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PubMed2006

Enhanced urinary bladder and liver carcinogenesis in male CD1 mice exposed to transplacental inorganic arsenic and postnatal diethylstilbestrol or tamoxifen.

Pregnant CD1 mice received 85 ppm arsenite in the drinking water from gestation day 8 to 18, groups (n = 35) of male offspring were subsequently injected on postpartum days 1 through 5 with diethylstilbestrol (DES; 2 microg/pup/day) or tamoxifen (TAM; 10 microg/pup/day), and tumor formation was assessed over 90 weeks. Arsenic alone increased hepatocellular carcinoma (14%), adenoma (23%) and total tumors (31%) compared to control (0, 2 and 2%, respectively). Arsenic alone also increased lung adenocarcinoma, adrenal cortical adenoma and renal cystic tubular hyperplasia compared to control. Compared to arsenic alone, arsenic plus DES increased liver tumor incidence in mice at risk 2.2-fold and increased liver tumor multiplicity (tumors/liver) 1.8-fold. The treatments alone did not impact urinary bladder carcinogenesis, but arsenic plus TAM significantly increased formation of urinary bladder transitional cell tumors (papilloma and carcinoma; 13%) compared to control (0%). Urinary bladder proliferative lesions (combined tumors and hyperplasia) were also increased by arsenic plus TAM (40%) or arsenic plus DES (43%) compared to control (0%) or the treatments alone. Urinary bladder proliferative lesions occurred in the absence of any evidence of uroepithelial cytotoxic lesions. Urinary bladder lesions and hepatocellular carcinoma induced by arsenic plus TAM and/or DES overexpressed estrogen receptor-alpha, indicating that aberrant estrogen signaling may have been a factor in the enhanced carcinogenic response. Thus, in male CD1 mice, gestational arsenic exposure alone induced liver adenoma and carcinoma, lung adenocarcinoma, adrenal adenoma and renal cystic hyperplasia. Furthermore, DES enhanced transplacental arsenic-induced hepatocarcinogenesis. In utero arsenic also initiated urinary bladder tumor formation when followed by postnatal TAM and uroepithelial proliferative lesions when followed by TAM or DES.

Animals↗

PubMed2004

Body and organ weight, sperm acrosomal status and reproduction after genistein and diethylstilbestrol treatment of CD1 mice in a multigenerational study.

The effect of genistein (GEN) and diethylstilbestrol (DES) on body weight, weight of different organs, sperm acrosomal status and in vivo fertility of CD1 mice was tested in a multigenerational study. The adult parental generation of mice and F1 and F2 generations were exposed to selected drugs for all their life. GEN had effect on different body parameters of 30-day-old mice, but not of adult mice in the first generation. Contrary to that, treatment by DES had a strong effect on body weight, other body parameters and on the levels of serum hormones. In the first generation only sterile pairs of mice were observed. Monoclonal antibody against mouse intra-acrosomal sperm protein was used for analysis of the acrosome state and as biomarkers of sperm damage. In the control groups, about 93% of acrosome-reacted sperm was found, acrosome staining decreased to 78-84% (P<0.01). However, the GEN had no effect on fertility of CD1 mice. On the other hand, the fertility of mice exposed to DES was disrupted, especially in the first generation.

Acrosome↗

PubMed2004

Estrogen receptor-alpha mediates the detrimental effects of neonatal diethylstilbestrol (DES) exposure in the murine reproductive tract.

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-alpha (alphaERKO or estrogen receptor-beta (betaERKO), 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-alpha 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 alphaERKO females. In the male, alphaERKO 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 ERbeta is highly expressed in the prostate epithelium, DES-exposed betaERKO 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 alphaERKO uterus and prostate provides unequivocal evidence of an obligatory role for ERalpha in mediating the detrimental actions of neonatal DES exposure in the murine reproductive tract.

Animals↗

PubMed2006

Diallyl sulfide induces the expression of estrogen metabolizing genes in the presence and/or absence of diethylstilbestrol in the breast of female ACI rats.

