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PubMed1996

Up-regulation of nuclear IGF-I receptor by short term exposure of stilbene estrogen, diethylstilbestrol.

In the present study we report the novel findings that IGF-I receptors are present in the nucleus based on the evidence from binding assay, detection of receptors by affinity labeling and Western blotting, and localization by immunofluorescence. The level of nuclear IGF-I receptors (nIGF-IRs) almost doubled in stilbene estrogen (diethylstilbestrol, DES) treated hamster kidneys compared to the controls. The binding constants Kd and Bmax of nIGF-IR of controls, 22.1 nM and 6.6 nmol/mg protein, respectively, were changed in response to DES treatment to 5.3 nM and 16.3 nmol/mg protein (P < 0.001), respectively. The enhanced level of IGF-IR in DES-treated nuclei was confirmed by both affinity labeling and Western blotting. These data suggest that IGFs may exert their biological effect through the IGF-I receptor present in the nucleus. Whether the up-regulation of nIGF-IR by exposure to a carcinogenic dose of DES may be a factor in the induction of renal cancer in Syrian hamsters, is not clear.

Animals↗
PubMed1986

Undifferentiated sarcomas induced in Syrian hamsters by subcutaneous injection of diethylstilbestrol.

The carcinogenic effects of weekly subcutaneous injections of dimethylnitrosamine (NDMA: 0.05 of the LD50) and diethylstilbestrol (DES: 1.5 mg/kg body wt) or a combination of both carcinogens were studied in 64 Syrian hamsters. There was no additional tumorigenic effect on NDMA-induced liver tumours in hamsters which received DES treatment prior to NDMA treatment. In contrast to the previously reported DES effects, 72% of the DES-treated hamsters unexpectedly developed undifferentiated sarcomas around the interscapular injection site. This finding suggests a local carcinogenicity of DES, which might not be related to its hormonal effects.

Animals↗
PubMed1987

Ovariectomy of adult mice exposed prenatally to diethylstilbestrol.

Mice exposed prenatally to diethylstilbestrol (DES) were ovariectomized at 5-10 weeks of age, or at 15 months of age. They were maintained to old age and studied for incidence of DES-related pathologic changes. Uterine metaplasia and adenomyosis were not seen after early ovariectomy, but adenomyosis persisted after late ovariectomy. No adenocarcinomas of the genital tract were found in 30 mice ovariectomized early, or in 18 mice ovariectomized at 15 months of age. This result is significantly different from the 14% frequency of genital tract adenocarcinomas reported previously in non-ovariectomized mice of this strain exposed prenatally to DES.

Age Factors↗
PubMed1987

Metabolic activation of diethylstilbestrol by stimulated human leukocytes.

Previous studies have implicated both peroxidases and leukocytes in the metabolic activation of the human carcinogen diethylstilbestrol (DES). Here we demonstrate that DES is converted during the oxidative burst of human leukocytes to reactive protein binding species. Although luminol-dependent chemiluminescence indicated that peroxidase-dependent metabolism was occurring, the protein binding was not inhibitable by azide. This suggested that either peroxidase-mediated metabolism was not responsible for the formation of the reactive protein binding species or that this binding was occurring in a cellular compartment inaccessible to azide. The addition of catalase alone and in combination with superoxide dismutase (SOD) did, however, result in significant inhibition of binding. Hypochlorous acid was also shown to be capable of directly converting DES to protein binding species. These results indicate that a product of the oxidative burst, most likely a highly oxidizing species derived from H2O2, is capable of converting DES to a potentially carcinogenic binding species.

Catalase↗
PubMed1987

Induction of DNA fragmentation and DNA repair synthesis in human and rat hepatocytes by diethylstilbestrol.

The synthetic estrogen diethylstilbestrol (DES), a known human carcinogen, was examined for cytotoxicity, and the induction of DNA damage and repair in primary cultures of human and rat hepatocytes. In both species concentrations of DES ranging from 5.6 to 18 micrograms/ml constantly produced reduction of cell viability and DNA fragmentation in dose-related amounts. However, large individual quantitative differences in the sensitivity to the cytotoxic and DNA-damaging activities of DES were observed among cultures derived from the 5 human donors. DES capability of eliciting DNA-excision repair was weak but statistically significant in both human and rat hepatocytes. Taken as a whole these results contribute to support the hypothesis of a genotoxic mechanism in DES-induced carcinogenesis.

