 years in both groups, but daughters of the exposed women attained menstrual regularization later (mean age of 16.2 years vs. 15.8 years; P = 0.05), and were more likely to report irregular menstrual periods, odds ratio (OR) = 1.54 [95% confidence interval (95% CI 1.02-2.32)]. A possible association between mothers' DES exposure and daughters' infertility was compatible with chance, age, and cohort adjusted OR = 2.19 (95% CI 0.95-5.07). We found limited evidence that daughters of the exposed had more adverse reproductive outcomes, but daughters of exposed women had fewer live births (1.6) than the unexposed (1.9) (P = 0.005). CONCLUSIONS: The high risk of reproductive dysfunction seen in women exposed to DES in utero was not observed in their daughters, but most women in our cohort have not yet attempted to start their families, and further follow-up is needed to assess their reproductive health. Our findings of menstrual irregularity and possible infertility in third-generation women are preliminary but compatible with speculation regarding transgenerational transmission of DES-related epigenetic alterations in humans.

Adult↗

PubMed2003

Dietary diethylstilbestrol but not genistein adversely affects rat testicular development.

Isoflavones, including genistein, contribute to the health benefits of a soy diet. However, the estrogenic activity of genistein suggests that there may be adverse effects on reproductive tract development. We investigated the potential of exposure to genistein (250 and 1000 mg/kg diet) and the synthetic estrogen and known male reproductive toxicant, diethylstilbestrol (DES, 75 micro g/kg diet) from d 21 to d 35 to alter rat testicular development. These dietary genistein concentrations resulted in serum concentrations that approximate or exceed concentrations in Asian men on a soy-containing diet. DES exposure reduced testicular weights, altered morphology and increased apoptosis in the seminiferous tubules. The effects of DES were accompanied by a reduction in androgen receptor (AR) protein concentrations, predominantly localized to Sertoli cells. Increased expression and immunostaining for the epidermal growth factor receptor (EGFR) and its downstream extracellular signal-regulated kinases (ERK) 1 and 2 in spermatagonia and spermatocytes were also observed. Immunohistochemical analysis of serial sections demonstrated that greater EGFR expression correlated with increased cellular proliferation, rather than apoptosis, and reflected impaired testicular development in DES-treated rats. Genistein in the diet did not significantly alter testicular weights, morphology, AR, EGFR and ERK expression or apoptosis. However, the higher concentration significantly reduced testicular aromatase activity, an effect that may contribute to reduced estrogen concentrations and suppression of prostate cancer development. These data suggest that exposure to genistein in the diet at concentrations that result in serum concentrations at the upper limit of humans consuming soy products does not adversely affect testicular development, but may provide health benefits.

Animals↗

PubMed1979

Accretion of biopsy specimens of vaginal adenosis from patients exposed in utero to diethylstilbestrol, when transplanted to athymic nude mice.

Vaginal adenosis biopsy specimens from 10 patients exposed in utero to diethylstilbestrol were transplanted for 30 days into athymic (nude) mice. Almost all grafts were recovered, and they had morphologic features closely resembling those of the original biopsy specimens, i.e., cystic, complex, and simple occult glands covered mainly with an endocervical type of epithelium showing extensive squamous metaplasia. Autoradiographic analysis of these grafts after pulse administration of [3H]thymidine into the mice revealed extensive labeling of epithelial cells. These results imply that female athymic (nude) mice are compatible hosts for accretion of the human adenosis.

Adolescent↗

PubMed1990

Tumors in female offspring of control and diethylstilbestrol-exposed mice fed high-fat diets.

