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PubMed1990

Clear cell adenocarcinoma of the lower genital tract. Correlation of mother's recall of diethylstilbestrol history with obstetrical records.

The written obstetric records of maternal exposure to diethylstilbestrol (DES) were used as a criterion standard and compared with the DES exposure history recalled by mothers of women with vaginal, cervical, or indeterminable vaginal/exocervical clear cell adenocarcinoma. Among cervical cases, the sensitivity of maternal recall was 50% (N = 2), and its specificity was 100%. Among vaginal and vaginal/exocervical cases, this sensitivity was 72%; specificity was 60%; and the majority of these mothers who said they did not take DES were DES positive by written records. Thus investigators should avoid using maternal recall alone to measure DES exposure. Among subjects for whom written maternal obstetric records were available, 88% of vaginal cases and 46% of cervical cases were DES positive. The authors conclude that few cases of vaginal clear cell adenocarcinoma should occur in young women as the cohort of women exposed in utero to DES continues to age, whereas cases of cervical origin may continue to occur.

Adenocarcinoma↗

PubMed1986

Upper genital tract abnormalities in the Syrian hamster as a result of in utero exposure to diethylstilbestrol. II. Scanning electron microscope analysis of endometrium cell surfaces.

Using scanning electron microscopy (SEM), we show that an in utero exposure to diethylstilbestrol (DES) will induce endometrial abnormalities postnatally. These changes are magnified when a subsequent postnatal DES treatment is given. More specifically, changes in cell surface morphology are associated with alterations in cell size and shape (from columnar to cuboid/squamous), and in microvilli and mucus secretion. Uteri from hamsters treated postnatally with DES and derived from normal (CD) or DES-treated mothers (DD) show that accumulated mucoid secretion products are not expelled in the uterine lumen but are "stored" in cystic dilated glandular spaces of the fibrocellular stroma of polyps and papillae filling the uterine lumen. Uteri from female hamsters that have been prenatally treated with DES (DC) show endometrial mucosal crypts containing mucus and other cell debris including migrating granulocytes. In all cases, DES-treated uteri show mucosal cell surface pleomorphism in the sequence DD greater than CD greater than DC Merocrine and/or cystic secretions were observed. Microvilli cover cell surfaces and include some rare and peculiar long microvillous growth. In contrast, DC hypoplastic uteri present no secretory activity. Structures similar to those described for CD uteri can be observed only after 250 days of age in DC uteri. This report confirms and complements previous observations, favoring the choice of the hamster as an animal mode for the study of endometrial carcinogenesis.

Abnormalities, Drug-Induced↗

PubMed1980

Lymphopenic response of patients presenting with chronic lymphocytic leukemia associated with carcinoma of the prostate to diethylstilbestrol: correlation of response to the in vitro synthesis of RNA by patient lymphocytes and its relationship to transcortin.

Three patients with chronic lymphocytic leukemia (CLL) and carcinoma of the prostate were treated for the latter condition with diethylstilbestrol (DES). All three patients responded with rapid reductions in their peripheral white counts. The previously observed lymphocytic infiltration of the bone marrow of one patient was not evident after three months of DES treatment. The response of this patient to DES correlates well with the enhanced level of plasma transcortin subsequent to treatment. Treatment of this patient with DES alters the ability of peripheral lymphocytes to incorporate radioactive uridine into RNA as well as the in vitro response to either cortisol or beta-estradiol.

Carcinoma↗

PubMed2002

Characterization of diethylstilbestrol-induced hypospadias in female mice.

The urethral duct and vagina are formed from the urogenital sinus (UGS) during the early neonatal period in mice. Neonatal estrogen exposure results in hypospadias, or the malpositioning of vaginal and urethral openings, with wide cleft clitoris. We sought to characterize diethylstilbestrol (DES) influence on UGS morphogenesis and hypospadias formation. Newborn (day 0) and 1-4-day-old female mice (ICR/Jcl) were given (s.c.) oil or 3.0 microg DES. Animals were killed 24 hr later; then hypospadias formation and epithelial apoptosis and proliferation within the developing UGS were assessed. DES did not alter normal UGS morphogenesis by day 1, in comparison with controls. However, hypospadias formation was observed in DES-treated mice by day 3. In these mice, the distal dorsal urethral duct appeared to fuse with and open into the lower vaginal solid cord region. Further, DES treatment produced a gradual significant increase in dorsal urethral epithelial apoptosis (P < 0.05) just prior to and during fusion and hypospadias formation. DES-induced urethral epithelial and sinus cord proliferation appeared significantly increased (P < 0.05) and unchanged, respectively, just prior to fusion. By day 5, DES-treated mice exhibited wide cleft clitoris. In addition, if DES was given on day 3 or 5, a gradual, distinct caudal shift in the vaginal-urethral junction was observed compared to mice treated on days 0-2. Although hypospadias was not induced when neonates were given DES on day 7, these mice continued to display early vaginal opening. Dose-response analysis indicated that 0.03 microg DES for 5 days is the lowest known critical dose for hypospadias induction. We have shown for the first time that DES-induced hypospadias onset may primarily be the result of changes in developing dorsal urethral epithelial cell apoptotic and proliferative activity, and that the location of DES-induced hypospadias formation is dependent on age at time of exposure.

