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PubMed1989

Enzyme immunoassay screening procedure for the synthetic anabolic estrogens and androgens diethylstilbestrol, nortestosterone, methyltestosterone and trenbolone in bovine urine.

Immunoassays are often used for the screening of anabolic residues in edible tissues and excreta (urine, faeces) from inspected animals. Radioimmunoassays have been used for ten years for the determination in biological samples of the main natural and synthetic anabolic estrogens and androgens. In order to simplify the sample preparation and analysis and to reduce the cost, competitive enzyme immunoassays (EIA) were developed for the main synthetic anabolics used illegally in livestock fattening. EIA are based on a competition between the analyte (hormone or metabolite) and the enzyme-labelled hormone for binding to specific antibodies immobilized in wells of a microtitration plate. Two enzymes were evaluated: horseradish peroxidase (HRP) and Bacillus licheniformis beta-lactamase (BLL) using hydrogen peroxide-o-phenylenediamine or benzylpenicillin-starch-iodine as substrates, respectively. The same derivative was used for chemical coupling of the hormone to enzyme (tracer preparation) and to bovine serum albumin to produce specific antibodies in rabbits. Hormone doses that inhibited 50% of the tracer (HRP-hormone) binding to antibody (ID50) were 18, 8, 6 and 11 pg per well for diethylstilbestrol, nortestosterone, methyltestosterone and trenbolone, respectively. These values were lower than those observed in RIA. The reproducibility and accuracy of EIA in urine analysis were similar to those of RIA. Very small amounts of urine were needed (2.5 microliters). This simple method may require less than 2 h. With the BLL-hormone tracer, the enzymatic activity remaining in the wells and hence the hormone content of the sample could be estimated with the naked eye using benzylpenicillin-starch-iodine as substrate.

Animals↗
PubMed2003

Voltammetric investigation of diethylstilbestrol.

In this work electrooxidation of diethylstilbestrol (DES) was investigated by cyclic voltammetry (CV) and differential pulse voltammetry (DPV) using a glassy carbon (GC) electrode. It was statistically shown that both methods could be used for the determination of DES in the concentration range of 2 x 10(-5)-6 x 10(-4) M by CV and 1 x 10(-5)-1 x 10(-3) M in methanol (MeOH) and 4 x 10(-5)-6 x 10(-4) M in acetonitrile (ACN) by DPV and both of the methods could be applied to human serum. A mechanism was proposed about the electrooxidation of this substance.

Diethylstilbestrol↗
PubMedDate not supplied

Hepatic alpha(2u)-globulin mRNA levels and diethylstilbestrol-associated testicular atrophy in rats.

Biosynthesis of alpha(2u)-Globulin (alpha(2u)-g) is under multihormonal regulation. In this study, we investigated histopathologic changes in the testis and hepatic alpha(2u)-g messenger ribonucleic acid (mRNA) levels in male rats after administration of the potent estrogen diethylstilbestrol (DES) at 0. 01, 0.1, or 1 mg/kg/day by gavage for 14 days. DES treatment decreased hepatic alpha(2u)-g mRNA levels in a dose-dependent manner accompanied by atrophic histopathologic changes in the testis. In addition, alpha(2u)-g mRNA levels were lowest in animals with the most marked testicular changes. Hepatic alpha(2u)-g mRNA may be a useful biomarker for the evaluation of endocrine disruption in male rats.

Alpha-Globulins↗
PubMedDate not supplied

Developmental effects of perinatal exposure to bisphenol-A and diethylstilbestrol on reproductive organs in female mice.

