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PubMed1993

Improved thin-layer chromatographic detection of diethylstilbestrol and zeranol in plasma and tissues isolated with alumina and ion-exchange membrane columns in tandem.

Clean-up procedures for the isolation of zeranol and diethylstilbestrol (DES) were modified to reduce the analysis time and to increase the efficiency of purification. Several dyes (Fast Blue BB, Fast Corinth V, Fast Blue RR, Fast Blue B, Fast Red Violet B and Fast Violet B) were evaluated, and their minimum detectabilities were determined. Conditions for non-instrumental, semi-quantitative thin-layer chromatography were optimized. Zeranol and DES in plasma and tissues were determined using modified procedures. Enzyme digestion brought about significant improvement in detectabilities of zeranol and DES in both fortified and incurred plasma, serum and tissues. Minimum detectabilities for zeranol and DES were 25 ppb in fortified plasma and tissues. The amount of incurred zeranol measured in the serum of an experimental cow was increased four times, i.e. from 50 to 200 ppb, after protease digestion. Glucuronidase digestion showed an eight-fold increase in detection of incurred zeranol levels in bovine liver eight times. These results suggest that digestion releases zeranol and DES from protein and glucuronide complexes, thereby allowing detection of low levels of zeranol and DES which may not be detectable without digestion. Further modification of the purification with an ion-exchange membrane reduced the analysis time by 25%, and the membranes were regenerated up to ten times without loss of activity, allowing an automated process. This method utilizes inexpensive equipment and avoids use of organic solvent, in this case diethyl ether.

Aluminum Oxide↗

PubMedDate not supplied

Long-term evaluation of the diethylstilbestrol (DES) syndrome in adult female rhesus monkeys (Macaca mulatta).

This study was designed to examine the transplacental effects of diethylstilbestrol (DES) in rhesus monkeys (Macaca mulatta). Nineteen pregnant females received an approximate human therapeutic dose of 1 mg/day DES beginning on gestational day 21 (Group I), day 100 (Group II), or day 130 (Group III) until term. Colposcopic examination and vaginal biopsies were performed in eight female offspring at 6- and 12-month intervals beginning at 3.5 years of age until death between 5 and 12 years of age. Gross and histological evidence of vaginal adenosis was observed in five of eight (62.5%) females. Adenosis, which occurred in all treatment groups, did not develop into neoplasia; rather, it underwent metaplasia and reversion to squamous epithelium, a frequent observation in human DES cases. The vaginal ridging and/or cervical hooding characteristic of the human syndrome was observed in all exposed females. Although menstrual cyclicity was not impaired, there appeared to be a lower pregnancy rate in treated animals compared to age-matched controls. This long-term evaluation of reproductive morphology and function in the rhesus monkey has provided a useful model for studying the history of benign vaginocervical abnormalities induced by prenatal DES treatment.

Abnormalities, Drug-Induced↗

PubMed1990

Sensitivity to diethylstilbestrol-(DES)-induced abortions is influenced by the Whitten effect.

Group-housed female mice, when introduced to a male, will undergo a synchronized estrous cycle with a characteristic pattern of mating where the majority of animals mate on the third day. This phenomenon is termed the Whitten effect. Exposure of pregnant mice to diethylstilbestrol (DES), a potent nonsteroidal estrogen, is capable of inducing premature parturition. The purpose of this study was to evaluate abortion induced by a single injection of DES on day 15 of gestation and compare the sensitivity depending on the day of mating. Initial observations confirmed that those animals that mated on day 3 were significantly more susceptible to DES-induced abortion than animals that mated on any other day. The possibility that this increase in sensitivity to abortion may be the result of differences in number or size of embryos at the time of DES exposure was examined. No significant difference was observed in the number of embryos at day 4 of gestation, at day 15 of gestation, or at birth. There was no difference in the weight of embryos at day 15 of gestation or at birth. A significant increase in the ratio of embryos between uterine horns was observed in the animals that mated on day 3 (ratio = 2.13) compared to animals mating on other days (ratio = 1.23 to 1.48). The cause of increased sensitivity to DES in animals that mated on day 3 is unclear. Our results may indicate that the induction of ovulation associated with the Whitten effect causes unequal embryo distribution leading to functional differences in sensitivity of the pregnancy to exogenous stimuli.(ABSTRACT TRUNCATED AT 250 WORDS)

Abortion, Spontaneous↗

PubMed1992

Alterations in hypothalamic and pituitary hormone levels induced by neonatal treatment of female mice with diethylstilbestrol.

