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PubMed1975

Reduction of enzyme efflux from isolated skeletal muscle and heart by diethylstilbestrol.

It was previously shown that the efflux of creatine phosphokinase (CPK) and lactate dehydrogenase (LDH) from isolated mouse gastrocnemius was reduced 20% by a daily dose of 10 mug of diethylstilbestrol (DES) given for 14 or 21 days. The present study was designed to ascertain to what degree increasing doses of DES could suppress the CPK and LDH efflux from isolated skeletal muscle, and if DES affected heart in a similar manner. A total of 36 mice were injected with saline or 20, 100, 250 and 500 mug DES in saline daily for 14 days. The spontaneous efflux of CPK and LDH from the isolated gastrocnemius and heart was then compared in control and treated mice. The reduction in efflux was partially dose-dependent: increasing doses up to 100 mug DES per day, progressively reduced skeletal muscle efflux of CPK to 50% and LDH to 30%; higher doses had no additional effect. LDH efflux from heart was similarly reduced by DES, but over a narrower dosage range. This is the first agent shown to lower the spontaneous enzyme efflux from these two organs. These studies confirm that DES lowers the enzyme efflux from skeletal muscle; and though this effect is dose-related, the efflux could not be completely suppressed. The mechanism responsible for this reduction remains to be determined.

Animals↗

PubMed2002

Mass spectral analysis of PC-SPES confirms the presence of diethylstilbestrol.

INTRODUCTION/OBJECTIVES: PC-SPES is an herbal mixture available over the counter for the treatment of prostate cancer. It was re-called in January 2002 due to alleged contamination with warfarin. Other laboratories, including our own, claim that the potent synthetic estrogen, diethylstilbestrol (DES) which has been used for many years to treat hormone dependent prostate cancer, could be detected in the herbal mixture. Recent clinical studies report objective responses in men with hormone dependent and naïve prostate cancer, and also describe isolated cases of estrogenic side effects. A lack of effective conventional treatments for advanced hormone refractory prostate cancer has led to a widespread use of PC-SPES by patients across the North America continent. The presence of DES in PC-SPES might explain both clinical response and observed side effects in men taking 6-9 capsules per day. METHODS: We tested five batches of commercially available PC-SPES using gas chromatography (GC) and high performance liquid chromatography (HPLC) upon methanolic extraction. Duplicate aliquots were tested for each batch and the results compared to standard curves generated using DES (99% purity). RESULTS AND CONCLUSIONS: We detected significant levels of DES in three out of five tested batches. The presence of a synthetic steroid in PC-SPES is not likely to have occurred as a result of its extraction from a herbal source. The implications of this finding highlight the necessity of regulated quality control and standardization of natural health products.

Chromatography, Gas↗

PubMedDate not supplied

Diallyl sulfide inhibits diethylstilbestrol-induced lipid peroxidation in breast tissue of female ACI rats: implications in breast cancer prevention.

Diallyl sulfide (DAS) is a component of garlic and prevents cancer in several animal models in various organs. The chemopreventive effects of DAS are attributed to modulation of enzymes to alter the bioactivation of xenobiotics. Diethylstilbestrol (DES) is a synthetic estrogen that causes breast cancer in female ACI rats subsequent to metabolism with concurrent free radical production. This study assessed the effect of DAS on DES-induced reactive oxygen species (ROS) using lipid peroxidation as an empirical endpoint. We have demonstrated that acute exposure to DES results in a significant increase in lipid hydroperoxides (LPH) in breast tissue and DAS attenuated DES-induced LPH concentrations. Two-week exposure to DES caused significant increases in LPH concentrations in breast and liver tissues. DES-induced LPH concentrations were decreased by coadministration of DAS at this time point. There were no statistical differences in the concentrations of LPH in breast and liver tissues of rats treated for 4/6 weeks with DAS/DES. These results demonstrate that DAS inhibits the production of ROS which suggests that DAS effectively inhibits DES bioactivation in female ACI rats which may have implications for chemopreventive intervention strategies. Our results suggest that garlic consumption might be useful for the prevention of human breast cancers.

Allyl Compounds↗

PubMed2003

Exposure of neonatal rats to diethylstilbestrol affects the expression of genes involved in ovarian differentiation.