Reproductive tract development is influenced by estrogen. The aim of this study was to determine the effects of an environmental estrogenic chemical bisphenol-A (BPA) on prenatal and postnatal development of female mouse reproductive organs. In the prenatal treatment group, BPA or the synthetic estrogen diethylstilbestrol (DES) were given by subcutaneous (s.c.) injections to pregnant mice during gestational days 10-18. Some offspring treated prenatally with 10 and 100 mg/kg bw BPA or 0.67 and 67 microg/kg bw DES were ovariectomized at 30 days and sacrificed at 40 days of age. Vaginal smears were examined in the remaining offspring, then these offspring were mated with normal males. Prenatal exposure to 10 mg/kg BPA reduced the number of mice with corpora lutea compared to sesame oil controls at 30 days, but more than 80% of mice from either prenatally exposed BPA group were fertile at 90 days. Mice exposed prenatally to maternal doses of 67 microg/kg DES were sterile and showed ovary-independent vaginal and uterine epithelial stratification; however, mice exposed prenatally to BPA did not show ovary-independent vaginal and uterine changes. The number of offspring and litter sex ratio from mice exposed prenatally to BPA (10 or 100 mg/kg) or 0.67 microg/kg DES were not different compared to controls. In postnatal treatment group, female mice were given s.c. injections of BPA (15 or 150 microg/pup) or DES (0.3 or 3 microg/pup) for 5 days from the day of birth, then some mice were ovariectomized at 30 days and examined at 40 and 90 days. In the remaining mice, vaginal smears were examined from 61 to 90 days and ovarian histology was evaluated at 90 days. Mice exposed postnatally to 150 microg BPA exhibited ovary-independent vaginal epithelial stratification. Postnatal DES (0.3 and 3 microg) treatment also induced ovary-independent vaginal stratification. Polyovular follicles having more than one oocyte in a follicle were induced by postnatal injections of BPA (150 microg) or DES (0.3 or 3 microg) at 30 days. These findings indicate for the first time that a large dose of BPA can induce ovary-independent vaginal epithelial changes when given postnatally but not prenatally.

Animals↗
PubMedDate not supplied

Low dose effect of in utero exposure to bisphenol A and diethylstilbestrol on female mouse reproduction.

In utero exposure to bisphenol-A (BPA) at doses relevant to human consumption has been reported to accelerate weight gain and puberty in female mice, but the effect of low dose BPA on female reproduction has not been described. In this study, we investigated low dose effects of BPA on sexual maturation and reproduction in female ICR/Jcl mice. Pregnant ICR mice (F0) were injected (s.c.) with BPA (2 and 20 microg/kg), diethylstilbestrol (DES; 0.02, 0.2, and 2 microg/kg) or oil vehicle once per day from gestational days 11-17. For both female and male offspring (F1), body weights were measured on postnatal day (PND) 0 (the day of birth), 11, 22, and 60, and anogenital distance (AGD) was measured on PNDs 22 and 60. Pups were weaned at PND 22 and males were caged separately from females. Vaginal smears were taken daily beginning the day of vaginal opening for 30 days. The age at vaginal opening was significantly earlier in all exposed females except for 2 microg/kg BPA females compared to oil controls. Body weight at vaginal opening was lower than controls in all exposed females. The first vaginal estrus was earlier in all exposed females except for the 2 microg/kg BPA group females compared to controls. From PND 90 to 120, gestationally exposed F1 female mice were mated with unexposed males. Total numbers of pups and sex ratio in F1 mice exposed to BPA or DES, and those of their offspring (F2) were not different from controls in any treatment group. The present results indicate that prenatal exposure to low doses of BPA and DES induces early vaginal opening, but does not affect reproductive functioning at the first breeding.

Animals↗
PubMedDate not supplied

Effects of 4-tert-octylphenol, 4-tert-butylphenol, and diethylstilbestrol on prenatal testosterone surge in the rat.

