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PubMed1984

Induction of Müllerian duct derivatives in testicular feminized (Tfm) mice by prenatal exposure to diethylstilbestrol.

When pregnant mice carrying the Tfm mutation gene were injected with diethylstilbestrol (DES) from Days 9 to 16 of gestation, the regression of the Müllerian duct derivatives was inhibited in their wild male and Tfm male offspring. The degree of persistence of the Müllerian duct derivatives demonstrated a dependence on DES dose. Complete or almost complete preservation of the Müllerian ducts was observed in the animals exposed to high doses of DES. Since Tfm males from non-injected mothers had no reproductive tract except the vaginal anlage, despite the presence of testes, bilateral occurrence of the Müllerian duct derivatives in Tfm males following prenatal exposure to DES indicates that the characteristic features of the reproductive tract in these animals are almost the same as that in normal females.

Androgen-Insensitivity Syndrome↗

PubMed1986

Polyovular follicles in the ovary of immature mice exposed prenatally to diethylstilbestrol.

Polyovular follicles (PF) occur in the ovary of 30-day-old offspring of ICR/JCL mice given 4 daily subcutaneous injections of 20-2,000 micrograms diethylstilbestrol (DES)/day from days 15 to 18 of gestation. PF containing 2-9 oocytes per follicle in the prenatally DES-exposed mice are increased 33- to 112-fold as compared to controls. In 5- to 25-day-old offspring of mothers given injections of 2,000 micrograms DES/day, PF are observed 17-65 times more frequent than in controls.

Aging↗

PubMed1983

The binding of steroid hormones and diethylstilbestrol to proteins of human cells in culture.

The binding of 3H-labeled steroid hormones and a non-steroidal synthetic estrogen, diethylstilbestrol (DES), to proteins of cultured human embryonic lung cells (HEL 299) was studied according to the methods of Diamond et al. [Cancer Res 27: 890-897 (1967)] and Kuroki and Heidelberger [Cancer Res 31: 2168-2176 (1971)]. Ecdysone, estradiol, hydrocortisone, progesterone, testosterone, and DES were selected as test compounds. The aim of this study was to determine the protein binding ability of DES, known as a transplacental carcinogen and teratogen for humans, and to compare it with those of the steroid hormones. DES was bound to proteins to the highest extent, and the amount of binding of estradiol was slightly lower than that of DES. Hydrocortisone, testosterone, and progesterone bound to proteins to smaller extents than DES and estradiol. Very little binding of ecdysone to cellular proteins was detected.

Cell Line↗

PubMed1977

Metabolic activation of diethylstilbestrol and aminostilbene-derivatives.

Diethylstilbestrol and trans-4-dimethylaminostilbene are metabolically activated and several of their metabolites are able to react with cellular macromolecules. Some of the problems are discussed which are encountered in linking a particular metabolite with the mutagenic and carcinogenic properties of these compounds.

Animals↗

PubMed1977

Hyperplastic and metaplastic lesions in the reproductive tract of male rats induced by neonatal treatment with diethylstilbestrol.

Newborn male Wistar rats were castrated on the day of birth (= day 1) and treated daily with diethylstilbestrol (DES) from days 1 to 30; 1 microgram for the first 10 days of life, 2 microgram for the next 10 days and 4 microgram for the last 10 days. The animals were autopsied at 30, 90 and 270 days of age. The epithelium of the coagulating glands (CGs) and ejaculatory ducts (EDs) underwent metaplastic transformation in all DES-treated rats. These pathological changes were more marked with age. The most striking changes were found in the periurethral regions of the CGs and EDs and associated regions of the dorsal urethral wall. The normal transitional epithelial lining almost disappeared and large papillary epithelial outgrowths occurred near the opening of the EDs and CGs. This type of neoplastic change was most marked in the group of rats sacrificed at 9 months of age.

Animals↗

PubMed1978

Diethylstilbestrol potentiation of the dopamine-elicited formation of adenosine 3',5'-monophosphate in incubated male rat hypothalamus.