Exposing neonatal rats with the synthetic estrogen, diethylstilbestrol (DES), induces morphological and functional abnormalities in the adult ovary. We examined the events that lead to this condition using female rats that were exposed to DES for the first five days after birth. The expression of steroidogenic acute regulatory protein (StAR) and cholesterol side-chain cleavage cytochrome P450 (P450scc), which are both required for steroidogenesis in the theca/interstitial region was markedly reduced. The expression of Mullerian inhibiting substance (MIS) was transiently increased in small growing follicles in the ovary of DES-treated rats at postnatal day 7 (P7), and the expression profile in the ovary differed between DES- and vehicle oil-treated rats at P14 and P21. The expression of the transcription factor, steroidogenic factor-1 (SF-1), reduced in theca/interstitial cells, but increased in granulosa cells of primary follicles. These results indicate that altered steroidogenesis and MIS production are mechanisms through which DES induces abnormal ovarian development, and support the notion that androgens and MIS are both critical factors in regulating early ovarian differentiation.

Analysis of Variance↗

PubMedDate not supplied

Testing of cyclophosphamide and diethylstilbestrol for their ability to enhance virus survival in normal human cells.

A relatively simple assay for determining the capability of chemicals to induce the reactivation of UV-irradiated pseudorabies virus in human embryo cells is presented. Using this assay cyclophosphamide (CP) and diethylstilbestrol (DES) were tested in the presence and in the absence of exogenous metabolizing system. N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) was used for comparison. CP increased the survival of UV-irradiated pseudorabies virus exclusively in the presence of exogenous metabolizing system. In the cells pretreated with CP or MNNG the survival of the virus was dependent on time interval between host cell pretreatment and virus infection. No enhancement of virus survival was obtained in the cells pretreated with DES.

Animals↗

PubMedDate not supplied

Effects of neonatal exposure to diethylstilbestrol on protein expression by vagina and uterus in mice.

Neonatal treatment of female mice with diethylstilbestrol (DES) results in genital tract abnormalities including ovary-independent vaginal proliferation and cornification. Protein profiles were examined in vagina and uterus from 45-day-old, ovariectomized C57BL/Tw mice which had been given 5 daily injections of 2 micrograms DES or oil vehicle alone from the day of birth, and in those from 45-day-old, ovariectomized mice given 3 daily injections of 0.1 microgram DES from 42 days of age. Proteins extracted were analyzed by two-dimensional polyacrylamide gel electrophoresis. In the vagina, expression of 37 non-keratin proteins was altered by postpubertal injections of DES as compared with the controls. In the neonatally DES-exposed vagina, expression of 26 of 37 proteins was altered as compared with controls. In the uterus, expression of 22 proteins was altered in the postpubertally DES-exposed group as compared with that in the control; however, the protein expression pattern of the neonatally DES-exposed group closely resembled that of the control except for one protein (no. 23, pI = 6.1, MW = 39.5 kDa) which was specifically increased in the neonatally DES-exposed group. By immunoblot analysis, 6 keratin polypeptides (49.5, 50, 52, 53, 57 and 58 kDa) were identified in vaginae of ovariectomized mice exposed neonatally and postpubertally to DES and of the controls. These results indicate that neonatal DES exposure induces organ specific alterations in the synthesis of proteins in mouse vagina and uterus.

Animals↗

PubMedDate not supplied

Effects of postpubertal treatment with progesterone on protein expression in the vagina and uterus of mice exposed neonatally to diethylstilbestrol.

Postpubertal progesterone injections slightly inhibited the proliferation and cornification of the vaginal epithelium induced by neonatal injections of diethylstilbestrol (DES). In vaginae of neonatally DES-exposed mice (DES mice), 9 protein expressions (PEX) appeared newly; 13 PEX decreased; 5 PEX increased compared to those in the controls. In vaginae of DES mice, PEX were altered by postpubertal injections of progesterone (DES-P); 3 PEX disappeared; 11 PEX were reversed to those in the controls. Progesterone injections impaired the proliferation of the vaginal epithelium, reversing 11 PEX compared to those in DES mice. In uteri of DES-P mice, 3 PEX increased, 2 PEX decreased, 2 PEX appeared and 1 PEX disappeared compared to those in DES mice. In conclusion, it was shown that postpubertal injections of progesterone alter the protein expression in the vagina and uterus of DES mice.

Animals↗

PubMed2003

Effect of diethylstilbestrol on polyamine metabolism in hamster epididymis.