In the present study, we evaluated the effects that 4-tert-octylphenol (OP) and 4-tert-butylphenol (BP) had on the prenatal testicular testosterone surge at embryonic day (ED) 19.5 in the rat. In utero exposure to alkylphenols (0.1-100 mg/kg maternal weight) on EDs 13.5, 15.5, and 17.5 did not decrease testicular testosterone content, whereas exposure to diethylstilbestrol (DES) caused a significant depression in testosterone synthesis and secretion. The depression was maintained during ex vivo tissue culture. In order to elucidate the observed differences in the in vivo effects between alkylphenols and DES, the exposures were also carried out in tissue culture of intact ED 19.5 testes. Basal testosterone, progesterone, cAMP production and hCG-induced testosterone levels were determined during and after a 3-h culture period. DES (100 mg/l) did not alter testosterone production but caused a two-fold increase in progesterone. OP (10, 100, 500 mg/l) and BP (100 mg/l) significantly increased testosterone and progesterone levels by up to seven-fold. In the presence of BP 100 mg/l, however, the intratesticular testosterone content did not correlate with the significantly increased fraction of secreted, or leaked, testosterone. The latter was correlated with tissue damage observed at electron microscopic level. Consistent with this, BP 500 mg/l elevated testicular testosterone level slightly during the first hour in the culture but the level subsequently returned to the control value. At the electron microscopic level, alkylphenols caused most severe changes in Leydig cell membrane structures and lipid droplets. In the DES-treated testes, membrane vesicle formation around the lipid droplets and increased mitochondrial pleiomorphy were observed. Altogether, the present in vivo and in vitro analyses confirm different effects of alkylphenols and DES on fetal rat steroidogenesis and tissue structure.

Animals↗
PubMedDate not supplied

Genital tract abnormalities in female rats exposed to diethylstilbestrol in utero.

Genital tract morphology in 14-month old female rats exposed prenatally to diethylstilbestrol (DES) was analyzed as part of an examination of the effects of transplacental exposure to DES on estrogen sensitive tissues. Pregnant Sprague-Dawley rats were injected with sesame oil alone or with DES in sesame oil on days 10 and 13 of gestation (total dose 1.2 micrograms DES) or on days 15 and 18 (total dose 1.2 micrograms or 120 micrograms DES). Female offspring (9-15 per group) were sacrificed at 14 months of age. Effects of DES exposure varied with the dose given and with the stage of differentiation of the fetal tissues. In the ovaries of rats exposed to 120 micrograms of DES on days 15 and 18 of gestation, follicular elements were reduced and replaced by dense sheets of stromal cells; oophoritis was noted in five of nine rats. Hypercellularity of oviductal stroma was another common feature, as was suppurative salpingitis. Ovaries of rats exposed to 1.2 micrograms DES on days 10 and 13 of gestation were more likely to contain numerous corpora lutea than the other DES-exposed groups of controls. An increased incidence of benign uterine abnormalities was observed in DES-exposed offspring, including squamous metaplasia and suppurative endometritis. In the cervices of all nine rats exposed to 120 micrograms DES on days 15 and 18 of gestation, the epithelial surface showed a convoluted pattern, lined by stratified squamous and stratified cuboidal cells. Thus, prenatal exposure to DES, especially at the higher dose used, has long-term consequences on reproductive tract morphology in Sprague-Dawley rats.

Abnormalities, Drug-Induced↗
PubMed2000

1,2-Dimethylhydrazine carcinogenesis in CBA male mice prenatally treated with diethylstilbestrol.

CBA female mice, at the 17th day of pregnancy, received single intraperitoneal injection of diethylstilbestrol (DES) at the dose of 1 mg/kg body weight (b. w.). Their descentands at the age of 2 months started receiving subcutaneous injections of 1,2-dimethylhydrazine (DMH) at the dose level of 8 mg(base)/kg b. w., total 15 weekly injections. Prenatal DES treatment of male mice considerably accelerated the development and increased the incidence of DMH-induced androgen-dependent renal adenomas and, notably, renal capsule angiosarcomas (RCA). In males receiving prenatal DES (without subsequent DMH-treatment), there was a statistically significant increase of renal adenomas and 9% of RCA were observed which are exceedinly rare in untreated mice. The enhancement of androgen-dependent tumourigenesis may be considered as an indication, even though indirect, of the hyperandrogenization produced in male mice by the prenatal DES treatment.