Neonatal female mice of the NMRI strain were treated with the synthetic estrogen diethylstilbestrol (DES), 5 micrograms daily for the first 5 days after birth, or with vehicle only. Levels of LH and FSH (pituitary and serum) and LHRH (hypothalamus) were measured by radioimmunoassay (RIA) in 6- to 56-day-old females with 6- to 7-day intervals. Compared to controls, DES-treated females had low levels of LH on days 6, 12, and 21 in the pituitary, and on days 6 and 12 in serum; increased LH levels were seen in both the pituitary and serum on day 42. The FSH levels of DES-treated females were decreased on days 6 and 12 in the pituitary and on day 6 in serum; an increased FSH content occurred on day 21 in the pituitary. In the preoptic area and basal hypothalamus of DES-treated females, levels of LHRH were increased on day 21 and decreased on day 42. On day 56, the serum levels of FSH and LH and the hypothalamic content of LHRH were similar in controls and DES females. A second study including both synthetic and natural estrogen was performed in 12-day-old females. Treatment with 10(-2) micrograms DES or lower doses or 5 micrograms estradiol-17 beta (E2) on days 1 to 5 after birth had no depressive effect on serum LH. The hypothalamic-pituitary-ovarian feedback system reacted similarly to ovariectomy and E2 challenge in 15-day-old control and DES-treated females. DES-treated 56-day-old females had a reduced LH response to ovariectomy but increased response to exogenous E2 compared to controls. These results show that neonatal treatment with DES has pronounced effects on the hypothalamic-pituitary system in the developing female mouse, which may be of importance for the altered ovarian function in these females as adults.

Animals↗

PubMedDate not supplied

Effect of testosterone on diethylstilbestrol toxicity and comparison to a recovery study in the rat epididymis and vas deferens.

Effects of diethylstilbestrol (DES) treatment (30 daily i.m. injections) in reproductive function in the male rat were investigated. These functions were evaluated with sperm counts, motility, fertility, morphology, serum testosterone, and a number of biochemical tests in rat epididymis and vasa deferentia. DES treatment resulted in a 15% loss of body weight and a 60 to 90% loss of weight of testes, epididymis, and vas deferens. Sperm parameters and fertility were reduced to nil by DES treatment. Likewise, the majority of the biochemical measures were severely depressed by the DES treatment. In general, the measured parameters were less affected or recovered with either testosterone cotreatment or 60 days of recovery, showing the role of androgen in maintaining functional integrity and metabolism. However, sperm parameters and fertility did not recover with testosterone cotreatment, which differs from withdrawal of treatment.

Animals↗

PubMedDate not supplied

Induction of estrogen receptor and cell division in genital tracts of male mice by neonatal exposure to diethylstilbestrol.

Estrogen receptor (ER) and ER mRNA expression and cell division induced by neonatal diethylstilbestrol (DES) exposure in male C57BL/Tw mouse genital organs were studied using immunohistochemistry, in situ hybridization, and cell counting at metaphase. A single injection of 3 micrograms DES on the day of birth induced ER in both epithelial (E) and stromal (S) cells of the epididymis and the seminal vesicles, in E cells of the ductus deferens, and in S cells of the ductus efferens and the anterior prostate 24 h after the injection. After 5 daily injections of DES, ER was induced in S cells of the ventral prostrate at 5 days of age. The staining intensity of ER increased in E cells of the epididymis and the ductus efferens at 5 days. A single injection of DES induced ER mRNA in both E and S cells of the ductus efferens, the caput epididymis, and the ductus deferens 4 to 12 h after injection of the newborn mice. A single injection of DES stimulated cell division of both E and S cells in the ductus deferens and the epididymis; cell division of S cells of the ductus efferens, the anterior prostate, and the urethra was stimulated 24 h after the injection. After 5 daily injections of DES, cell division was stimulated significantly in E and S cells of the epididymis, the ductus deferens, and the ventral prostate, and in S cells of the seminal vesicle at 5 days. At 30 days of age, mitotic rates were significantly higher in E cells of the seminal vesicles and the epididymides of mice given 5 daily injections of DES.(ABSTRACT TRUNCATED AT 250 WORDS)