Animals↗
PubMed1988

Vaginal tumors in mice from methylcholanthrene and prenatal exposure to diethylstilbestrol.

To test the hypothesis that mice exposed prenatally to diethylstilbestrol (DES) develop adenocarcinomas due to sensitivity of vaginal and cervical adenosis to carcinogens, sponges impregnated with methylcholanthrene (MCA) were lodged against the cervix and vaginal fornices of 6-month-old strain CD-1 mice exposed prenatally to DES. Only squamous cell carcinomas developed in these mice, but at a significantly higher rate than in MCA-treated mice not exposed prenatally to DES. An adenosquamous carcinoma and a precursor of adenocarcinoma developed in DES-exposed mice with control sponges.

Adenocarcinoma↗
PubMed1988

Vaginal abnormalities in ovariectomized BALB/cCrgl mice after neonatal exposure to different doses of diethylstilbestrol.

Newborn BALB/cCrgl female mice received five daily injections of various doses of diethylstilbestrol (DES), 0.0001-10 micrograms. Mice were killed at 6 days of age or at 4 months after ovariectomy at 40-42 days. Subepithelial nodules of polygonal cells in the upper (Mullerian) vagina during early postnatal life were associated with the later occurrence of ovary-independent persistent stratification with or without cornification in mice treated neonatally with 0.1-10 micrograms DES and thus are a possible predictor of this phenomenon. The thresholds for the induction of ovary-independent epithelial pegs, downgrowths and adenosis (glandular formations) were 0.1 microgram and 0.5 microgram DES/day, respectively.

Age Factors↗
PubMed1990

Growth responses of prostatic epithelial cells from male mice neonatally exposed to diethylstilbestrol in serum-free collagen gel culture.

Growth of anterior and ventral prostatic epithelial cells from mice neonatally exposed to diethylstilbestrol (DES) and from unexposed control mice was compared at different time points in serum-free collagen gel culture. A longer maintenance of the initial plating density (lag in growth) was observed in cultured DES-exposed ventral prostatic cells. Neonatal DES exposure resulted in two colony types: one similar to colonies arising from unexposed cells and one which appears to be non-growing. Keratinization was observed in some DES-exposed anterior prostatic cell colonies. Removal of epidermal growth factor from the serum-free medium significantly decreased growth in 3 of the 4 groups compared with their growth in the complete serum-free medium.

Animals↗
PubMed1991

Postnatal vaginal nodules induced by prenatal diethylstilbestrol treatment correlate with later development of ovary-independent vaginal and uterine changes in mice.

Pregnant ICR/JCL mice were given 4 daily subcutaneous injections of 0.2-2000 micrograms diethylstilbestrol (DES) starting on day 15 of gestation. Offspring of mothers given DES were killed at 1-10 days of age and examined for nodules of enlarged polygonal cells under the epithelium of the Müllerian (upper) vagina. Some offspring were ovariectomised at 30 days and killed at 120 days. The nodules which appeared in the prenatally DES-exposed mice (2-2000 micrograms/day) at 3-7 days were not connected with the epithelium of the sinus vagina and reacted positively to an antibody to epidermal growth factor. Nodule formation may prove to be prodromic of later ovary-independent vaginal changes in the DES-exposed mice. Epithelial stratification (2-2000 micrograms/day) and downgrowths and/or pegs (20-2000 micrograms/day) occurred in vaginae of ovariectomized mice exposed prenatally to DES; however, adenosis-like lesions occurred only in the offspring of mothers given the highest prenatal injections of 2000 micrograms DES. Wolffian remnants and hypospadias (2-2000 micrograms/day) were also encountered in the DES-exposed mice. Ovary-independent stratification of the uterine epithelium (20-2000 micrograms/day) and disorganization of the circular musculature (2-2000 micrograms/day) were also observed in the DES-exposed mice. None of these changes was found in ovariectomised 0.2 micrograms DES-exposed and control mice.