1,2-Dimethylhydrazine↗
PubMed2003

Expression of perivitelline membrane glycoprotein ZP1 in the liver of Japanese quail (Coturnix japonica) after in vivo treatment with diethylstilbestrol.

Avian perivitelline membrane, an oocyte extracellular matrix homologous to the zona pellucida in mammals or chorion in fish, is composed of at least two glycoproteins. Previous studies have indicated that one of the components, a glycoprotein homologous to mammalian ZPC, is produced in the granulosa cells of the developing follicles of quail ovary on stimulation with testosterone. However, little is known about the molecular biology of the other component of the avian perivitelline membrane, ZP1, and information about gene expression is particularly lacking. We have cloned the ZP1 in Japanese quail and examined its gene expression. A cDNA encoding quail ZP1 was isolated from the livers of mature females using reverse transcription-polymerase chain reaction (RT-PCR) and rapid amplification of cDNA ends. It encoded a 934-amino acid protein that showed greatest homology (87.8% identity) with the chicken ZP1. RT-PCR amplification indicated that the ZP1 mRNA in the liver was restricted to mature laying females. The expression of ZP1 mRNA was stimulated by in vivo treatment with diethylstilbestrol in immature females as well as males. These results suggested that androgens and estrogens coordinately regulate the formation of quail perivitelline membrane proteins. In addition, the use of ZP1 transcriptional induction in males or immature females as a biological marker of environmental estrogens is discussed.

Amino Acid Sequence↗
PubMed2003

Perinatal exposure to diethylstilbestrol improves olfactory discrimination learning in male and female Swiss-Webster mice.

During late prenatal and early postnatal brain development, estrogen induces structural sex differences that correspond to behavioral differences in certain domains such as learning and memory. The typically superior performance of males is attributed to the action of elevated concentrations of estrogen, derived inside neurons from the aromatization of testosterone. In contrast, female performance appears dependent on minimal estrogenic activity. Rat models of the relationship between hormones and cognitive behavior predominate the field, but the advent of genetically modified mice as research tools necessitates development of analogous mouse models. This study examined how early postnatal exposure to the synthetic estrogen diethylstilbestrol (DES) affected the ability of male and female Swiss-Webster mice to learn a two-choice olfactory discrimination and three repeated reversals. Mice treated with subcutaneous injections of DES from postnatal days 1-10 learned reversals more readily than oil-treated controls, a difference that became evident after repeated testing. DES-exposed males and females learned reversals at a comparable rate, suggesting that early postnatal estrogen exposure does not influence this mode of learning through a sexually differentiated mechanism in mice. An analysis of response patterns during qualitatively different phases of reversal learning revealed that DES-induced improvements probably were not due to greater inhibitory control. Instead, DES appeared to enhance associative ability. Early postnatal estrogen exposure may have the potential to preserve certain cognitive skills in adulthood.

Animals↗
PubMedDate not supplied

Diethylstilbestrol (DES) update: recommendations for the identification and management of DES-exposed individuals.

Diethylstilbestrol (DES) was etiologically linked to clear cell adenocarcinoma of the vagina in 1971. This article reviews on-going research and emerging information relevant to DES-related health risks, thereby enabling women's health care providers to maintain an evidence-based practice for their DES-exposed patients. To accomplish these goals, the Center for Disease Control and Prevention (CDC) has initiated a national education campaign. This article describes the reasons for this new initiative, the target audiences, the DES historical framework (including major studies and findings), and populations that are affected. Clinical steps for the identification and management of the DES-exposed individual and resultant implications for midwifery and women's health practices are reviewed.