Animals↗

PubMed2005

Diethylstilbestrol exposure in utero: a paradigm for mechanisms leading to adult disease.

The synthetic estrogen diethylstilbestrol (DES) was administered to pregnant women between the 1940s and the mid-1970s and is believed to be responsible for numerous uterine/cervical/vaginal malformations and cancers that appeared after birth and in young adult life. This medical tragedy has served as one of the prototypical examples of a phenomenon known as "endocrine disruption," in which either environmental agents or other compounds disrupt normal hormonal signaling in the body. Whereas DES signals through estrogen receptors, the subsequent molecular targets were largely unknown. We had identified Wnt7a as a target in this pathway and have used genetic analyses of mutant mice to demonstrate that disruption of Wnt7a is the key event leading to the DES phenotypes and cancers. We find that Wnt7a expression is only transiently deregulated in response to DES exposure, leading to the conclusion that critical events during early reproductive tract development results in a permanent change or "reprogramming" in subsequent development.

Animals↗

PubMed2003

Simulation of the different biological activities of diethylstilbestrol (DES) on estrogen receptor alpha and estrogen-related receptor gamma.

We describe the application of the molecular dynamics (MD) and molecular mechanics-generalized Born/surface area (MM-GB/SA) approaches to the simulation of the different biological activity of diethylstilbestrol (DES) on two highly homologous nuclear receptors-estrogen receptor alpha (ER-alpha) and estrogen-related receptor gamma (ERR-gamma). DES exerts an agonistic effect against ER-alpha and an antagonistic effect against ERR-gamma. Using the x-ray crystal structures of ER-alpha in the canonical agonist bound form (PDB code: 3ERD) and antagonist bound form (PDB code: 3ERT), ERR-gamma homology models have been constructed for the receptor in two different conformations. MM-GB/SA binding free energy calculations of DES in the ER-alpha and ERR-gamma structures suggest that DES exhibits a greater free energy of binding in the agonist bound conformation of ER-alpha, while the antagonist bound conformation is preferred for ERR-gamma. Further dissection of the free energy contributions coupled with calculation of the ligand binding pocket volume suggests that the van der Waals interactions for DES within the smaller binding pocket volume of ERR-gamma are less favorable and this is the main factor for DES antagonism in ERR-gamma. This approach has potential general applicability to the prediction of the biological activity of nuclear receptor ligands.

Amino Acid Sequence↗

PubMed2006

Colloidal gold-based immunochromatographic assay for detection of diethylstilbestrol residues.

One-step membrane-based competitive colloidal gold-based immunoassays in immunochromatographic formats for the rapid detection of diethylstilbestrol (DES) were developed. Nitro-cellulose membrane strip was separately coated with goat anti-rabbit IgG (control line) and DES hapten-ovalubumin conjugate (test line). Anti-DES polyclonal antibody labeled with colloidal gold particles was first incubated with DES. A positive reaction as a result of the remaining antibody-gold conjugate combining with antigen coated on the membrane was obvious by visual detection, with detection limits for immunochromatographic of 0.5 microg/kg for detecting DES standard solution, and the limit of detection was 5 microg/kg for detecting the DES spiked in swine pork and liver. The assay time for test was less than 5 min, suitable for rapid testing on-site.

Animals↗

PubMed1978

The mass spectra of diethylstilbestrol and related compounds.