Strong correlations have been established internationally between female reproductive system cancer rates and dietary fat. To test the hypothesis that the prenatal period is a critical time for exposure to high dietary fat, we placed adult female strain CD-1 mice with or without prenatal exposure to diethylstilbestrol (DES) on diets with low or high levels of fat and mated them. After delivery of the litters, these mice were given the commercial diet on which they had been raised. Their female offspring were raised on this commercial diet until terminal illness occurred. Of the 47 offspring of control mice on low-fat diets, only five had reproductive system tumors, whereas tumors developed in 39 of 78 offspring of mice on high-fat diets. For DES-exposed mice, tumors developed in 18 of 64 offspring of mice on low-fat diets and 38 of 70 offspring of mice on high-fat diets. Nine mice with metastatic mammary tumors and seven with pituitary tumors were offspring of mice on high-fat diets.

Animals↗

PubMed1996

Induction of apoptosis by diethylstilbestrol in hormone-insensitive prostate cancer cells.

BACKGROUND: Diethylstillbestrol (DES) and diethylstilbestrol diphosphate (DESdP) are effective agents for the treatment of advanced prostate cancers. Tumor-inhibiting effects of DES and DESdP are presumed secondary to suppression of androgen production in vivo. Little is known, however, about the direct cellular mechanisms of the tumor inhibition. Estrogens have been reported not only to stimulate growth but also to disrupt microtubule formation in prostate cancer cells. PURPOSE: The study was designed to examine and compare mechanisms of in vitro growth inhibition of DES and DESdP in human androgen-insensitive prostate cancer cells (DU145, 1-LN, and PC-3) and human androgen-sensitive prostate cancer cells (LNCaP) and to examine estrogen receptor modulation of such effects. METHODS: The cytotoxic effects of DES and DESdP were examined in vitro by use of a standard microculture tetrazolium assay to quantitate numbers of viable cells. Immunofluorescence microscopy, DNA fragmentation analysis, and fluorescence flow cytometry were used to investigate microtubules, the induction of apoptosis, and changes in cell cycle distribution. The degree of estrogen receptor positivity of untreated and treated cells was determined by immunohistochemistry and quantitative image analysis. RESULTS: LD50 levels (the dose at which 50% of cells are no longer viable) in the concentration range of 19-25 microM were observed for both DES and DESdP in all cell lines examined. DESdP-induced growth inhibition was found to be dependent on heat-labile phosphatases present in fetal calf serum. DES-induced cytotoxicity was not affected by the presence of 17 beta-estradiol, and it was not dependent on the presence of estrogen receptor. Estrogen receptor-positive cells and estrogen receptor-negative cells were equally responsive to DES. PC-3 cells stained with fluorescent anti-tubulin, phalloidin (actin stain), and 4',6-diamidino-2-phenylindole (DNA stain) showed no inhibition of microtubules or actin filaments but revealed the presence of apoptotic bodies in the nuclei. Fluorescence flow cytometry of nuclear DNA content of propidium iodide-stained nuclei from androgen-insensitive prostate cancer cells treated with 15 or 30 microM DES or DESdP revealed an increase in relative numbers of hypodiploid (apoptotic) nuclei, a depletion of G1- and S-phase cells, and an accumulation of cells in G2/M phase. Conversely, androgen-sensitive cells contained a lower percentage of hypodiploid nuclei but no accumulation of cells in G2/M phase. CONCLUSIONS: Direct cytotoxic effects of DES in prostate cancer cells are estrogen receptor independent and do not involve disruption of microtubule architecture but do involve the promotion of cell cycle arrest and apoptosis. These are the first data confirming direct cytotoxic effects of DES and DESdP in prostate cancer cells via an apoptotic mechanism. IMPLICATIONS. These results suggest that DES and DESdP have potential value as agents against androgen-insensitive prostate neoplasms through induction of an apoptotic cascade.

Antineoplastic Agents, Hormonal↗

PubMed2001

Cancer risk in men exposed in utero to diethylstilbestrol.