Androgens↗

PubMed1996

Self-reported allergy, infection, and autoimmune diseases among men and women exposed in utero to diethylstilbestrol.

Immunotoxicology studies of prenatal or neonatal exposure to diethylstilbestrol (DES) show effects on immune function of the adult animal. Prenatally exposed humans are known to be at increased risk of vaginal adenocarcinoma, but little research has been done to assess immunologic function. A placebo-controlled clinical trial of DES was conducted in the early 1950s. The sons and daughters born to participants of this clinical trial were traced and interviewed about immune-related health problems. Symptom and disease rates for the DES exposed (253 sons and 296 daughters) were compared with rates for the unexposed (241 men and 246 women). DES-exposed men and women reported rates of allergy, infection, and autoimmune disease similar to the unexposed. However, because autoimmune diseases are rare, a larger sample is needed to evaluate further DES-associated risk of autoimmunity.

Adult↗

PubMed1991

Multiple estrogen binding sites in the uterus: stereochemistry of receptor and non-receptor binding of diethylstilbestrol and its metabolites.

Indenestrol A (IA), an oxidative metabolite of the synthetic estrogen diethylstilbestrol (DES), has high binding affinity for estrogen receptor in mouse uterine cytosol but possesses weak biological activity. Racemic mixture of optically active [3H]indenestrol A (IA-Rac) was separated and purified into individual enantiomers on a semi-preparative scale by HPLC with a Chiralpak OP(+) column. The structure-activity relationship was investigated among the [3H]IA enantiomers (IA-R and IA-S) and [3H]DES through direct saturation binding assays using mouse uterine cytosol. Specific binding curves and Scatchard plots were obtained for each [3H]ligand; DES, IA-Rac, IA-R and IA-S. IA-S enantiomer (Kd = 0.67) binds to the estrogen receptor with the same affinity as DES (Kd = 0.71) and four times higher affinity than IA-R (Kd = 2.56). The number of binding sites for IA-S is approximately the same as estradiol, DES and IA-Rac while IA-R binds far fewer sites than the other ligands. Saturation binding assays indicated that [3H]DES and [3H]IA enantiomers exhibited a higher level of non-specific binding to the cytosol receptor compared to estradiol which has a low level of non-specific binding. These binding studies led to the detection of an additional binding component for the stilbestrol compounds in estrogen target tissue cytosol preparations. Sucrose density gradient separation assays under low salt conditions showed that both [3H]DES and [3H]IA compounds bound to the 8S form of the receptor, the same as E2. But, in addition both DES and IA bound to another binding component in 4S region. The binding to the 4S component were partially displaced by the addition of excess unlabeled E2 and DES. Further characterization of the 4S component is described.

Animals↗

PubMed1992

Long-term effects of postnatal exposure to diethylstilbestrol on uterine estrogen receptor and growth.

Diethylstilbestrol (DES) treatment of female rats on postnatal days (PND) 1-5 reduces uterine growth, estrogen receptor (ER) level and gland number by PND 25, while daily DES treatment on PND 1-25 increases uterine growth 4-fold, further reduces ER level and completely suppresses gland formation. We now report the persistence of these effects in adults. By PND 60, uterine weight was 70% of controls in rats injected with DES on PND 1-5 but only 10% of controls in rats injected PND 1-10 or longer. In fact, uterine weights were the same on PND 10 and 60. Uterine gland numbers were reduced to 30% of controls in all DES-treated rats regardless of exposure length; however, luminal and glandular epithelial cell heights were reduced to less than 50 and 70%, respectively, of controls when DES was given on PND 1-25 but not when given on PND 1-5. Ovariectomy 7 days prior to sacrifice on PND 60 reduced uterine weight in controls by 67% and in rats injected with DES on PND 1-5 by 53%, but had no effect in rats injected with DES on PND 1-10. DES exposure at either PND 1-5 or 1-10 lowered ER levels by 35-50% at both 60 and 90 days. Treatment with a high dose of estradiol (E2) 1 week before sacrifice significantly down-regulated ER to the same concentration in all treatment groups at PND 60 and 90. Following E2 treatment, all groups also showed increased uterine weight at PND 60 and 90. These data show there is a short period of development (PND 5-10) in which further DES exposure indirectly inhibits uterine growth.