Diethylstilbestrol (DES) induces mammary tumors in female ACI rats and is associated with an increased risk of developing breast cancer in humans. Diallyl sulfide (DAS) has been shown to prevent cancer in animals. Previously, we have shown that DAS inhibits the production of DES induced DNA adducts when given prior to DES. We hypothesize that DAS alters the expression of genes responsible for DES metabolism. To test this hypothesis, four groups of 10 female ACI rats were treated daily for four days as follows: (1) corn oil, (2) 50mg/kg DES, (3) 50mg/kg DAS, and (4) 50mg/kg DAS+50mg/kg DES. RNA was isolated from breast tissue and mRNA levels of CYP1A1, CYP1B1, glutathione-S-transferase (GST) and superoxide dismutase (SOD) were analyzed by real-time PCR. DES, DAS, and DES/DAS treatments increased the expression of CYP1A1 by 2.1-, 4.7-, and 12.7-fold, respectively. Similar results were seen for CYP1B1. DES decreased the expression of GST by 23%, whereas DAS and DAS/DES treatments increased the expression of GST by 12- and 16.7-fold, respectively. Similar results were seen with SOD. These results suggests that DAS may prevent the formation of DES induced DNA damage by altering the expression of DES metabolizing genes.

Allyl Compounds↗

PubMed2006

Comparative study of reactions of endocrine disruptors bisphenol A and diethylstilbestrol in electrochemical treatment and chlorination.

Transformations of diethylstilbestrol (DES) and bisphenol A (BPA) in conventional chlorination and electrochemically (EC) treated solutions were examined using spectrophotometry and chromatographic analyses. EC treatment was carried out using an undivided EC cell with a PbO2 anode and a stainless steel cathode. EC-treatment and conventional chlorination caused DES and BPA to undergo a rapid degradation accompanied by the generation of low molecular weight chlorinated organic species indicative of the breakdown of DES and BPA. The identified compounds were predominated by chloroacetic acids (HAAs), but approximately 80% of the total organic halogen (TOX) was comprised by unidentified species. For EC treatment, the HAA yields were lower and HAAs were predominated by monochloroacetic acid (MCAA), while in the case of conventional chlorination, trichloroacetic acid (TCAA) was predominant and MCAA was virtually absent. The changes in the HAA speciation and yields were concluded to be caused by the EC-driven reductive dehalogenation which, however, did not affect the unidentified fraction of TOX. This indicated that the unidentified part of TOX was comprised by aromatic chlorinated forms of BPA and DES. Their resistance to degradation in EC reactors indicates that these compounds may be stable in conditions typical for drinking water treatment and distribution.

Benzhydryl Compounds↗

PubMedDate not supplied

Limb reduction defects in the first generation and deafness in the second generation of intrauterine exposed fetuses to diethylstilbestrol.

Maternal treatment with diethylstilbestrol (DES) during pregnancy can produce vaginal adenocarcinoma and other abnormalities of the vagina in her daughters when they reach adolescence or adulthood, miscarriages and absence of full term infants. Concerning malformations in newborns whose mothers were treated with DES, clitoromegaly and malformations of the uterus were reported in females and genital lesions in males. However, the frequencies of major congenital anomalies were not greater than expected. We report three cases of limb reduction defects (LRD) in the first generation of children whose mothers were treated with DES during pregnancy, and two children (one male, one female) with deafness in the second generation after intrauterine exposure to DES. The LRD were not associated with other congenital anomalies. The malformed children with LRD were born between 1965 and 1973. The deafness was also isolated. The two mothers who have no hearing problems and who are healthy were exposed in utero to DES in 1963 and 1965, respectively. Their children were born in 1989 and 1994, respectively. In conclusion, the association of LRD and hearing loss with intrauterine exposure to DES could be coincidental. However, some hypothesis may explain these associations. Congenital hearing loss in the second generation may suggest a transgenerational effect.

Adult↗

PubMed2001

Cytoskeleton-interacting activity of geiparvarin, diethylstilbestrol and conjugates.