The low resolution mass spectra of E-3,4-bis-(p-hydroxyphenyl)-hex-3-ene (diethylstilbestrol), E-[1,1,1-3H3]3,4-bis-(p-hydroxyphenyl)-hex-3-ene, E-2,3-bis-(p-hydroxyphenyl)-but-2-ene (dimethylstilbestrol), E,E-3,4-bis-(p-hydroxyphenyl)hexa-2,4-diene (dienestrol) and 3,4-bis-(p-hydroxyphenyl)-hexane (hexestrol) were examined as the parent compounds, their diacetates, dimethyl ethers, and bis-trimethylsilyl ethers. In addition, the mass spectra of the diethyl ether and the hexadeuteriodimethyl ether of E-3,4-bis-(p-hydroxyphenyl)-hex-3-ene were studied. Each compound gives rise to several sets of characteristic fragment ions associated with loss of alkyl groups, loss of aryl groups and rearrangements. An ion of m/e 165 (C13H9) was found in the spectra of all the compounds studied. With the aid of high resolution mass spectrometry empirical formulae were assigned to major ions of the free diphenols.

Adenocarcinoma↗

PubMed1985

Quantitative secondary ion monitoring gas chromatography/mass spectrometry of diethylstilbestrol in bovine liver.

A procedure is described for the extraction of diethylstilbestrol (DES) from animal tissue for quantitative capillary gas chromatography/mass spectrometry (GC/MS). The procedure is based upon use of a strong anion exchange polystyrene divinylbenzene resin for sample purification. The recovery of DES from the resin clean up was 88% in the high parts per trillion (ppt) range. Criteria for identification of DES using selected ion monitoring (SIM) GC/MS are presented. Liquid chromatography/mass spectrometry (LC/MS) was used to investigate altered DES cis/trans ratios observed in biological extracts.

Animals↗

PubMed1986

A rapid method for the simultaneous detection by collisionally activated dissociation mass-analysed ion kinetic energy spectrometry of parts per trillion of diethylstilbestrol, zeranol and trenbolone in plasma and edible tissues of cattle.

The current methods for the control of the illegal use of anabolics in cattle breeding are far from satisfactory in terms of specificity and sensitivity. Here we describe a method for the simultaneous detection of diethylstilbestrol, zeranol and trenbolone in plasma and edible cattle tissues. The method is rapid (total analysis time 30 min), specific and sensitive (ppt level). The technique employed is a tandem mass spectrometric method: collisionally activated decomposition mass-analysed ion kinetic energy (CAD MIKE) spectrometry. Detection involves the injection of the crude ethanol extracts of plasma and tissues and selection/collision of molecular ions of each targeted compound. Confirmation of the presence of particular compounds is made by matching the complete CAD spectra so obtained with those of the pure compounds.

Animals↗

PubMed2003

Phase II trial of oral cyclophosphamide, prednisone, and diethylstilbestrol for androgen-independent prostate carcinoma.

BACKGROUND: The authors evaluated the combination of oral cyclophosphamide, oral prednisone, and diethylstilbestrol (DES) in patients with androgen-independent prostate carcinoma (AIPC). METHODS: Thirty-seven patients with prostate carcinoma refractory to androgen ablation who had undergone antiandrogen withdrawal (if previously treated with an antiandrogen) were enrolled in the current study. They were treated with oral cyclophosphamide 100 mg per day on Days 1-20, prednisone 10 mg per day continuously, and DES 1 mg continuously, on a 30-day cycle. Warfarin 1 mg per day was given as prophylaxis for thrombosis. Patient levels of prostate-specific antigen (PSA) were monitored on a monthly basis, with imaging studies every 3 months. Patients continued to receive therapy until disease progression or the occurrence of significant toxicity. The effect of therapy on the patient's quality of life was assessed using the Functional Assessment of Cancer Therapy-Prostate. RESULTS: Thirty-six patients were evaluable for response. Of the 36 patients, 15 (42%) had a 50% or greater decline in PSA levels from pretreatment levels and 1 patient (6%) with measurable disease had a partial response to therapy. The median duration of response was 4.5 months (range, 4-18 months). The overall median survival period was 16.4 months. The treatment was well tolerated, with only three patients removed from the study for toxicities associated with treatment. One patient, who had been treated for more than 24 months, developed acute leukemia. Quality of life evaluation in 17 patients showed a significant improvement in responders, whereas nonresponders had no deterioration while receiving therapy. CONCLUSIONS: Cyclophosphamide, prednisone, and DES represent a well tolerated, low-cost combination therapy with significant activity in the treatment of patients with AIPC.

Administration, Oral↗

PubMed2006

In utero exposure to diethylstilbestrol (DES) does not increase genomic instability in normal or neoplastic breast epithelium.