Aging↗

PubMed1993

Altered patterns of proteins released in vitro from oviductal and uterine tissue from adult female mice treated neonatally with diethylstilbestrol.

Proteins released during incubation in vitro of oviductal and uterine tissues from 8-week-old female NMRI mice treated neonatally with diethylstilbestrol (DES) or vehicle were studied. The objective was to study if neonatal DES treatment altered the patterns of proteins released from the oviduct and uterus, as earlier studies had shown a detrimental effect of the oviductal environment in DES exposed females on early embryo development. In separate experiments nonlabeled and 35S-labeled proteins released from oviductal/uterine tissues during organ incubations were characterized with 1 and 2D gel electrophoresis. The incubation media of both oviducts and uteri from DES females had increased levels of a serum derived nonlabeled protein, identified as apolipoprotein A1. The amount of this protein in the incubation medium was not influenced by previous ovariectomy but increased by in vivo treatment with estradiol, in both ovariectomized controls and DES treated females. Three other unlabeled proteins were consistently found in higher amounts in the incubation media from DES exposed oviduct/uterine tissue, than in incubates of control tissue. In tissue incubates of oviducts from DES females, three synthesized proteins (35 kDa-pl 6.2, 112 and 143 kDa) were released in lower amounts and two in higher amounts (53 kDa-pl 6.6 and 53 kDa-pl 6.8) than in controls. In uterus from DES treated females one labeled protein was released in increased amounts (80 kDa-pl 6.7) and one in decreased amounts (43 kDa-pl 6.6), when compared with controls. In estrogen induced uterine luminal fluid from 8-week-old DES treated females the levels of four proteins (26, 42, 53 and 97 kDa) were increased and two (24 and 32 kDa) were decreased. These results show permanent alterations in levels of secreted proteins in both the oviduct and uterus of adult but neonatally DES treated females, which could be of importance for their poor reproductive performance.

Amino Acid Sequence↗

PubMed1994

Biochemical parameters in the anterior pituitary during the course of tumorigenesis induced by diethylstilbestrol treatment.

Treatment of F344 rats with diethylstilbestrol (DES) for 1-2 months induces a prolactin (PRL)-secreting pituitary adenoma. After 8 weeks of DES treatment, we have shown that the ratio of regulatory subunits of the cAMP-dependent protein kinase (RI/RII) increased in the tumors. Presently we report the variations in RI/RII ratio, pituitary weight, DNA content, serum PRL, nuclear estrogen receptor (E2R) and of ornithine decarboxylase (ODC) activity from the time of DES pellet implantation until 8 weeks. Pituitary weight, DNA content and serum PRL rose significantly at 4 weeks with a maximum at 6-8 weeks, and significantly correlated with each other. E2R and ODC activity increased from week 1 onwards, with a maximum at 2 weeks and decreased at 8 weeks. Both variables showed a positive correlation but neither E2R nor ODC activity correlated with pituitary weight, DNA or serum PRL. Values for RI remained stable with time, but RII decreased progressively. The RI/RII ratio was maintained around unity between 1-4 weeks, increasing to 1.6-2 thereafter. This ratio positively correlated with pituitary weight and DNA. It is suggested that during tumor induction by estrogen in a sensitive strain of rats, growth signals with different time-courses become activated. Increases in pituitary weight and DNA content, indicators of mammotroph hypertrophy and hyperplasia, were preceded by early rises in E2R and ODC activity. Increases in the RI/RII ratio accompanied the adenomatous change, suggesting their role in cell transformation after 6 weeks of estrogen exposure.

