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PubMed1988

Binding and biologic activity of diethylstilbestrol in the hamster: influence of a serum component on estrogen receptor binding and estrogenic activity.

The purpose of this study was to compare the biological activity and estrogen receptor (Re) binding affinity of diethylstilbestrol (DES) and estradiol (E2). Uterine weight response and cytosolic progesterone receptor (Rp) induction were equivalent following daily (3 days) injections of DES or E2 to ovariectomized animals. The biological equivalence of DES and E2 was not reflected by competition assays done with either uterine cytosolic or nuclear Re: the relative binding affinity (RBA) of DES to cytosolic Re was 46 +/- 5.3 and to nuclear Re was 380 +/- 42 compared to E2 (100). The RBAs of estrone, estriol and enclomiphene with cytosolic or nuclear Re were not significantly different. Further studies showed that this discrepancy in RBA of DES between cytosolic and nuclear Re could not be attributed to salt concentration but could be mimicked by addition of serum to nuclear Re preparations. The RBA of DES done with ammonium sulfate precipitated cytosolic Re approached that observed for nuclear Re. Gel filtration chromatography (Sephacryl S-300) of serum bound tritiated DES was shown to coelute with bovine serum albumin. These results suggest that a serum component (tentatively identified as albumin) can bind DES and cause a decrease in in vitro binding affinity and a reduction in biological activity in vivo.

Ammonium Sulfate↗

PubMed1989

Plasma testosterone levels and ovarian testosterone content in adult mice treated with diethylstilbestrol neonatally.

Neonatal female NMRI mice (n = 16) were treated with 5 micrograms diethylstilbestrol (DES) per day, for the first 5 days after birth and killed postpubertally. Control females (n = 52) were injected with vehicle only and killed in different stages of the estrous cycle. The plasma testosterone level was significantly lower in DES females than in control females in any of the estrous phases. Ovariectomy (n = 5), adrenalectomy (n = 5) or a combination of both ablations (n = 3) did not affect the plasma testosterone in DES treated females while it was significantly reduced in control females (ovariectomy n = 5; adrenalectomy n = 9); most effective was the combination ovariectomy-adrenalectomy (n = 7). Ovarian homogenates from DES treated females (n = 10) had a significantly lower testosterone content than homogenates from control females in any phase of the estrous cycle (6-10 females per phase), which held true on both a per ovary basis and when related to ovarian weight. After a 2 h incubation in vitro, the testosterone levels had increased significantly in DES homogenates (n = 6) and to a lower extent in homogenates from control females in estrus (n = 9). No similar effect was found in homogenates from diestrus (n = 10) or proestrus (n = 9) females. The results are discussed in relation to the special ovarian morphology of adult but neonatally DES treated females and also with respect to endocrine control mechanisms.

Adrenalectomy↗

PubMed1989

Influence of neonatal diethylstilbestrol treatment on androgen and estrogen receptor levels in the mouse anterior prostate, ventral prostate and seminal vesicle.

Perinatal exposure to the synthetic estrogen, diethylstilbestrol (DES), affects the structure of both male and female reproductive systems. Changes may also occur in the levels of steroid hormone receptors. Cytosolic and nuclear androgen and estrogen receptor levels (expressed per mg DNA) from the sex accessory glands of male BALB/c mice exposed neonatally to DES were analyzed by exchange assays. Neonatal DES exposure caused significant decreases in: (1) cytosolic androgen and cytosolic and nuclear estrogen receptor levels in the anterior prostate and (2) cytosolic estrogen receptor levels in the ventral prostate. A significant increase was seen in the cytosolic estrogen receptor levels in the seminal vesicle. Significant decreases in cytosolic protein levels occurred in all DES-exposed glands.

Animals↗

PubMed1990

Steroid binding alterations in tissue compartments of the vagina of control and neonatally diethylstilbestrol-treated adult mice.