Animals↗
PubMed1992

Evidence of hypothalamic involvement in the mechanism of transplacental carcinogenesis by diethylstilbestrol.

Disruption of hypothalamic sex differentiation in the fetus is one hypothesis to explain female reproductive system anomalies and cancer arising from prenatal exposure to diethylstilbestrol (DES). To further test this hypothesis, breeding performance and behavior were monitored in a colony of mice exposed prenatally to DES, using a schedule previously shown to produce anomalies and cancer of the female reproductive system. Fertility decreased with age more rapidly in DES-exposed females than in control females. DES-exposed females were less accepting of the male than control females. These observations support the hypothesis of abnormal hypothalamic sex differentiation as a basic mechanism in DES transplacental carcinogenesis.

Animals↗
PubMed1992

Altered mammary responsiveness to estradiol and progesterone in mice exposed neonatally to diethylstilbestrol.

Mammary glands from ovariectomised neonatally diethylstilbestrol (DES)-exposed (0.1 microgram daily for the first 5 days of life) mice seem morphologically indistinguishable from those of ovariectomised controls. However, administration of exogenous hormones reveals a differential response. In DES-exposed mice, estrogen implantation resulted in greater incidence of dilated ducts along with greater incidence of dilated ducts along with greater incidence and severity of terminal ductal hyperplasia and greater severity of cystic alveolar adenosis; combined estrogen and progestin treatment resulted in greater severity of terminal duct hyperplasia and less alveolar formation, and progestin treatment resulted in lower incidence and degree of lateral budding. Thus, mammary sensitivity to sex steroids is altered by early exposure of mice to DES.

Animals↗
PubMed1993

Diethylstilbestrol liver carcinogenicity and modification of DNA in rats.

Administration of diethylstilbestrol to female Sprague-Dawley rats at 10 mg/kg body weight daily by gavage for 1 year induced liver adenomas and carcinomas and pituitary adenomas. Using the 32P-postlabeling assay for DNA alterations, at 24 h after administration of a single dose of 100 mg/kg, modified bases were found.

Adenoma↗
PubMed1995

In vivo binding of diethylstilbestrol to nuclear proteins of kidneys of Syrian hamsters.

We demonstrate here that stilbene estrogen (diethylstilbestrol) is converted to nuclear protein binding metabolite(s) both in vitro and in vivo. In vitro reaction of DES with nuclei from hamster liver or kidney in the presence of cumene hydroperoxide or NADPH revealed binding of [3H]DES in nuclear proteins (histones; nonhistones precipitable by 2% TCA, NH2; nonhistones soluble in 2% TCA, NH30). The binding was significantly inhibited by cytochromes P450 inhibitors. In an in vitro system [3H]DES quinone, one of the metabolites of DES, was able to bind to pure nonhistone proteins RNA polymerase and DNA polymerase. The binding of [3H]DES quinone to nonhistones RNA polymerase and DNA polymerase was inhibited by low molecular weight thiols, i.e. glutathione and cysteine, or thiol modifiers, such as n-ethylmaleimide, dithionitrobenzoic acid and hydroxymercuric benzoate. DES and DES metabolites inhibited transcriptional activity. In vivo [3H]DES was able to bind to nuclear proteins of hamster liver, kidneys and testes. The level of in vivo [3H]DES binding to all three types of nuclear proteins (histones, NH2, NH30) in the kidney (target organ) was two or more fold higher than that observed in the liver or testis (nontarget organs). Four nuclear NH30 proteins (mol wts.: 56, 37, 33 and 28 kDa) were irreversibly bound to [3H]DES in vivo. The in vivo binding of [3H]DES to transcriptionally active chromatin NH30 proteins also was observed. The data reported here establish that DES was able to bind to liver or kidney nuclear proteins in vitro, which was catalyzed by nuclear enzymes when fortified with an appropriate cofactor. DES quinone may be one of the protein binding metabolites. DES and DES metabolites inhibited transcriptional activity. The level of in vivo binding of [3H] DES to nuclear proteins of kidney (target organ) was double in comparison with that observed in liver or testis (nontarget organs). In vivo modifications in the chromatin proteins may be a factor in the development of DES-induced renal carcinogenesis is not clear.