AIM: To investigate the effect of diethylstilbestrol (DES), one of the most potent endocrine disruptors, on the metabolism of polyamines in hamster epididymis. METHODS: Male golden hamsters of 7-week-old were kept under a light and dark cycle of 14 h and 10 h for 1 week to stimulate maximally the gonadal function. DES was injected subcutaneously at doses of 0.01 mg . kg(-1) . day(-1), 0.1 mg . kg(-1) . day(-1) and 1 mg . kg(-1) . day(-1) for one week. RESULTS: DES treatment caused a significant decrease in the weight of epididymis. The activity of epididymal ornithine decarboxylase (ODC) increased 1 day after DES treatment, kept at a high level for 4 days and then decreased to nearly normal level at day 7. The activity of spermidine/spermine N1-acetyltransferase (SSAT) also increased transiently after DES treatment. The contents of putrescine, spermidine, spermine and N(1)-acetylspermidine were increased 1 day approximately 4 days after DES treatment and restored to normal at day 7. All these changes showed a marked difference between the caput and the cauda. CONCLUSION: The polyamine biosynthesis in the hamster epididymis can be affected by DES, a xenoestrogen. DES may probably affect polyamine metabolism in the epididymis by regulating the rate-limiting enzymes involved in the polyamine biosynthesis.

Acetyltransferases↗

PubMed1977

Induction of urogenital anomalies and some tumors in the progeny of mice receiving diethylstilbestrol during pregnancy.

Pregnant mice were given a single dose (10 mug/g body weight) of diethylstilbestrol (DES) on Days 7 to 19, which correspond to the first to fifth lunar months in humans, after the authors, using a 14C-labeled compound, confirmed easy placental penetration by DES. Treatment with DES on Days 15 to 19 resulted in the induction of persistent urogenital sinus (15.8 to 92.5%) and hypertrophy of the portio vaginalis (11.8 to 73.3%) in female offspring, and treatment on Days 17 and 19 resulted in the induction of undescended testes and their hypogenesis (70.4 to 73.3%) in male offspring, although treatment with DES at other stages of pregnancy and after birth did not cause these alterations. The incidence of various tumors (lung adenoma, granulosa cell tumor, etc.) increased significantly (31.0 to 37.9%) when DES was given on Days 15 and 17, which correspond to the stage sensitive to other carcinogens. However, adenosis and adenocarcinoma of the vagina were not observed in the offspring.

Abnormalities, Drug-Induced↗

PubMed2003

Effect of diethylstilbestrol on Ca2+ handling and cell viability in human breast cancer cells.

In human breast cancer cells, the effect of the widely prescribed estrogen diethylstilbestrol (DES) on intracellular Ca2+ concentrations ([Ca2+]i) and cell viability was explored by using fura-2 and trypan blue exclusion, respectively. DES caused a rise in [Ca2+]i in a concentration-dependent manner (EC50 = 15 microM). DES-induced [Ca2+]i rise was reduced by 80 % by removal of extracellular Ca2+. DES-induced Mn(2+)-associated quench of intracellular fura-2 fluorescence also suggests that DES induced extracellular Ca2+ influx. In Ca(2+)-free medium, thapsigargin, an inhibitor of the endoplasmic reticulum Ca(2+)-ATPase, caused a monophasic [Ca2+]i rise, after which the increasing effect of DES on [Ca2+]i was greatly inhibited. Conversely, pretreatment with DES to deplete intracellular Ca2+ stores totally prevented thapsigargin from releasing more Ca2+, whereas ionomycin added afterward still released some Ca2+. These findings suggest that in human breast cancer cells, DES increases [Ca2+]i by stimulating extracellular Ca2+ influx and also by causing intracellular Ca2+ release from the endoplasmic reticulum. Acute trypan blue exclusion studies suggest that 10-20 NM DES killed cells in a time-dependent manner.

Antineoplastic Agents, Hormonal↗

PubMedDate not supplied

Estrogen receptor expression in the genital tract of female mice treated neonatally with diethylstilbestrol.

The distribution of the estrogen receptor (ER) was investigated immunohistochemically in the genital tract of 0 (day of birth)--to 50-day-old C57BL/Tw female mice given 5 daily injections of 2 micrograms diethylstilbestrol (DES) from the day of birth using an anti-ER monoclonal antibody. In the oviduct, cervix and vagina of control mice, both epithelial and stromal cell nuclei showed positive ER immunoreaction at 0 day. Nuclei of uterine stromal cells also showed strong ER immunostaining even at 0 day. In contrast, the ER in uterine epithelial cells began to appear by day 5. The number of positive epithelial cells and staining intensity gradually increased until 10 days. In neonatally DES-exposed mice, ER appeared in uterine epithelial cells 24 h after the injection. Polygonal cells appearing in the vaginal epithelium of DES-exposed 3-day-old mice showed weak ER staining. Neonatal DES exposure reduced staining intensity of columnar vaginal epithelial cells and uterine stromal cells at 3 days. Vaginal epithelial cells undergoing ovary-independent stratification and cornification in neonatally DES-exposed mice and normal estrous mice showed ER immunoreaction only in the basal cells.

Animals↗

PubMed2004

Effect of prenatal exposure to diethylstilbestrol on gubernacular development in fetal male mice.