BACKGROUND: In 1992, the National Cancer Institute (NCI) established the Continuation of Follow-Up of DES-Exposed Cohorts to study the long-term health effects of exposure to diethylstilbestrol (DES). Genetic effects on human breast tissue have not been examined. The authors investigated whether breast tissue of women exposed in utero to DES might exhibit the genetic abnormalities that characterize other DES-associated tumors. METHODS: Subjects enrolled in the NCI Cohort were queried about breast biopsies or breast cancer diagnoses. Available tissue blocks were obtained for invasive cancers (IC), in situ cancers (CIS), or atypical hyperplasia (AH). Exposure status was blinded, lesions were microdissected, and their DNA was analyzed for microsatellite instability (MI) and loss of heterozygosity (LOH), or allele imbalance (AI), at 20 markers on 9 chromosome arms. RESULTS: From 31 subjects (22 exposed, 9 unexposed), 273 samples were analyzed (167 normal epithelium, 16 AH, 30 CIS, 60 IC). Exposed and unexposed subjects exhibited no differences in breast cancer risk factors or demographic characteristics, except for age at diagnosis (exposed vs. unexposed: 43.2 vs. 48.8 years of age, P = .02). The authors found that MI was rare and that AI was common, with frequencies consistent with previous reports. The global age-adjusted relative rate (RR) of AI was 1.3, 95% CI = 0.8-2.4. No statistically significant associations were observed after adjustment for risk factors or after stratification by histology or by chromosome arm. CONCLUSIONS: In utero DES exposure does not appear to significantly increase genomic instability in breast epithelium, as measured by MI and AI. Breast tissue may respond differently from that of the reproductive tract to in utero DES exposure. Consequences of in utero DES exposure on the breast may be mediated by proliferative effects of estrogen.

Adult↗

PubMed1981

Diethylstilbestrol-diphosphate induces chromosomal aberrations but not sister chromatid exchanges in murine bone marrow cells in vivo.

Diethylstilbestrol diphosphate (DES-dp) clastogenesis was examined in the bone marrow of C57Bl/6 male and female mice. Significant and sex-related dose effects were observed for the induction of chromatid-type chromosomal aberrations and for the inhibition of cellular proliferation. Females were more sensitive to the effects of DES-dp than males when assessed for either induced chromosomal aberrations or proliferative inhibition. Contrary to other published results, we did not observe either an increase in sister chromatid exchanges or an increased incidence of aneuploidy. Ovariectomy reduced the ability of DES-dp to inhibit cellular proliferation and decreased the high degree of variability between animals at high doses of DES-dp. The results of our studies show that DES is a clastogenic agent in vivo which may relate to its carcinogenicity.

Aneuploidy↗

PubMed1984

DNA-damaging potential of diethylstilbestrol evaluated in the germ cell unscheduled DNA synthesis assay.

Despite the fact that the nonsteroidal estrogen diethylstilbestrol (DES) exerts its toxic effects primarily on the reproductive system, little is known about the possible interference of this compound with germ cell DNA. The measurement of unscheduled DNA synthesis (UDS) in spermatocytes and early spermatids of mice germ cells is a valid indicator for the DNA-damaging potential of a compound. UDS occurrence was thus determined after IP administration of 10, 30, 60 or 180 mg/kg DES to male mice. Tritiated thymidine ( [3H]dThd) was then injected into the testes, the spermatozoa were serially collected, the sperm heads isolated, and UDS determined by the amount of [3H]dThd incorporation. [3H]dThd measurements in germ cells of mice which were treated with 10 mg/kg DES were comparable to those of the controls. Higher incorporation of [3H]dThd, indicating UDS, was measured in sperm cells which had been spermatocytes at the time of treatment with 30 and 60 mg/kg DES; this increase was statistically significant at 60 mg/kg. Administration of 180 mg/kg DES caused [3H]dThd incorporation which was comparable to that of the controls, suggesting that DES interfered with repair mechanisms or delayed spermatogenic cycles at high dose levels. General toxicity was manifested in a dose-dependent decrease of the sperm cell numbers in the spermatogenic stages investigated. This study provides evidence that DES, or its metabolite(s), reached the germ cells of adult mice in sufficient amounts to produce DNA damage. The levels of radioactivity measured were comparable to those measured after cyclophosphamide treatment, but [3H]dThd incorporation was about 10 times less than in methylmethane sulfonate-treated animals.

Animals↗

PubMedDate not supplied

Diethylstilbestrol-induced jaundice in the Chinese and Armenian hamster.