Steroid binding in both the vaginal epithelium and the vaginal fibromuscular wall (FMW) was compared in control and neonatally estrogen-treated mice. Neonatal treatment with a low dose of the estrogen diethylstilbestrol (DES) had no significant effect on adult estrogen binding within the assayed vaginal compartments; however, this treatment caused a 2-fold increase in the level of cytosolic progestin binding in the vaginal FMW over that in vehicle-treated mice. This low neonatal dose did not affect the level of progestin binding in the vaginal epithelium. In contrast, neonatal treatment with a larger dose of DES caused marked increases in cytosolic progestin binding, decreases in cytosolic estrogen binding, and increases in nuclear estrogen binding within the FMW. Furthermore, as a result of the changes in specific binding induced by the neonatal DES treatment, the degree of the estrogen binding within in each tissue shifted from a predominantly cytosolic site to a nuclear one.

Animals↗

PubMed1990

Effects of various inducers on diethylstilbestrol metabolism, drug-metabolizing enzyme activities and the aromatic hydrocarbon (Ah) receptor in male Syrian golden hamster liver.

In order to elucidate the role of metabolic activation of the synthetic estrogen, diethylstilbestrol (DES), in the mechanism of liver tumor formation in male Syrian golden hamsters observed after combined treatment with DES and 7,8-benzoflavone (7,8-BF), the metabolism of DES and the concentrations and activities of various drug-metabolizing enzymes were studied in hamster liver microsomes after various pretreatments. The levels of the hepatic aromatic hydrocarbon (Ah) receptor were also determined. Pretreatment with 7,8-BF increased both P450 and cytochrome b5 levels, whereas phenobarbital (PB) and 3-methylcholanthrene (MC) induced P450 but not cytochrome b5. 7,8-BF pretreatment increased 7-ethoxyresorufin-O-deethylase (EROD) 3-fold and 7-pentoxyresorufin-O-dealkylase (PROD) 2.5-fold, whereas aromatic hydrocarbon hydroxylase (AHH) and 7-ethoxycoumarin-O-deethylase (ECOD) activities were only slightly induced by 7,8-BF. MC pretreatment increased EROD 8-fold and PROD activity 7-fold, whereas PB pretreatment enhanced AHH 4.5-fold and PROD activity 4-fold. In contrast to PB, pretreatment with 7,8-BF and MC reduced the oxidative metabolism of DES in hepatic microsomes, but the pattern of metabolites was identical with that in untreated controls. Treatment of hamsters with the inducers changed the hepatic Ah receptor level. PB and MC-pretreatment resulted in an increase of the receptor level 1.5-fold and 1.3-fold, respectively, whereas 7,8-BF-pretreatment leads to a 1.5-fold decrease. The dissociation constant Kd is 170 nM for the reaction of 7,8-BF with the hamster Ah receptor compared to 70 nM for 5,6-BF and 38 nM for 2,3,7,8-tetrachlorodibenzofuran (TCDF). The Kd-value is 3.6 nM for TCDF with the rat receptor protein. It is concluded from these data that metabolic activation of DES is not involved in the mechanism of hepatocarcinogenesis in this animal tumor model.

Animals↗

PubMed1984

Effects of neonatal treatment with diethylstilbestrol and 17 alpha-hydroxyprogesterone caproate on in vitro pituitary prolactin secretion.

The effects of neonatal hormone treatment with diethylstilbestrol (DES) and 17 alpha-hydroxyprogesterone caproate (HPC) on days 1-5 of life on serum prolactin (PRL) levels and 3H-PRL synthesis and release were studied in C3H/MTV+ mice at 2, 4, 6, 8 and 10 weeks of age. Neonatal treatment of mice with 2.5 micrograms/day DES was the only treatment that affected the developmental pattern of serum PRL levels. Serum PRL levels were significantly decreased at 6 wks of age with this dose of DES. Neonatal treatment with 2.5 micrograms/day DES and 150 micrograms/day HPC affected the developmental pattern of H-PRL synthesis by the pituitary. At 10 wks of age 3H-PRL synthesis was significantly decreased by these doses of DES and HPC. The percent of 3H-PRL released did not differ between neonatally hormone treated and control animals, suggesting that neonatal treatment affected mechanisms that regulate PRL synthesis but not those that regulate release.