Adenoma↗

PubMed2005

Electrochemical behaviors of diethylstilbestrol and its application in pharmacokinetics.

The electrochemical behaviors of diethylstilbestrol (DES) at a glassy carbon electrode were investigated by cyclic voltammetry, linear sweep voltammetry, and differential pulse voltammetry (DPV). Based on these, a sensitive and selective DPV method was developed for determination of DES. The linear response range of DES is 1.0 x 10(-4)-2.0 x 10(-6) mol/L and the detection limit was 8.0 x 10(-8) mol/L. The developed method has been used for the pharmacokinetics of DES in rabbit blood plasma.

Animals↗

PubMed2006

Rapid time-resolved fluoroimmunoassay for diethylstilbestrol residues in chicken liver.

A competitive time-resolved fluoroimmunoassay (TR-FIA) was developed for the determination of diethylstilbestrol (DES) residues in chicken liver. Prior to analysis, the residues were extracted from chicken liver with acetonitrile. The assay could be used in a quantitative or qualitative mode. The limit of detection (LOD) was determined to be 0.05 ngg(-1), and the limit of quantification (LOQ) was less than 0.18 ngg(-1). The intraassay variations were less than 10%, and the interassay variations were from 9.8 to 12.7%. The mean recoveries established at six concentration levels varied from 84.3 to 109.6%, and the coefficients of variation were from 8.3 to 12.4%. The results obtained by the TR-FIA and enzyme-linked immunosorbent assay (ELISA) showed a good correlation. The established TR-FIA was validated for the determination of incurred chicken liver and was confirmed by liquid chromatography and tandem mass spectrometry (LC-MS/MS). This proposed technique could be applied to routine residue analysis.

Animals↗

PubMed2004

The Chinese rare minnow (Gobiocypris rarus) as an in vivo model for endocrine disruption in freshwater teleosts: a full life-cycle test with diethylstilbestrol.

Chinese rare minnow (Gobiocypris rarus), a freshwater teleost, was exposed to diethylstilbestrol (DES) at 0.05, 0.5, 1 and 5 microg/L from fertilized eggs for up to mature period under flow-through condition. Several endpoints that related to development, reproductive fitness and transgenerational effects were evaluated. It was found that body length and body weight were significantly reduced and vitellogenin (Vtg) levels were significantly increased for fish exposed to DES. Histological examination showed that the sex ratios of F0 fish skewed to female and about 2% of the fish exposed to 0.05 microg/L DES developed testes-ova. The reproductive success, as determined from data on egg production, was reduced in female fish exposed to 0.05, 0.5, 1 and 5 microg/L DES. The lowest-observed-effect concentrations (LOEC) for changes of sex ratios, reproductive success and histology alteration of F0 are 0.05 microg/L. In the offspring, transgenerational effects on egg hatching rate, egg fertilization and Vtg levels of juvenile individuals were not observed. However, survival of F1 generation fry significantly declined. The analysis of sex steroid levels revealed a significant decrease of testosterone (T) in the whole body homogenates (WBH) of male progeny and somewhat elevation of estradiol (E2) in the WBH of female offspring. These findings indicate that exposure to DES causes a variety of developmental, reproductive and transgenerational effects.

Animals↗

PubMed2003

Iron and magnesium exchange via the low affinity iron transporter in rabbit erythroid cells-exchange rates and the action of valinomycin, diethylstilbestrol and protein kinase inhibitors.