Adenocarcinoma, Clear Cell↗
PubMed1986

Effects of diethylstilbestrol, 2,2'-dithiodipyridine, and chloral hydrate on the esterase activity of sheep liver cytoplasmic aldehyde dehydrogenase.

The binding of diethylstilbestrol (DES) to aldehyde dehydrogenase (ALDH) has a very similar effect on the dehydrogenase activity of the enzyme as has modification of the enzyme by 2,2'-dithiodipyridine [Kitson, T.M. (1982) Biochem. J. 207, 81-89]. The latter modification may occur at the site of the esterase activity of the enzyme [Kitson, T.M. (1985) Biochem. J. 228, 765-767]. This suggests that DES might be a competitive inhibitor of the esterase reaction. However, in the absence of oxidized nicotinamide adenine dinucleotide (NAD+) or reduced nicotinamide adenine dinucleotide (NADH), and at low concentrations of substrate (4-nitrophenyl acetate, PNPA), DES is a potent partial noncompetitive inhibitor. It is concluded therefore that DES binds at a site different from the esterase active site and that the enzyme-DES complex retains some ability to act as an esterase. High concentrations of PNPA appear to displace DES from its binding site. In the presence of NAD+, DES is a weaker inhibitor, and in the presence of NADH, DES has very little effect. Esterase activity is enhanced by NADH when PNPA concentrations are high but is inhibited when they are low. The rate of reaction of ALDH with 2,2'-dithiodipyridine is only slightly reduced by DES, suggesting that the site at which thiol modifiers react and the DES binding site are different. When ALDH is modified by 2,2'-dithiodipyridine, it has reduced esterase activity, which declines further as the modified enzyme loses its 2-thiopyridyl label. In the presence of NAD+, chloral hydrate is a simple competitive inhibitor of the esterase reaction.(ABSTRACT TRUNCATED AT 250 WORDS)

2,2'-Dipyridyl↗
PubMed1989

Diethylstilbestrol-linked cytotoxic agents: synthesis and binding affinity for estrogen receptors.

The syntheses of diethylstilbestrol derivatives with a C4 side chain at the double bond bearing various functional and potentially alkylating groups (9-25, 38-40, 43, 44) as well as the coupling product with daunorubicin (41) are described. Derivatives with free phenolic groups show easy isomerization to (Z)-stilbenes and styrenes, which could be minimized with silyl protecting groups. Estrogen receptor binding is decreased by polar groups such as carboxylic acids (10) as well as sterically demanding substituents.

Alkylation↗
PubMed1998

Large-scale synthesis of the catechol metabolites of diethylstilbestrol and hexestrol.

Diethylstilbestrol (DES) and hexestrol (HES) are carcinogenic synthetic estrogens. The major metabolites of these compounds are their catechol derivatives, 3'-OH-DES and 3'-OH-HES. Oxidation of these metabolites leads to the electrophilic quinones, which are presumably involved in the tumor-initiating process. A synthetic route based on the McMurry coupling reaction was developed for the synthesis of 3'-OH-DES. Using commercially inexpensive starting materials, this compound was synthesized in four steps, and the cis and trans isomers were separated and identified. Following the same synthetic route, 3'-OH-HES was synthesized in five steps.

Catechols↗
PubMed1999

Comparative effect of chlormadinone acetate and diethylstilbestrol as promoters in mammary tumorigenesis of rats irradiated with gamma-rays during lactation.