Dopamine (DA) stimulates the cAMP-generating system in the male rat hypothalamus only to a very low extent (25% above control). Diethylstilbestrol (DES), a synthetic estrogen, was found to be extremely potent (a 4- and 16-fold stimulation at 20 micron and 100 micron, respectively). Addition of either one to an incubation medium containing varying concentrations of the other resulted in a synergistic response. The potentiation by 20 micron DES of the effect elicited by 100 micron DA was the most remarkable, namely, a 3-fold stimulation of the combined response. A 4- and 7.5-fold stimulation of cAMP accumulation was observed when adenosine (100 micron) or adenosine (100 micron) + DA (100 micron) were present in the incubation medium. Theophylline (0.5 mM), an adenosine antagonist, could effectively reduce this effect, as did adenosine deaminase (10 microgram/ml). Clomiphene (50 micron), an estrogen antagonist, exhibited a marked decrease in DES + DA-elicited cAMP formation. Pimozide (40 micron) had the ability to significantly block the stimulatory effects of DES and DA.

Adenosine Deaminase↗

PubMed1982

Upper genital tract abnormalities in the Syrian hamster as a result of in utero exposure to diethylstilbestrol. I. Uterine cystadenomatous papilloma and hypoplasia.

Prenatal exposure to diethylstilbestrol (DES) causes a significant increase in the carcinogenic response of the hamster's reproductive tract to subsequent DES treatment. Uteri from DES treated females from untreated- and DES treated mothers (C.D & D.D) have abnormal hyperplasia with characteristic finger-like structures projecting into the lumen of the uteri. Inside these papillae along with the rest of the stroma are cystic glands. We found that these glands had no openings into the uterine lumen and that they "begin" and "end" in the stroma. In addition there are two types of cells lining the cystic gland i.e., pale cells and acidophilic cells. Capillary beds surround the cystic glands. We have named these uterine structures "cystadenomatous papilloma". In addition, we found a spectrum of hyperplastic abnormalities in C.D and D.D uteri and carcinoma in situ in D.D uteri. Similar neoplasms have been described in human pathology. Ultrasound observations have demonstrated that in utero exposure to DES may result in uterine hypoplasia and because it appears to be similar to the changes seen in prenatally DES treated (D.C) hamsters, cross sectional areas of C.C (untreated control), D.C, C.D and D.D uteri were compared. Our results show that later in life uterine hypoplasia also occurs in the 100 days old D.C hamsters and since D.C uteri present hyperplasia with cystic structures, our data support the hypothesis that in utero DES-treated human females may later in life develop benign and malignant lesions in their reproductive tract. Much of these data corresponds to what has been found in humans, and consequently warrants further investigation into the use of Syrian hamster as a model to understand the uterine abnormal morphogenesis in regards to hypoplasia, adenocarcinoma and carcinoma development in the human.

Animals↗

PubMed1990

Lectin bindings and diethylstilbestrol effects on the recognition of mullerian inhibiting substance (MIS) on chick mullerian ducts by MIS-antiserum.

A high intensity of lectin bindings was demonstrated on the epithelial cells and serosa cells of the regressing right Mullerian ducts (Mds) in the female chick embryos. The strong lectin bindings occurs on, or in the regressing Md cells along with marked surface MIS bindings at the age of day 13. However, at the age of days 5-7 1/2, bindings of lectins were weak. Neither Wheat-germ agglutinin (WGA) or Concanavalin A (Con-A) labelings before MIS-antiserum (MIS-Ab) incubation can block antibody recognitions to the antigens, including MIS and growth hormone at the age of day 13. Our previous studies indicated that after WGA labeling on the surfaces of Md epithelial cells prior to the incubation of MIS-Ab at day 10 did not prevent the recognition of MIS-Ab (Wang 1989). On the contrary, at day 7 1/2, the specific binding of MIS was eliminated after preincubations with lectins and prenatal diethylstilbestrol (DES) treatment at the age of day 5. It is suggested that DES provides a protection to the Mds from MIS-induced regression by preventing the MIS binding to its specific membrane receptors. An increase of extra- and intracellular glycoproteins or carbohydrates of regressing Md epithelial cells were suggested. Internalization of WGA but not MIS molecules was found in Md epithelial cells. The Golgi saccules were negative of lectin bindings.