17-alpha-Hydroxyprogesterone↗

PubMed1993

A comparison of the temporal effects of estradiol and diethylstilbestrol on pituitary content of DNA, prolactin mRNA and prolactin and on serum prolactin levels in ovariectomized Holtzman rats.

Ovariectomized Holtzman rats implanted with Silastic capsules of estradiol-17 beta (E2) or diethylstilbestrol (DES) were decapitated at intervals between 4 hours and 10 days of steroid treatment and the anterior pituitaries were collected and analyzed for DNA, prolactin mRNA, and prolactin content. Serum prolactin was also determined. Untreated ovariectomized rats decapitated at 10 days after ovariectomy served as controls. Pituitary DNA levels were not consistently affected by either steroid until 10 days of treatment when levels approximately doubled. In contrast both steroids increased prolactin mRNA and pituitary and serum prolactin levels within 4-8 hours of treatment. Prolactin mRNA levels increased throughout the 10 day period. Pituitary prolactin levels paralleled mRNA levels until day 7 then decreased significantly (P < 0.05) at day 10. Serum prolactin levels increased at 4 and 8 hours, decreased slightly at 24 hours only to increase dramatically at 48 hours. Then at 4 and 7 days of treatment serum levels decreased to the levels seen at 24 hours, followed by a significant (P < 0.05) increase at day 10. Both steroids were equipotent in their effects on serum prolactin; however, DES was significantly (P < 0.05) more potent in increasing pituitary prolactin content than was E2; whereas, E2 was more potent in increasing prolactin mRNA and pituitary DNA. It is concluded that both natural and synthetic estrogens have rapid and sustained, although not equivalent, actions on the levels of prolactin mRNA in the rat. Further, pituitary DNA and pituitary and serum prolactin do not consistently follow the temporal pattern of change seen for prolactin gene expression.

Animals↗

PubMed1993

Reduction of plasma prolactin by acute administration of CB-154 in ovariectomized F344 and Holtzman rats treated with diethylstilbestrol: a comparison of RIA and Nb2 lymphoma bioassay.

Fischer 344 (F344) and Holtzman Sprague-Dawley female rats were ovariectomized and implanted with a s.c. Silastic capsule of diethylstilbestrol (DES). At 1, 4 and 8 weeks of DES exposure, blood samples were obtained by infraorbital sinus puncture under light ether anesthesia before and 2 hours after s.c. administration of CB-154 (2.5 mg/rat). The plasma obtained was assayed for prolactin by radioimmunoassay (RIA) and Nb2 lymphoma cell bioassay (BA). At 1 week of DES treatment plasma prolactin in F344 rats measured by RIA was decreased by CB-154 (approximately 60%) whereas the level measured by BA was not changed and the BA:RIA ratio was increased from 2.4 +/- 0.2 to 4.8 +/- 0.9. CB-154 decreased plasma prolactin levels at 4 weeks but the effect seen by RIA (approximately 80%) was greater than that seen by BA (approximately 60%) and the BA:RIA ratio was increased (2.2 +/- 0.2 vs 3.4 +/- 0.5). By 8 weeks of DES exposure, CB-154 was as effective in reducing the levels measured by BA (approximately 89%) as those measured by RIA (approximately 85%) and the BA: RIA was not affected by the dopamine agonist. In Holtzman rats CB-154 decreased prolactin levels measured by RIA and BA to the same extent at both 1 and 4 weeks resulting in no change in the BA:RIA ratio, but at 8 weeks the BA:RIA was decreased by CB-154 (2.1 +/- 0.1 to 1.7 +/- 0.1). As was observed in F344 rats, the reduction in plasma prolactin induced by CB-154 increased as the duration of DES treatment increased (1 week approximately 45%; 4 weeks approximately 55-60%; 8 weeks approximately 80-85% inhibition) regardless of assay method. It is concluded that DES increases the BA:RIA ratio of plasma prolactin and that acute CB-154 treatment increases, decreases or does not change the BA:RIA ratio depending on the strain of rat used and the duration of DES treatment.