The purpose of this study was to determine the promotional role of estrogen and progestin in the development of radiation-induced mammary tumors. To eliminate the effects of endogenous ovarian hormones on tumor promotion, all rats were ovariectomized immediately after the initiation by irradiation with 2.6 Gy gamma-rays at day 21 of lactation, and were divided into 3 groups. For the control experiment, rats were implanted with a cholesterol pellet 1 month after the irradiation. Only one rat developed a fibroadenoma (4.3% mammary tumor incidence) during the 1 year period of the implantation. In the other two groups, chlormadinone acetate (CMA) to increase progestin level or diethylstilbestrol (DES) to increase estrogenic activity were administered, respectively, as tumor promoters for 1 year. Treatment with CMA did not significantly increase the incidence of mammary tumors as compared with the controls. However, administration of DES resulted in a significantly higher mammary tumor incidence (79.3%) than control treatment. Compared with cholesterol administration, DES treatment caused an increase in prolactin concentration in serum (5-fold), and reduction of estradiol-17beta concentration (22% of control). These results suggest that DES ia a potent effective promoter for tumorigenesis of radiation-initiated mammary cells, but CMA is not. DES may act directly on the irradiated mammary cells by binding to ER, and indirectly by stimulating prolactin secretion from the pituitary glands.

Animals↗
PubMed1999

Randomized trial of diethylstilbestrol vs. tamoxifen in postmenopausal women with metastatic breast cancer. An updated analysis.

One hundred fifty-one postmenopausal women with progressive metastatic breast cancer and no prior hormonal therapy were treated with either diethylstilbestrol (DES) or tamoxifen (TAM). One hundred forty-three eligible patients were followed until death or for a minimum of 14.1 years on the DES arm or 16.7 years on the TAM arm. The overall objective response was 42% for DES and 33% for TAM (p = 0.31) and the median duration of response was 11.8 months for DES and 9.9 months for TAM (p = 0.38). Duration of response and progression-free survival were not found to be significantly different between DES and TAM (p = 0.32 and 0.65, respectively). The median survival was 3.0 years for DES vs. 2.4 years for TAM. The 5-year survival was 35% for the DES arm and 16% for the TAM arm. Survival was significantly better for women on DES than for women on TAM (adjusted p = 0.039). Review of records did not show any difference in pattern of treatment failure or subsequent treatments in the DES and TAM arms. Treatment with DES was more commonly associated with toxicity such as nausea, edema, vaginal bleeding, and cardiac problems, whereas hot flashes were commonly seen with TAM therapy. The initial treatment with DES is associated with increased survival. The basis of this survival advantage is not known. TAM still is the preferred agent in the treatment of metastatic breast cancer, but this trial underscores the fact that estrogens have activity and remain in the armamentarium for treatment of selected patients with metastatic breast cancer.

Aged↗
PubMed2002

Risk of breast cancer in women exposed to diethylstilbestrol in utero: prelimiinary results (United States).

BACKGROUND: A synthetic estrogen, diethylstilbestrol (DES), was widely prescribed to pregnant women during the 1950s and 1960s but was later discovered to be associated with an increased risk of clear-cell carcinoma of the vagina and cervix in female offspring. DES has not been linked to other cancers in female offspring, but studies of other prenatal factors such as twin gestation and pre-eclampsia have indicated that in-utero estrogen levels may influence breast cancer risk. We evaluated the relation of in-utero DES exposure to the risk of adult breast cancer. METHODS: A cohort of 4821 exposed women and 2095 unexposed women, most of whom were first identified in the mid-1970s, were followed by mailed questionnaires for an average of 19 years. Reported cancer outcomes were validated by medical record review. Breast cancer incidence in DES-exposed daughters was compared with cancer incidence in unexposed daughters with use of Poisson regression analysis, adjusting for year of birth, age at menarche, age at first birth, and number of births. FINDINGS: The rate ratio for incidence of invasive breast cancer in exposed versus unexposed women was 1.4 (95% confidence interval (CI) = 0.7-2.6). DES exposure was not associated with an increased risk of breast cancer in women under 40 years, but among women aged 40 and older the rate ratio was 2.5 (95% CI = 1.0-6.3). The rate ratio for the association of DES exposure with estrogen receptor-positive tumors was 1.9 (95% CI = 0.8-4.5). INTERPRETATION: While not statistically significant, the overall 40% excess risk, arising exclusively from the subset of estrogen receptor-positive cases, raises a concern calling for continued investigation.

Adult↗