Evidence was presented previously that rabbit erythroid cells possess a low-affinity Fe2+ transport system which operates via the Na+/Mg2+antiport [Biochim. Biophys. Acta 1282 (1996) 163]. This was investigated further by measurements of Mg2+ efflux as well as Fe2+ uptake by the cells and by examining the inhibitory effects of valinomycin, diethylstilbestrol (DES) and protein kinase inhibitors. Mg2+ efflux and Fe2+ uptake were measured using rabbit reticulocytes and mature erythrocytes incubated in isotonic KCl or NaCl solutions. Both processes were slower in mature cells than reticulocytes. Mg2+ efflux into KCl solution was much lower than into NaCl solution but was stimulated by addition of Fe2+ to the solution. The rate of Fe2+-stimulated Mg2+ efflux closely followed that of Fe2+ uptake in a one-to-one molar ratio. Valinomycin, DES and the protein kinase inhibitors all inhibited Fe2+ uptake from KCl solution. Valinomycin also inhibited Fe2+-stimulated Mg2+ efflux into KCl solution but markedly stimulated the efflux into NaCl. Maximal inhibition of Fe2+ uptake from KCl solution required the presence of K+, Rb+ or Cs+ ions with which valinomycin forms strong complexes. The results could not be explained on the basis of changes in cell membrane potential or cell volume. By contrast, the increase in Mg2+ efflux into NaCl solution produced by valinomycin was accompanied by cell shrinkage and production of a more negative membrane potential, either of which may be responsible for the effect. The inhibition produced by the protein kinase inhibitors indicate that phosphorylation of the transporter or an associated protein by protein tyrosine kinase is probably required to activate the transporter.

Animals↗

PubMed2005

Management of breast cancer in patients prenatally exposed to diethylstilbestrol: are we prepared?

The use of diethylstilbestrol (DES) for high risk pregnancy has exposed millions of mothers to an increased risk of breast cancer, and also resulted in a generation of women with genital tract abnormalities, such as vaginal adenosis. It is still too early to say that exposure to DES will also result in an increased risk of breast cancer in the offspring, though there is some preliminary evidence to support this. The employment of optimal hormonal therapy (for breast cancer) in this special population may be hampered by the fact that agents with oestrogen agonistic activity (such as tamoxifen) may be contraindicated. Though some of the newer hormonal agents, such as the pure anti-oestrogen Fulvestrant and the aromatase inhibitors, could be considered interesting alternatives for postmenopausal patients, their safety in this population has never been evaluated. Finally, the prevalence prenatal exposure to DES may have been underestimated patients diagnosed with breast cancer, though this information might have major implications in their management. We report on the interesting example of a young woman with a history of vaginal adenosis, who was also diagnosed with early breast cancer.

Adult↗

PubMed2005

Analysis of gene expression induced by diethylstilbestrol (DES) in human primitive Mullerian duct cells using microarray.

The Mullerian ducts are strongly influenced by natural estrogen, estradiol (E2) and diethylstilbestrol (DES) in their development. We screened E2 and DES responsive genes using a microarray analysis in human primitive Mullerian duct cell line, EMTOKA cells expressed estrogen receptor (ER) beta. c-myc oncogene and other target genes expression was detected in cells treated by high-dose DES, but ER antagonist ICI 182,780 could not prevent c-myc induction above. Results of our present study suggested the presence of ER independent pathway in oncogenes induction process by high-dose DES treatment in a human primitive Mullerian duct cell line.

Antineoplastic Agents, Hormonal↗

PubMed2004

Vitellogenin in rare minnow (Gobiocypris rarus): identification and induction by waterborne diethylstilbestrol.

Rare minnow (Gobiocypris rarus) is a tiny Chinese carp that has a short life cycle and is easily cultured in the laboratory. In this study, juvenile rare minnows were exposed to waterborne diethylstilbestrol (DES) at 0.05, 0.5 and 5 microg/l in laboratory aquaria. After exposure for 4, 8, 13 and 21 days, juvenile fish were collected and vitellogenin (Vtg) was measured in whole body homogenates. Native and SDS electrophoresis followed by Western blotting were performed for Vtg identification, and a non-competitive ELISA was developed. In the DES exposure groups (0.5 and 5 microg/l DES), Vtg appeared after 4 days, increased significantly after 8 days and reached a maximum on day 13. Further, a significant increase in the hepatosomatic index (HSI) was found in the 5 microg/l DES exposure group after 21 days. These results indicate that rare minnow provides a good model for assessing endocrine disruption by environmental estrogens.

Animals↗