Geiparvarin, a natural compound isolated from the leaves of Geijera parviflora, inhibits the growth of various tumor cell lines with a mode of action which may be attributed to its anti-microtubular activity. Our previous findings indicated that geiparvarin is able to inhibit the in vitro polymerization of tubulin and to derange the microtubular network in fibroblasts more effectively in the presence of paclitaxel. To further explore its biological activity here we have studied the effects exerted on the other components of the cytoskeleton by geiparvarin and two derivatives obtained by conjugating the 3(2H)-furanone ring of geiparvarin with diethylstilbestrol (DES). Firstly, observations by electron microscopy confirmed anti-microtubular properties, a near-total absence of microtubules is detected when tubulin is incubated with drugs in the presence of paclitaxel, whereas microtubule formation is not inhibited by drugs when assembly is induced by guanosine 5'-triphosphate (GTP). Immunofluorescence assays demonstrated that geiparvarin and DES act in a vinblastine-like fashion, causing a marked depletion of intermediate filaments while the network of microfilaments is not affected. Both the conjugates alter the 'stress fibers' organization of actin and disrupt the vimentin pattern; generally they derange cytoskeleton more markedly than the parent compounds. The cell growth inhibiting effects of geiparvarin and derivatives are dose-dependent; they vary according to the cell line used, when compounds were administered either alone or simultaneously with paclitaxel. Unlike other anti-microtubule agents, they do not exhibit cell-cycle compartment specificity and do not influence thymidine uptake in the cell.

3T3 Cells↗

PubMedDate not supplied

Peroxidase-mediated in vitro metabolism of diethylstilbestrol and structural analogs with different biological activities.

The comparative peroxidative metabolism of diethylstilbestrol (DES) and structurally related compounds of different biological activity was investigated in vitro with horseradish peroxidase (HRP) and hydrogen peroxide (H2O2) as a model peroxidase system: UV spectroscopy revealed the formation of p-quinone intermediates in HRP-H2O2 catalyzed incubations of DES, 3',3",5',5"-tetrafluoro-DES (TF-DES) and dimethylstilbestrol (DMS) and the tautomerization of the quinones to their dien compounds, Z,Z-dienestrol (Z,Z-DIES), tetrafluoro-dienestrol (TF-DIES) and dienmestrol (DIMS) respectively, which were characterized by HPLC and GC/MS. Z,Z-DIES, E,E-DIES, TF-DIES and DIMS were subject to further peroxidative metabolism; however, quinone intermediates were not formed in the HRP-H2O2 containing incubations according to UV spectroscopy. Similarly, hexestrol (HES), 4'-O-methyl-DES (M-DES) and 4',4"-O-dimethyl-DES (DM-DES) did not form quinone intermediates; moreover, they showed little or no apparent metabolic conversion under conditions where DES, TF-DES and DMS were readily peroxidized. However, at a 20-fold higher peroxidase concentration HES and M-DES showed metabolic conversion whereas DM-DES did not.

Carbon Radioisotopes↗

PubMed1982

Reduced fertility in female mice exposed transplacentally to diethylstilbestrol (DES).

Prenatal exposure to diethylstilbestrol (DES), a synthetic estrogen, has been associated with a low incidence of vaginal adenocarcinoma as well as a variety of more numerous benign abnormalities in the reproductive tract of human beings and experimental animals. For the purpose of assessing the effects of prenatal exposure to DES on postnatal reproduction tract function, timed pregnant CD-1 mice were treated subcutaneously with doses of DES ranging from 0.01 to 100 microgram/kg/day on days 9 through 16 gestation. The fertility of the female offspring was determined postnatally by a repetitive forced breeding technique. The most striking effect observed was a dose-related decrease in reproductive capacity ranging from minimal subfertility at the lower DES doses to a high frequency of total sterility at the highest DES doses. Reduced reproductive capacity appeared to be a reflection of both a decrease in the total number of litters and smaller litter sizes. A major component of the sterility seen in those females given higher doses of DES was oviductal/ovarian, since the number of ova recovered from the oviductal ampullae after induced ovulation was less than 30% that of controls. In addition, structural abnormalities of the oviduct, uterus, cervix, and vagina were observed, and contributed to infertility. These data suggest that in utero exposure to DES results in permanent impairment of female mouse reproductive capacity. Recent reports of altered pregnancy outcomes in young women who were exposed in utero to DES demonstrate the clinical importance of the findings obtained in mice.