Animals↗

PubMed1978

Colchicine-like effect of diethylstilbestrol (DES) on mammalian cells in vitro.

Diethylstilbestrol (DES), a synthetic estrogen, showed colchicine-like effects in vitro on cells of the cell lines such as Chinese hamster fibroblast of thymus origin (CHT), rat liver (DL), rat erythroblastic leukemia (EDEN-1/TC) and HeLa-S3. Metaphase arrest was induced 3 h after treatment with 15 microgram/ml of DES and polyploid or polynucleated cells were prominently observed more than 24 h after treatment. The arrest, however, was reversible when the agent was removed from the medium. Tetraploid karotypes induced by DES in CHT cells consisted of all double sets of diploid chromosome constitution except one chromosome marker. By clonal selection, several hypotetraploid sublines were successfully isolated from a CHT cell population after the treatment with 15 microgram/ml of DES for 48 h. Some comparative studies of cytological effects of DES with those induced by colcemid indicated that the DES effect was also a mitotic inhibition similar to colchicine.

Aneuploidy↗

PubMed1982

Genetic activity of diethylstilbestrol in Saccharomyces cerevisiae: enhancement of mutagenicity by oxidizing agents.

Diethylstilbestrol (DES), a synthetic estrogen, is known to cause cancer in humans and experimental animals. Although it has been established that DES can induce unscheduled DNA synthesis, sister-chromatid exchange, and cell transformation in various short-term tests, the efforts to demonstrate its mutagenic activity in bacterial and mammalian systems have largely failed. It has been shown that DES can covalently bind to DNA after being oxidized either chemically, in the presence of iodine and hydrogen peroxide, or metabolically, by mammalian cells in tissue culture and also in the presence of rat-liver microsomes. We studied genetic activity of DES in growing cultures of the strains XV185-14C and D5 of S. cerevisiae in the presence and absence of oxidizing agents, namely, iodine and hydrogen peroxide. We demonstrated that DES alone exhibits a weak mutagenic response in the strain XV185-14C. On the other hand, the treatment of cells with DES in the presence of iodine or hydrogen peroxide plus ferrous sulfate induced a large increase in the frequency of induced mutations in strain XV185-14C and mitotic recombination and gene conversion in strain D5. This enhancement in the genetic activity of DES in our test assays in the presence of chemical oxidative systems indicates that DES undergoes oxidation to produce a genetically active metabolite.

Cytochrome P-450 Enzyme System↗

PubMed1983

Inability of diethylstilbestrol to induce 6-thioguanine-resistant mutants and to inhibit metabolic cooperation of V79 Chinese hamster cells.

The mutagenicity of diethylstilbestrol (DES) in V79 Chinese hamster cells was examined under a variety of conditions. DES over a concentration range 0.01-10 micrograms/ml failed to induce any increase above the spontaneous frequency of 6-thioguanine-resistant V79 cells. The effect of varying the expression time after treatment in the mutation assay from 3 to 9 days was studied and DES was nonmutagenic at all time points, while N-methyl-N'-nitro-N-nitrosoguanidine was highly mutagenic with a peak response after a 5-7 day expression time. The mutagenicity of benzo[a]pyrene and DES, both of which induce morphological and neoplastic transformation of Syrian hamster embryo (SHE) cells, was tested by cocultivating V79 cells with SHE cells for possible metabolic activation of the chemicals. Neither compound was mutagenic to V79 cells in the absence of SHE cells. Benzo[a]pyrene, but not DES, was mutagenic to V79 cells cocultivated with SHE cells. These results support the observation that DES can induce cell transformation under conditions that do not result in any measurable gene mutations. Moreover, the ability of DES to enhance the recovery of 6-thioguanine-resistant mutations was studied by determining the ability of DES to inhibit metabolic cooperation of V79 cells. Unlike the tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate, DES was a weak or inactive inhibitor of metabolic cooperation.