AIM: To study the effect of prenatal exposure to diethylstilbestrol (DES) and the role of actin and proliferating cell nuclear antigen (PCNA) on testicular gubernaculum development in fetal male Kunming mice. METHODS: Pregnant mice were randomly assigned to 6 groups and injected with DES subcutaneously from gestational day 9 (E9) to day 17 (E17) at doses of 0, 25, 50, 100, 200 microg.kg-1.d-1 in 0.2 mL dimethyl sulfoxide (DMSO). On E17 they were sacrificed and fetuses quickly removed for fixation. Male fetuses were sliced on serial coronal plane. Histological changes were observed under the light microscope (LM) and ultrastructural changes with the scanning and transmission electron microscopes (SEM and TEM). The expression intensity of actin and PCNA in the gubernacula was quantitated by immunohistochemistry. RESULTS: The mortality of the fetuses was higher in the DES-treated groups than that in the DMSO and saline controls (P<0.05). Under LM the gubernacula were seen to be poorly developed with smaller bulbs. On SEM the bulbs lose the clear demarcation between the mesenchymal inner core and the muscular outer layer and looked like a small cone instead of the normal cylindrical appearance. On TEM there were some smaller disordered myofibrils and sparse cytoplasmic organelles in the gubernacular muscular cells of the treated groups. The expression intensity of actin and PCNA in the gubernacula was significantly weaker in the treated groups than that in the DMSO and saline controls (P<0.05). CONCLUSION: DES induces underdevelopment of the gubernacula in a dose-dependent manner in fetal male mice and down regulates the actin and PCNA expression.

Animals↗

PubMed2004

[Diethylstilbestrol-induced uterine sarcoma in mice].

Female mice of CBA strain received diethylstilbestrol (DES) 1 g body weight intraperitoneally. High incidence of histiocytic uterine sarcoma was observed in parents (25%), first generation (F1), descendants (10.9%), and generation F2m (through F1 males mated with females in control) (17.8%). Morphologically, tumor cells examined through light and electron microscopy were referred to as histiocyte-like elements. Half of the animals had metastases in the liver, kidneys, lungs, spleen, pineal and adrenal glands and stomach. The development of tumors in generation F2m, which was not exposed to DES, might be accounted for by "transgeneration" carcinogenesis, i.e. passage of carcinogenic effect through a generation.

Animals↗

PubMedDate not supplied

Permanent induction of morphological abnormalities in the penis and penile skeletal muscles in adult rats treated neonatally with diethylstilbestrol or estradiol valerate: a dose-response study.

This study evaluated the effects of neonatal exposure to different doses of diethylstilbestrol (DES) or estradiol valerate (EV) on penile morphology, penile skeletal muscles, and fertility. Male pups received DES or EV at a dose of 10 microg, 1 microg, 100 ng, 10 ng, or 1 ng per rat on alternate days from postnatal days 2-12. Fertility was tested at 120 days, and tissues were examined at 150 days. Generally, DES and EV induced similar effects within the 10- and 1-microg groups. Fertility was reduced to 0; the weight, length, and diameter of the penis and the weight of penile skeletal muscles, especially bulbocavernosus muscle, were decreased (P <.05) in a dose-dependent manner; the preputial sheath was partially released or its release was delayed; testicular descent was delayed; and the cavernous spaces and smooth muscle cells in the corpora cavernosa penis were replaced by fat cells. Conversely, all of the above parameters were similar in controls and the lower dose groups, except in the 100-ng DES group, in which 4 of 7 males did not sire pups (compared with 1 of 7 in controls and 2 of 6 in the 100-ng EV group). The loss of fertility in these 4 males of the DES group and 1 male of the EV group was associated with partial release of the preputial sheath and abnormal penile morphology. Plasma testosterone was reduced (P <.05) in the 100-ng and higher dose groups for DES and EV. Hence, neonatal exposure to DES or EV at a cumulative dose of 600 ng per rat or more lowers fertility, which is associated with permanent alterations in penile morphology and penile skeletal muscles and decreased testosterone.

Animals↗

PubMed2005

Effects of single administration of diethylstilbestrol on murine langerhans cells.