Animals↗

PubMed1992

Prenatal exposure to diethylstilbestrol (DES): childhood play behavior and adult gender-role behavior in women.

Data from lower mammals suggest a masculinizing or defeminizing influence of pre- or perinatal diethylstilbestrol (DES) exposure on various aspects of the sex-dimorphic behavior (including juvenile rough-and-tumble play) of genetic females. However, three previous studies on childhood play and adult gender-role behavior in human females have led to ambiguous results. In a follow-up study of 60 women with prenatal exposure to DES and 26 controls, we used psychometrically well-designed multi-item scales based on self-report inventories for the assessment of these aspects of behavior. No effects of DES could be demonstrated. We conclude that, at the doses studied, prenatal DES exposure in human females has not led to behavioral masculinization or defeminization of childhood play and adult gender-role behavior.

Adolescent↗

PubMed1990

The tumor-inhibiting effect of diethylstilbestrol and its diphosphate on the Nb-H and Nb-R prostatic carcinomas of the rat.

For many years, diethylstilbestrol (DES) and its diphosphate (DESPP; Honvan) have been standard therapies for prostatic carcinoma. The effects of DES, its monophosphate (DESP) and of DESPP on the weights of accessory sex organs of mice and rats, and on the experimental Noble Nb-H and Nb-R prostatic carcinomas of the rat were, therefore, compared. In intact mature mice, all three compounds led to a strong and dose-dependent inhibition of seminal vesicle weights and testosterone levels, whereas only a slight antiandrogenic activity in castrated mice was found. In intact rats, DES, DESP and DESPP strongly inhibited accessory sex organ weights and testosterone levels. In castrated rats, however, no antiandrogenic activity was determinable. The prostate carcinoma-inhibiting effects of DES and DESPP were tested in comparison with castration in the transplantable hormone-sensitive Nb-H and Nb-R prostatic carcinoma in rats. Whereas castration caused only a retardation of tumor growth, DES and DESPP (3 x 0.1 mg/kg and 1.0 mg/kg weekly s.c.) led to an almost complete inhibition, which was significantly (P less than 0.01) better than the effect of castration. As the weights of accessory sex organs were identically reduced by either castration or the estrogens, a direct tumor-inhibiting effect of DES and DESPP in addition to their testosterone-lowering activity is obvious. This was proved in an experiment with castrated rats. The only slightly inhibitory activity of castration was strongly potentiated by concomitant administration of DES. Moreover, histological examinations revealed that Nb-H and Nb-R tumors were much more damaged by treatment with DES or DESPP than after castration. Morphometry of the tumors showed that tumor reduction is associated with a decrease in the ratio of the epithelial to the stromal density, i.e. there was an even more pronounced decrease in epithelial cells than that found by merely measuring tumor area. These studies show that the prostate carcinoma-inhibiting effect of DES and DESPP in the Nb model is superior to the effect of castration and that they act directly on the tumor cells used, even in castrated rats.

Androgen Antagonists↗

PubMed1978

Alterations of the antibody response following in utero exposure to diethylstilbestrol.

The antibody response to SRBC and E. coli 0127 lipopolysaccharide were determined in offspring from mice exposed in utero to diethylstilbestrol. The antibody response to SRBC, a T-cell dependent antigen, was similar in control and exposed animals. In contrast, the LPS antibody response was suppressed in treated females and enhanced in treated males. These studies indicated that in utero exposure to DES alters the humoral immune system to T-independent antigens.

Animals↗

PubMed1988

Contraception for women exposed in utero to diethylstilbestrol.

Although the effects of in utero exposure to diethylstilbestrol (DES) have been extensively documented, there is an absence of information on the suitability of different contraceptives for use by DES-exposed women. This paper briefly describes some of the effects associated with DES exposure. Use of various contraceptive methods by DES-exposed women are considered in light of these effects.

Adolescent↗

PubMed1991

Prostaglandin H synthase dependent metabolism of diethylstilbestrol by ram seminal vesicle cell cultures.