Animals↗

PubMed1984

Experience with diethylstilbestrol-exposed infertile women in a program of in vitro fertilization.

Twenty infertile women with a history of diethylstilbestrol exposure in utero were seen in Norfolk for the purpose of in vitro fertilization. Seventeen patients had undergone 25 stimulated cycles with harvest of oocytes by laparoscopy. The serum estradiol response to stimulation in these patients and the number and quality of oocytes retrieved did not differ significantly from those of patients with infertility due to blocked fallopian tubes. There were four pregnancies in 17 patients after 21 cycles of embryo transfers, for a pregnancy rate of 23.5% per patient, or 19% per embryo transfer. Two of the pregnant patients have had a term delivery, one has had a preclinical abortion, and one has a single intrauterine gestation in progress.

Adult↗

PubMed1984

Genital tract examinations and zona-free hamster egg penetration tests from men exposed in utero to diethylstilbestrol.

Because most men with prenatal exposure to diethylstilbestrol (DES) are still young and have not attempted to father children, its reproductive effects are uncertain. In a previous pilot study, we had noted an association between in utero DES exposure and reduced penetration of zona-free hamster eggs by sperm. To test these findings in a controlled manner, we performed physical examinations on 51 men with in utero DES exposure and 29 unexposed men and evaluated the penetration of zona-free hamster eggs by their sperm. Epididymal cysts or abnormalities of the prostate, testicle, or penile meatus were present in 37% of men with in utero DES exposure, versus 4% of nonexposed men (P less than 0.001). The mean proportions of penetrated eggs were 25% after in utero DES exposure and 29% in the nonexposed group (P greater than 0.57). The genital abnormalities related to DES exposure were not related to reduced egg penetration. We conclude that in utero exposure to DES is not related to a significant change in the penetration of zona-free hamster eggs by sperm.

Abnormalities, Drug-Induced↗

PubMed1990

Are implantation and pregnancy outcome impaired in diethylstilbestrol-exposed women after in vitro fertilization and embryo transfer?

Forty-six infertile women with a history of diethylstilbestrol (DES) exposure in utero underwent 149 stimulation attempts for in vitro fertilization (IVF). The mean (+/- SE) number of preovulatory oocytes harvested at retrieval and transferred was 3.9 +/- 3.3 (536/138) and 2.6 +/- 1.4 (328/124). When compared with patients with tubal factor infertility and less than or equal to 4 pre-embryos transferred, the clinical pregnancy rate (15.3% versus 22%) was not statistically different. However, the term/ongoing pregnancy rate was significantly lower in the study group (8% versus 16%). Comparison of the IVF outcome with different uterine anomalies as detected by hysterosalpingogram (n = 29) showed a trend for a worse prognosis in women with constrictions and a combination of T-shape and constrictions. It is concluded that implantation and pregnancy outcome are impaired in DES-exposed women after IVF.

Adult↗

PubMed1993

Hysteroscopic metroplasty in the diethylstilbestrol-exposed uterus and similar nonfusion anomalies: effects on subsequent reproductive performance; a preliminary report.

OBJECTIVE: To determine the feasibility of correcting the uterine abnormalities seen in diethylstilbestrol (DES)-exposed women and similar anomalies. DESIGN: Patients served as their own controls. SETTING: University based and private practice tertiary referral practice. PATIENTS: Eight patients referred for infertility, recurrent pregnancy loss, or both with an abnormal uterine contour as seen by hysterosalpingogram. INTERVENTION: Hysteroscopic metroplasty. OUTCOME MEASURES: Ability to conceive and carry pregnancy to livebirth. RESULTS: Three of five patients with secondary infertility and recurrent pregnancy losses had livebirths as did a patient with secondary infertility. Two patients with primary infertility failed to conceive. CONCLUSION: Metroplasty may decrease pregnancy loss in these patients but may not enhance fertility.