BACKGROUND: An association between prenatal diethylstilbestrol (DES) exposure and cancer in men, especially testicular cancer, has been suspected, but findings from case-control studies have been inconsistent. This study was conducted to investigate the association between prenatal DES exposure and cancer risk in men via prospective follow-up. METHODS: A total of 3613 men whose prenatal DES exposure status was known were followed from 1978 through 1994. The overall and site-specific cancer incidence rates among the DES-exposed men were compared with those of the unexposed men in the study and with population-based rates. The relative rate (RR) was used to assess the strength of the association between prenatal DES exposure and cancer development. All statistical tests were two-sided. RESULTS: Overall cancer rates among DES-exposed men were similar to those among unexposed men (RR = 1.07; 95% confidence interval [CI] = 0.58 to 1.96) and to national rates (RR = 0.99; 95% CI = 0.65 to 1.44). Testicular cancer may be elevated among DES-exposed men, since the RRs for testicular cancer were 3.05 (95% CI = 0.65 to 22.0) times those of unexposed men in the study and 2.04 (95% CI = 0.82 to 4.20) times those of males in the population-based rates. The higher rate of testicular cancer in the DES-exposed men is, however, also compatible with a chance observation. CONCLUSIONS: To date, men exposed to DES in utero do not appear to have an increased risk of most cancers. It remains uncertain, however, whether prenatal DES exposure is associated with testicular cancer.

Carcinogens↗

PubMed2000

Diethylstilbestrol (DES)-induced cell cycle delay and meiotic spindle disruption in mouse oocytes during in-vitro maturation.

Due to the growing amount of data related to the deleterious effects of the synthetic oestrogenic compound, diethylstilbestrol (DES), on the female reproductive system, we tested the potential effects of this compound on mouse oocytes. Controlled time- and dose-dependent in-vitro experiments were carried out on isolated cumulus-oocyte-complexes (COCs) to examine the meiotic spindle assembly and chromosome distribution. alpha-tubulin, chromosomes and F-actin were labelled and detected by confocal laser scanning microscope. COCs were exposed to varying doses of DES (5-30 micromol/l) from the germinal vesicle (GV) stage to the end of metaphase II (MII) when meiosis I and meiosis II is normally completed. Exposure to DES during meiosis I caused a dose-dependent inhibition of cell cycle progression. In comparison with controls, fewer oocytes reached metaphase I (MI) at low doses (5 micromol/l) of DES, while none of the oocytes reached MI in high doses (30 micromol/l). When COCs were exposed to high doses of DES during meiosis II, fragmentation of first meiotic spindle was detected, whereas lower doses caused loosening of the first and the second meiotic spindles. No microtubular abnormalities were detected either in GV-stage oocytes or in cumulus cells. The above data demonstrate that one mode of action of DES on mouse oocytes is a severe yet reversible deterioration of meiotic spindle microtubule organization during maturation.

Animals↗

PubMed2000

Isolation of DNA probes specific for rat chromosomal regions 19p, 19q and 4q and their application for the analysis of diethylstilbestrol-induced aneuploidy in binucleated rat fibroblasts.

DNA probes specific for rat chromosomes 19p, 19q and 4q were isolated, characterized and used for the detection and analysis of diethylstilbestrol(DES)-induced aneuploidy. By denaturing and partially reassociating total genomic DNA a new rat repetitive DNA family was isolated, which was located on chromosome 19p21. Sequencing of a number of subclones from cos76-1 and other clones of this so-called 76-family revealed that the repeat units are interrupted with large areas of other (unique) DNA. Consequently, after fluorescence in situ hybridization (FISH) the signals in interphase nuclei are large and spread out. The other two probes, cos25 (chromosome 4q) and cos42-47 (chromosome 19q), were isolated by screening cosmid libraries with probes isolated previously in our laboratory. The repeat unit of cos25 is a 2174 bp long EcoRI unit that contains three Sau3A sites and is tandemly organized. Sequencing of subclones of cos42-47 revealed that this probe was in fact the 5S RNA gene, located on 19q12. In order to determine if these probes were suitable probes for aneuploidy detection, two series of dual colour FISH with the combinations cos25/cos76-1 (4q/19p) and cos42-47/cos76-1 (19q/19p) were carried out on slides from an in vitro micronucleus assay with DES. With all three probes used, an increase in binucleated cells with non-disjunction or chromosome loss was observed in the DES-treated cultures. Scoring of additional micronucleated cells on slides hybridized with the cos25/cos76-1 (4q/19p) probes revealed that the hybridization signal of probe cos25 (4q) was over-represented in the micronuclei of the control cultures. The simultaneous use of the 19q and 19p probes is a particularly valuable tool for the detection of aneuploidy, since it allows distinction between aneugenic and clastogenic events in binucleated cells. Results of this analysis showed that apart from aneuploidy, DES also induced structural chromosome aberrations, although to a lesser extent.