An unusual and impressive hyperbilirubinemia was induced in Chinese hamsters by administration of diethylstilbestrol (DES). This icterus was dose-dependent and affected females more severely than males. However, a similar mortality was detected in both sexes. Another hamster, the Armenian hamster, was even more susceptible to the icteric and lethal effects of DES. The hamster model of DES-induced icterus showed many clinical dissimilarities when compared to the human estrogen-induced jaundice, simple cholestatic jaundice. Furthermore, hepatic pathology was distinctly different as canalicular cholestatic was absent although other degenerative and regenerative hepatocellular changes were present. Livers of Armenian hamsters were more severely affected than were livers from Chinese hamsters and contained Mallory bodies even within 1 week after DES treatment. A modest, nonlethal jaundice also was detected in European hamsters after DES injection, whereas Syrian hamsters were not affected even after larger doses. This unique sensitivity to DES, and the spectrum of sensitivity within these related hamsters (Armenian greater than Chinese greater than European vs. resistant Syrian) provide an interesting model for study of DES effect on hepatic function.

Animals↗

PubMed2005

Diethylstilbestrol effects and lymphomagenesis in Mlh1-deficient mice.

Inherited defects in DNA mismatch repair (MMR) predispose to a variety of malignancies in humans and in mouse knockout models. In humans, hemizygosity for one of several DNA MMR genes greatly increases an individual's risk for colon and endometrial carcinoma. Hemizygous mice develop gastrointestinal tumors at a low to moderate frequency. Homozygous nulls have higher rates of gastrointestinal tumors and are particularly susceptible to lymphoma. In an effort to model endometrial carcinoma associated with mutation in MMR, we treated mice carrying knockout alleles for Mlh1 or Msh2 with the synthetic estrogen diethylstilbestrol (DES), a known promoter of uterine endometrial carcinoma. The C57BL/6 mice carrying DNA MMR mutations failed to develop endometrial carcinomas. However, the Mlh1-deficient mice treated with DES tended to become moribund at an early age and had very early onset of lymphoma. Comparison of DES-treated and untreated Mlh1-/- animals suggests the combination of Mlh1 deficiency and DES exposure accelerates lymphomagenesis.

Adaptor Proteins, Signal Transducing↗

PubMed1985

A prospective study of association of herpes simplex virus and human papillomavirus infection with cervical neoplasia in women exposed to diethylstilbestrol in utero.

One thousand one hundred thirty-four women, enrolled in a prospective study of the development of cervical neoplasia in women exposed to diethylstilbestrol (DES) in utero, were examined at least once a year. Twenty-three women developed cervical intraepithelial neoplasia (CIN) of different degrees during the 7-year follow-up period and were matched with women who did not develop CIN during the study period. Serum samples were obtained at the time of entry into the study and at the time of diagnosis of neoplasia. In the control group, a second serum sample was obtained close to the time when CIN was diagnosed in the other group of women. The sera were studied for antibodies to both types of herpes simplex virus (HSV) by microneutralization assay and by a radioimmunoassay using, as antigens, glycoproteins VP123 for HSV type 1 and VP119 for HSV type 2. Women who developed CIN had, in the enrollment specimen which preceded the neoplasia, a higher rate of antibodies to HSV-1 than did the matched controls (22%), while the two groups did not differ in frequency of antibodies to HSV-2 (9%). Similar differences were observed in the sample drawn at the time of diagnosis of CIN. Women who later developed CIN and had, at the time of entry into the study, cervical epithelial changes associated with DES exposure, were infected with HSV-1 at a higher rate than women who remained free of neoplasia or women with CIN but without DES-associated cervical epithelial changes. Morphologic evidence of associated papillomavirus (HPV) infection was observed in 74% of CIN cases and no such observation was made in biopsy specimens taken prior to development of CIN. Morphologic evidence of HPV infection was found in a women of the control group having squamous metaplasia. HPV structural antigens were found in 3 of 10 CIN I and CIN II cases, and none in the CIN III specimens. The possible role of the HSV and HPV infection in the pathogenesis of cervical neoplasia is discussed.

Adolescent↗

PubMed1992

Occurrence of tumours in the descendants of CBA male mice prenatally treated with diethylstilbestrol.

There is well documented evidence both in humans and in experimental animals that exposure to diethylstilbestrol (DES) during pregnancy results in an increased incidence of tumours in the progeny. The increased cancer risk has been reported to persist in the second generation descendants of DES-exposed pregnant mice. In the present experiment, female mice of the CBA strain were treated at day 17 of pregnancy with 1 microgram/g body weight of DES. The descendants of DES-treated mothers, described as F1DES, were mated among each other or with untreated animals. The F1DES females were found to be sterile when mated with either F1DES or untreated males. F1DES males were successfully mated with untreated females. In the female offspring so obtained, but not in the male, a statistically significant increased incidence of tumours was observed, in particular of uterine sarcomas, and also of benign ovarian tumours and of lymphomas.

Animals↗