Animals↗

PubMed1991

Dislocation of chromatin elements in prophase induced by diethylstilbestrol: a novel mechanism by which micronuclei can arise.

The in vitro micronucleus test with Syrian hamster embryo (SHE) cells assays the induction of micronuclei by chemical agents. Both chromosome fragments and lagging chromosomes can give rise to micronuclei. Nevertheless, only limited information is available on the ultrastructure of micronuclei and the mechanisms of their formation. Diethylstilbestrol (DES), a non-mutagenic carcinogen, as well as its analogue 3.3'-DES induce micronuclei in SHE cells. A comparison of the dose response of DES-induced micronucleus formation with the previously published ones for aneuploidy and transformation shows that all 3 run in parallel. Thus, a functional relationship between these endpoints, in the SHE system, may be implied. The present study is designed to address the formation of micronuclei using supravital UV microscopy, to test for the presence of defined chromosome domains within micronuclei using immunocytochemistry, and to define aspects of their ultrastructure by electron microscopy. Supravital UV microscopy showed that 3.3'-DES induces displacement of chromosomes/chromatids during prophase/anaphase and formation of micronuclei during cytokinesis. Immunocytochemistry revealed that micronuclei contain, at high frequencies, CREST antibody-reactive kinetochores, indicating the presence of whole chromosomes or centric fragments in these structures. Moreover, transmission electron microscopy showed that micronuclei exhibit ultrastructural details typical of interphase nuclei. Specifically, micronuclei exhibited morphological evidence of a nuclear lamina and segregation of karyoplasm into euchromatic and heterochromatic regions. All micronuclei examined were enclosed by a nuclear envelope of normal morphology and showed nuclear pore complexes. Together the findings provide evidence that DES interferes with the mitotic apparatus as early as prophase, resulting in the formation of micronuclei and, as a consequence, in the loss of chromatids or chromosomes.

4-Nitroquinoline-1-oxide↗

PubMed1994

Handedness in women with intrauterine exposure to diethylstilbestrol.

Completed forms containing the Edinburgh handedness inventory were received from 77 women exposed to diethylstilbestrol (DES) in utero. Laterality scores (LSs; range: -100 to +100) were calculated for each respondent based on the handedness inventory and were compared with LSs from 514 female controls. The handedness distribution in the DES daughters was significantly shifted away from strong righthandedness compared with the handedness distribution in the controls (chi-square = 22.0, P < 0.0001). Possible explanations for the association between handedness and DES exposure are presented, and aspects of handedness measurement are discussed.

Adult↗

PubMed1986

Effect of flutamide (an antiandrogen) and diethylstilbestrol on the reproductive behavior of Japanese quail.

Three experiments were conducted in order to investigate the role of brain androgen and estrogen receptors in sex hormone activated male reproductive behavior in Japanese quail. In Experiment 1, castrated male quail were injected with oil, testosterone propionate (TP), flutamide (FLUT), an androgen antagonist, or TP+FLUT. Males given TP+FLUT, compared with birds receiving TP alone, strutted much less and had smaller proctodeal (foam) glands. Copulation was reduced by FLUT only on the last test day and only on one measure (number of head grabs + mounts). These results suggest that binding of testosterone or one of its metabolites to an androgen receptor is part of the mechanism of TP activated strutting, and therefore that central nervous system androgen receptors are involved in a male reproductive behavior pattern. In Experiment 2, castrated male quail were injected with oil, with 50 micrograms estradiol benzoate (EB), or with 25, 50 or 100 micrograms diethylstilbestrol (DES), a synthetic estrogen that does not bind to androgen receptors. EB but not DES activated copulation to a significant extent. In Experiment 3 male and female quail with photically regressed gonads were given intraperitoneal Silastic implants of DES, estradiol (E) or cholesterol. DES was highly effective at activating male-typical copulation in males and receptivity in both sexes. Thus hormonal interaction with estrogen receptors alone is sufficient for the activation of male-typical as well as female-typical copulatory behavior in this species.