Abnormalities, Drug-Induced↗

PubMed1987

Alterations in immune responsiveness in women exposed to diethylstilbestrol in utero.

In order to study the effect of in utero diethylstilbestrol (DES) exposure on the immune system of adult women, the blastogenic response of peripheral blood lymphocytes to two mitogens was compared in eight DES-exposed patients and in eight age-matched controls with normal menstrual cycles and proven fertility. As measured by the uptake of 3H-thymidine (mean [+/- standard error]), response to the T-cell mitogen phytohemagglutin (PHA) was significantly higher (P less than 0.002) in cells of DES-exposed women (88.6 +/- 5.7 X 10(3) cpm) than in controls (44.0 +/- 8.9 X 10(3) cpm) at the lowest dose of mitogen tested (0.125 microgram/ml). Moreover, lymphocytes of DES-exposed subjects showed maximal blastogenic response to PHA at a concentration (0.125 microgram/ml) two to four times lower (P less than 0.002) than controls (0.25 microgram/ml to 0.5 microgram/ml). Cells of both DES-exposed subjects and controls were maximally responsive to pokeweed mitogen (PWM) at the lowest dose tested (0.625 microgram/ml). These findings suggest that in utero DES exposure is associated with a hyper-reactive immune response during the reproductive years.

Adult↗

PubMed1999

Effect of diethylstilbestrol on reproductive function.

OBJECTIVE: To review the effects of in utero exposure to diethylstilbestrol (DES) on müllerian development and subsequent reproductive function. DESIGN: The literature on DES and reproductive function was reviewed and summary data are presented. The studies were identified through the computerized MEDLINE database and a manual search of relevant bibliographies. RESULT(S): In utero exposure to DES resulted in reduced fertility and increased rates of ectopic pregnancy, spontaneous abortion, and preterm delivery. CONCLUSION(S): An understanding of the reproductive performance of women who were exposed to DES in utero is useful for counseling these patients regarding their risks and treatment options.

Diethylstilbestrol↗

PubMed1978

Stable derivatives for the gas chromatographic determination of synthetic anabolic stilbene residues (diethylstilbestrol, dienestrol and hexestrol) in meat and organs of treated cattle in the sub-parts per billion (10(9)) level.

A method for the determination of diethylstilbestrol and the related compounds dienestrol and hexestrol residues in meat and organs of treated cattle is described. After extraction and clean-up, these synthetic estrogens are subjected to reaction with pentafluorobenzoyl chloride, which gives very stable perfluoro esters that are suitable for gas chromatographic determination using an electron-capture detector. With the careful clean-up and the very sensitive response of these derivatives, it is possible to reach a limit of detection in the sub-parts per billion (10(9)) range starting with only 5 g of sample.

Animals↗

PubMed1977

Preparation and high-performance liquid chromatography of iodinated diethylstilbestrols and some related steroids.

Diethylstilbestrol and estradiol have been converted to their mono- and poly-iodinated derivatives by electrophilic substitution of positive iodine into the activated aromatic rings. Both chemical and electrochemical procedures have been employed for the iodination, and the latter procedure proved to be superior. These iodinated derivatives have been purified by preparative high-performance liquid chromatography, and characterized by ultraviolet and mass spectroscopy.

Chemical Phenomena↗

PubMed1979

Analysis of diethylstilbestrol and its impurities in tablets using reversed-phase high-performance liquid chromatography.

A high-performance liquid chromatographic (HPLC) method is described which is capable of resolving cis- and trans-diethylstilbestrol (DES), DES mono- and dimethyl ethers and 4,4'-dihydroxystilbene. The mobile phase and internal standard used stabilise the cis-trans DES isomer ratio, and the method is capable of quantitating both isomers in dosage forms without derivatisation. Recovery of DES from tablets is quantitative. Results of tablet analyses using this method are compared with those obtained with the official spectrophotometric procedure.

Chromatography, High Pressure Liquid↗