Aneuploidy↗

PubMed1991

Identification of risk factors for diethylstilbestrol-associated clear cell adenocarcinoma of the vagina: similarities to endometrial cancer.

This epidemiologic case-control study describes risk factors for clear cell adenocarcinoma of the vagina among 106 cases and 447 controls with in utero exposure to diethylstilbestrol (DES). Controlling for age, socioeconomic status, and time during gestation of initial DES exposure, the authors found a significantly increased risk of this cancer in women who were taller or more obese then their contemporaries at age 14-15 years. The relative risk of this cancer for women in the highest tertile for height compared with those in the lowest tertile was 2.5 (95% confidence interval 1.23-4.90). The relative risk from a similar comparison of body mass was 2.8 (95% confidence interval 1.20-6.53). Trend tests indicated that both factors had significant dose-response relations with risk of vaginal clear cell adenocarcinoma. These findings are particularly interesting since height and body mass are risk factors for endometrial cancer. DES-positive cases interviewed more than 10 years after diagnosis were also significantly thinner than cases interviewed less than 7 years after diagnosis (p = 0.01), providing the first evidence that adolescent adiposity level is associated with survival times for women with this disease.

Adenocarcinoma↗

PubMed1996

Transvaginal ultrasound studies of vascular and morphological changes in uteri exposed to diethylstilbestrol in utero.

The aim of this prospective study was to establish complementary data of uteri exposed to diethylstilbestrol (DES) in utero for transvaginal analysis and vascularity changes during the menstrual cycle. A total of 28 women with DES-exposed uteri were compared with 60 non-exposed women. Transvaginal ultrasound and colour Doppler imaging were performed on days 5 and 22 of the menstrual cycle. Uteri were measured on sagittal and transverse scans. Uterine length, width, thickness and uterine cavity length and width were measured. Uterine volume and uterine cavity area were calculated. DES-exposed uterine volume was equal to 31.84 +/- 3.37 cm3. The cavity area of DES-exposed uterus was equal to 35.85 +/- 3.93 cm2. Cervix length of DES-exposed uterus was significantly smaller than that of non-exposed uterus. The uterine artery pulsatility index (PI) of DES-exposed uterus was significantly higher than that of normal uterus. Blood flow remained stable throughout the menstrual cycle. The PI of DES-exposed uterus remained stable during the menstrual cycle, as in non-exposed uterus, and it decreased during the luteal phase. This lack of modification in vascularity of DES-exposed uterus may explain miscarriages and obstetric complications such as intrauterine growth retardation or pre-eclampsia. The data may have implications for the assessment of reproductive status and the design of future studies on disorders of implantation in DES-exposed uterus.

Adult↗

PubMed1991

Diethylstilbestrol-induced müllerian abnormalities, septate uterus, genital tuberculosis and twin pregnancy with term delivery after in-vitro fertilization.

We report a case of a twin pregnancy at term obtained after five multiple embryo transfers in a patient who presented diethylstilbestrol (DES)-associated cervical and uterine structural abnormalities, a septate uterus and bilateral tuberculous salpingitis. The suitability of in-vitro fertilization/embryo transfer in DES-exposed women is discussed.

Adult↗