Anilides↗

PubMed1979

A novel fluorinated derivative of diethylstilbestrol.

The synthesis of the diethylstilbestrol (DES) derivative with fluorine atoms present in the positions ortho to the hydroxyl in each ring is described. In vitro studies in a system containing horse radish peroxidase/H2O2 demonstrate extensive oxidation of tetrafluorodiethylstilbestrol to the corresponding dienestrol derivative. Tetrafluorodiethylstilbestrol and DES had comparable in vivo uterotropic activities at a dose of 100 microgram/kg. Competitive binding experiments demonstrated 20-25 fold reduced interaction with the mouse uterine estrogen receptor. This compound may be useful as an experimental estrogen in distinguishing between the biological and toxic effects of DES.

Animals↗

PubMed1979

Ligand properties of diethylstilbestrol: studies with purified native and fatty acid-free rat alpha 1-fetoprotein and albumin.

We report the equilibrium binding parameters for the interactions of the estrogen analogue diethylstilbestrol (DES) with highly purified rat alpha 1-fetoprotein (AFP) and serum albumin preparations. At 25 degrees C and pH 7.4, an association constant (Ka) of about 1.5 X 10(6)M-1 and 2 sites/mole are measured with the DES-AFP system, whereas for the DES-albumin interaction, we find a Ka of approximately 2 X 10(5)M-1 and about 11 sites/mole of protein. The removal of fatty acids from pure AFP causes a reversible 3 fold increase of the number of DES binding sites; the same delipidation procedure applied to albumin slightly diminishes its DES binding parameters. We also demonstrate the capability of DES to displace competitively estradiol-17 beta (E2) from its high affinity sites on the estrophilic rat AFP. Finally, the binding behaviour of the two serum proteins towards the synthetic estrogen is compared to their interaction with the natural hormones. The physiological and pharmacological relevance of these data is discussed.

Animals↗

PubMed1982

Specific cytosol binding of diethylstilbestrol in rat skeletal muscle.

Rat skeletal muscle cytosol proteins bound 3H-diethylstilbestrol (3H-DES). More than 90% of this binding was high capacity and low affinity. Serum albumin accounted for roughly 50-60% of the binding, as evidenced by its precipitation with anti-rat albumin IgG. About half of the binding was distinguishable from albumin and other serum proteins by its precipitation in 40% saturated ammonium sulfate. This material sedimented at 4-5S in high-salt sucrose gradients, and resolved into two components (8S and 4-5S) in low-salt. Following incubation at 23-27 degree C for one hour, 2% of the bound 3H-DES in whole cytosol (approximately 2 fmole/Mg cytosol protein) was retained by DNA cellulose, and was eluted with 0.6 M KCl. This small fraction of the total binding was inhibited by estrogens and DES analogues: estradiol-17 beta, DES, dienestrol, and hexestrol were strong inhibitors; isodienestrol, dimethylstilbestrol, estradiol-17 alpha, estrone, tamoxifen, MER-25, CI-628, and nafoxidine were weak inhibitors; dihydrotestosterone, testosterone, and prednisone did not compete. These observations indicate that specific estrogen-binding sites exist in rat skeletal muscle.

Ammonium Sulfate↗

PubMed1990

Direct radioimmunoassay for diethylstilbestrol in serum.

A radioimmunoassay method for the measurement of diethylstilbestrol directly on 50 microliters of human serum was established using a tritium-labeled radioligand and a double antibody as a separation reagent. The assay was sensitive (less than 0.17 micrograms/L), reproducible (intra-assay and interassay coefficient of variation values, 8.14% and 8.25%, respectively), and accurate (recovery up to 95%). Factors influencing the assay are identified and discussed.

Blood Proteins↗