Prostaglandin H synthase (PHS) peroxidase dependent metabolic activation has been suggested to play a role in mediating adverse effects of various carcinogens. Recently, we derived a cell line from ram seminal vesicles (SEMV cells) to conduct studies on the PHS-mediated metabolism of estrogens and xenobiotics in intact cells with the goal of relating this to an endpoint for genotoxicity inducible in this in vitro model. The present paper describes the drug-metabolizing capability of SEMV cells which has been investigated using radiolabeled diethylstilbestrol (DES) and analysing culture extracts by means of reverse phase HPLC with on-line radioactivity detection and after enzymatic hydrolysis of conjugate fractions. The synthetic estrogen DES is converted to sulfate conjugates and to the oxidative metabolite Z,Z-dienestrol (Z,Z-DIES) in a time-dependent manner. Compounds expected to modulate PHS-dependent co-oxidation of DES increased (arachidonic acid) or inhibited (indomethacin) Z,Z-DIES formation of SEMV cells in culture. A comparison of rates of arachidonic acid turnover to prostaglandins on the one hand and DES oxidation on the other reveals that DES is oxidized despite the presence of competing endogenous cosubstrates of PHS peroxidase. The results clearly indicate that SEMV cells catalyze PHS-dependent oxidation of DES as well as carrying out phase II metabolism in the absence of detectable monooxygenase activity. These features and recent data showing that DES can induce micronuclei in SEMV cells makes them an attractive model for further investigations of the role of PHS in mediating the genotoxicity of DES and other xenobiotics.

Animals↗

PubMed1977

Residue content of beef feedlot manure after feeding diethylstilbestrol, chlortetracycline and Ronnel and the use of stirofos to reduce population of fly larvae in feedlot manure.

Two beef cattle feedlot experiments were conducted to determine the amount of certain agricultural chemicals that are likely to be found in both fresh and stored feedlot manure and to investigate fly control in this manure. In experiment 1, diethylstilbestrol (DES), chlortetracycline (CTC), and ronnel were used as feed additives. Fresh manure, stored manure, runoff water, manure weathered on pasture, and soil from pasture fertilized with manure were analyzed for these additives. Stirofos was added to fresh manure as a larvicide for fly control. In experiment 2, the residue aspects of DES and CTC were repeated. In this experiment, stirofos instead of ronnel was fed with DES and CTC. Sixty-eight percent of the DES fed to cattle appeared in fresh manure and 52% in manure stored for 12 weeks. Comparable percentage values were 17 and 11% for CTC and 13 and 3% for ronnel; somewhat less DES and CTC were found when a concentrate diet was fed. Detectable amounts of DES, ACT, and ronnel were not found in runoff water, weathered manure, or soil. Adding an emulsifiable concentrate formulation of stirofos directly to manure at a rate of approximately 45 ppm of wet manure completely controlled the larvae of house fly (Musca domestica L.) whereas feeding stirofos at a rate of 1.5 mg per kg of body weight daily reduced larval counts 82% in manure from forage-fed heifers and 63% in manure from concentrate-fed heifers. Stirofos was not detected in runoff water, weathered waste, or soil.

Animal Feed↗

PubMed1992

Characterization of murine cell lines from diethylstilbestrol-induced uterine endometrial adenocarcinomas.