Diethylstilbestrol (DES) is a synthetic compound with potent estrogenic actions useful in the treatment of prostate carcinoma despite the fact that it can also induce some forms of neoplasia. Both effects are thought to be related to its estrogenic actions and very little attention has been focused on the possible effect of DES on the immune response. Skin is the largest organ of the body and constitutes the first line of defense against xenobiotics. The Skin Immune System (SIS) has become the center of attention of research for the development of new therapeutic approaches for neoplasic diseases. Langerhans cells (LC), as an element of SIS, are "professional" antigen presenting cells resident in the skin that participate in the immune response associated with tolerance and acquired immunity to antigens. Hence in this work we studied the effect of DES on LC of murine skin as a model to analyze the possible effect of DES on the immune response. Male CD-1 mice (20 to 35 g body weight) were treated topically (TO) or subcutaneously (SC) with DES (10 and 100 mg/kg, dissolved in ethanol) and sacrificed at 12, 84 and 228 hr. LC were quantified in the ear skin of mice using both an enzymatic histochemical technique to demonstrate ATP-ase activity; and an indirect immunohistochemical assay for detecting class II molecules of the major histocompatibility complex (MHC-II). DES induced a significant time- and dose- dependent reduction in the number of LC (P < 0.05). Data presented here suggest that estrogens may exert a modulatory action on LC.

Adenosine Triphosphatases↗

PubMed2005

[Vagina cancer in a young woman exposed to diethylstilbestrol: case report and literature review].

We analyzed a 20 year-old patient case exposed in utero to diethylstilbestrol, as probably predisposed factor in vaginal cancer. The histopathological report of the incisional biopsy was clear cell vaginal adenocarcinoma, stage III, widespread to the pelvic wall, with metastasis to regional lymph nodes, and lack of distant metastasis. We decided surgical management: protocolized laparotomy, peritoneal washing, retroperitoneal node biopsies and a radical hysterectomy, Piver III, with two thirds parts of vagina. By poor prognosis we decided to offer an adjuvant management, with systemic chemotherapy.

Adenocarcinoma, Clear Cell↗

PubMed1991

In vitro effects of estradiol, diethylstilbestrol and tamoxifen on testosterone production by purified pig Leydig cells.

The direct effects of estradiol-17 beta (E2), diethylstilbestrol (DES) and tamoxifen on testicular testosterone production by purified immature pig Leydig cells in vitro were studied. Leydig cells were obtained from 3-4 weeks old piglet testes by enzymatical dispersion followed by discontinuous Percoll gradient centrifugation. Leydig cells were treated with E2, DES, and tamoxifen in the absence or presence of LH after 12 h of incubation. Media were collected 48 h later for testosterone and cAMP measurement. E2 did not affect basal testosterone production. When Leydig cells were incubated with increasing concentrations (0.001-10.0 micrograms/ml) of E2, DES, or tamoxifen for 48 h, LH-stimulated testosterone production was reduced. The degree of this reduction was dependent on E2, DES, and tamoxifen, and a concentration of E2 and DES and tamoxifen higher than 100 ng/ml and 10 ng/ml was needed, respectively. DES and tamoxifen also reduced LH-stimulated cAMP formation. When equal concentrations of DES and tamoxifen were added concomitantly to Leydig cells, the inhibition was additive, indicating that tamoxifen does not prevent the inhibitory effects of DES. Forskolin, an activator of adenylate cyclase, stimulated testosterone production to an extent comparable to that attained with LH, and DES and tamoxifen reduced forskolin-stimulated testosterone production. DES and tamoxifen suppressed the conversion of exogenous pregnenolone and progesterone to testosterone, but did not affect the conversion of 17 alpha-hydroxyprogesterone to testosterone, suggesting a specific inhibition of 17 alpha-hydroxylase. These results suggest that E2, DES, and tamoxifen directly inhibit immature pig Leydig cell steroidogenesis, at least in part via an inhibition of cAMP formation and a decrease in the activity of 17 alpha-hydroxylase.

17-alpha-Hydroxyprogesterone↗

PubMed2006

Anticlastogenic action of vitamin C against genotoxicity of estrogenic drug diethylstilbestrol (DES) in the human lymphocyte chromosomes.

Several sex steroids and estrogenic drugs are genotoxic in varying conditions and cause oxidative stress, which has been a field of interest to study the molecular mechanism of the genetic damage. Among the estrogenic drugs, a strong toxic effect is exerted by diethylstilbestrol (DES). In the present study it has been attempted to study its genotoxic effects in human lymphocyte assay system along with ameliorative or anticlastogenic effects of vitamin C. The drug was used with different dosage of concentrations on human lymphocytes administered in vitro. The parameters used were Sister Chromatid Exchanges (SCEs) and Chromosomal Aberrations (CAs). Higher levels of clastogeny and SCEs have been observed indicating significant damaging effect by the drug. Interesting ameliorating effects were observed in the presence of vitamin C which is a well-known antioxidant. The results support the possibility of practical application of natural protectors against the mutagenic/oenotoxic action of chemical mutagens.

Ascorbic Acid↗