Neonatal treatment with estrogens is associated with development of uterine adenocarcinomas in CD-1 mice. Treatment with the synthetic estrogen diethylstilbestrol (DES) on Days 1 to 5 after birth results in 90% incidence of these hormone-dependent lesions in 18-mo.-old mice. Three cell lines were established from these DES-associated tumors. Each of these cell lines exhibited morphologic and ultrastructural characteristics of transformed epithelial cells, including an increased nuclear:cytoplasmic ratio, enlarged and irregular nuclei with multiple nucleoli and areas of chromatin condensation, positive staining for cytokeratin, desmosomes, and microvilli. After subcutaneous injection into nude mice, all three cell lines formed solid tumors within 4 wk. Although the primary uterine tumors and tumor transplants in nude mice had been shown to be estrogen-dependent and estrogen-receptor positive, neither the monolayer growth nor the tumorigenicity of any of the three cell lines in this study was enhanced by or dependent on estrogen. Estrogen receptor levels were low in early and intermediate passage cells. Allele-specific oligonucleotide hybridization analysis of PCR-amplified cell line DNA revealed no point mutations in the 12th, 13th, or 61st codons of the K-ras or H-ras protooncogenes. Southern analysis revealed no changes in genomic organization of the putative tumor suppressor gene DCC, but demonstrated a three- to four-fold amplification of the c-myc gene in one cell line. Expression of c-myc RNA was concomitantly increased in the same cell line. These three transformed cell lines represent the end point in the process of hormone-associated tumorigenesis and as such should prove useful in investigating the molecular changes and the mechanisms involved in hormonal carcinogenesis.

Adenocarcinoma↗

PubMed1984

Histochemical and ultrastructural characteristics of the endometrial connective tissue stroma from mice continuously fed diethylstilbestrol.

Histochemical and transmission electron microscopy were utilized to examine the endometrial connective tissue stroma of mice continuously fed diethylstilbestrol (DES). Virgin female mice were continuously fed diets containing 0, 320, or 640 ppb DES from 4 weeks of age until moribund. All animals reported on in this study were between 622 to 762 days of age when sacrificed. Light microscopy revealed irregular deposits of homogeneous acidophilic material throughout the connective tissue stroma with frequent accumulations seen immediately beneath the surface epithelial layer and surrounding blood vessels. Histochemical results indicated the presence of collagen and fibrin as components of the acidophilic material. Ultrastructural results revealed a homogeneous stroma consisting of short segments of collagen fibrils enmeshed in an amorphous component. Numerous plasma cells were seen in close approximation to macrophages and lymphocytes. Fibroblast cell membranes exhibited micropinocytotic vesicles. Eosinophils were numerous in the stroma and often seen in close approximation to fibroblast projections. Vascular endothelial layers contained numerous micropinocytotic vesicles and marginal flaps. The accumulation of homogeneous material within the connective tissue stroma may represent products from collagen degradation and a subsequent localized immune response as well as plasma components.

Animals↗

PubMedDate not supplied

Effect of 7,8-benzoflavone pretreatment on diethylstilbestrol metabolism, drug-metabolising enzymes and the aromatic hydrocarbon (Ah) receptor in male hamster liver.

Pretreatment of male Syrian golden hamsters with 7,8-benzoflavone (7,8-BF) leads to a marked increase of cytochrome P450 and cytochrome b5 levels in the liver, whereas phenobarbital (PB) and 3-methylcholanthrene (MC) induce cytochrome P450 but not cytochrome b5 7,8-BF pretreatment has only minor effects on the activities of aryl hydrocarbon hydroxylase and 7-ethoxycoumarin-O-deethylase, but 7-ethoxyresorufin-O-deethylase is increased 3-fold. In contrast to PB, pretreatment with 7,8-BF or MC reduces the oxidative metabolism of diethylstilbestrol (DES) by hepatic microsomes in vitro. The cytosolic level of the aromatic hydrocarbon (Ah) receptor in hamster liver is decreased by 7,8-BF and slightly enhanced by MC pretreatment. PB increases the receptor level 1.5-fold. The affinity of 7,8-BF to the Ah receptor in vitro is of the same order of magnitude as that of the known ligands 5,6-benzoflavone and 2,3,7,8-tetrachlorodibenzofurane. PB and DES show no binding to the receptor protein.

Animals↗

PubMed1996

The carcinogenicity of diethylstilbestrol: structural evidence for a non-genotoxic mechanism.

An analysis of the structure of diethylstilbestrol (DES) indicates that neither DES nor any of its metabolites are potential mutagens. Moreover, the present analyses suggest (a) that the observed carcinogenic spectrum of DES reflects the activity of metabolic intermediates and (b) that the carcinogenicity of DES in mice is due to the presence of a 6 A geometric descriptor that appears to be related to an estrogen receptor.

Animals↗