Animals↗
PubMed1995

Perturbation of cell cycle kinetics in the mammary gland by stilbene estrogen, diethylstilbestrol (DES).

In the present study we have examined the effect of stilbene estrogen on the proliferative activity, cell cycle kinetics and the differentiation of the mammary gland of female Noble rats. The exposure of animals to stilbene estrogen (diethylstilbestrol) or natural estrogen (estrone) (10 micrograms/24 h) significantly increased proliferation in mammary epithelial cells. Both labeling index and growth fraction were increased by DES or estrone treatment. In addition, both stilbene and natural estrogen exposure altered cell cycle kinetics. Stilbene estrogen exposure to animals increased the conversion of mammary epithelial cells from G0 to G1 and G1 to S-phase cells by 8.3- and 8.5-fold, respectively, compared to that of control. Differentiation measured by the degree of lobular maturation revealed that the conversion of immature structures to mature structures was significantly increased by 2.4-fold in response to DES or estrone exposure compared to that of control. Perturbation of cell cycle is considered as a risk factor for the development of cancer. Changes in proliferation and cell cycle have been shown to lead to genetic instability, ultimately resulting in cell transformation. Our results indicated an increase in labeling index and growth fraction and a perturbation in cell cycle kinetics from DES or estrone exposure. Perturbation of cell cycle in response to stilbene estrogen exposure may produce adverse effects in the mammary glands of the Noble rats.

Animals↗
PubMed1995

Influence of hormonal status in relaxant effect of diethylstilbestrol and nifedipine on isolated rat uterus contraction.

1. The effects of diethylstilbestrol (DES, 10(-7)-10(-5) M) and nifedipine (10(-10)-10(-7) M) on KCl (60 mM)-induced tonic contraction in the uterus of ovariectomized and 17 beta-estradiol (0.1 mg/kg/day, s.c.)-, 17 alpha-estradiol (0.1 mg/kg/day, s.c.)-, or progesterone (2 mg/kg/day, s.c.)-treated rats have been assayed. 2. The dose-dependent relaxation produced by nifedipine in ovariectomized rats (EC50 = 5.59 +/- 1.25 x 10(-9) M) is potentiated in uterus of rats treated with 17 beta-estradiol and progesterone (EC50 = 0.59 +/- 0.1 and 0.49 +/- 0.1 x 10(-9) M, respectively) but not in the 17 alpha-estradiol-treated rats (3.01 +/- 0.6 x 10(-9) M). 3. The relaxation produced by DES on ovariectomized rats (EC50 = 0.84 +/- 0.14 x 10(-6) M) is reduced when the rats are treated with 17 beta-estradiol (EC50 = 2.22 +/- 0.2 x 10(-6)M) or progesterone (EC50 = 1.24 +/- 0.08 x 10(-6) M), but unmodified by 17 alpha-estradiol (EC50 = 0.58 +/- 0.01 x 10(-6) M). 4. The nifedipine-induced relaxation is reversed with Bay K 8644 (10(-10)-10(-6) M) in all experimental conditions. However, Bay K 8644 counteracted the relaxation of DES at 45.7% on ovariectomized rats but this was lower than 30% in the other groups. 5. Our results suggest that in ovariectomized rats the effects of both nifedipine and DES are similar, but 17 beta-estradiol and progesterone produce a contrary effect on the relaxation induced by nifedipine and DES (by increasing the nifedipine and decreasing the DES effects).(ABSTRACT TRUNCATED AT 250 WORDS)

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1985

Diethylstilbestrol, genetics, teratogenesis, and tumor spectrum in humans.

Diethylstilbestrol (DES) is the first example of transplacental carcinogenesis in humans, as evidenced by an excess of clear cell adenocarcinoma of the vagina and cervix in exposed women. We hypothesize that: 1) in utero DES exposure will be responsible for a broader spectrum of cancer with variable age of onset as a function of latency effects in exposed humans of both sexes; 2) teratogenicity of DES will be more far-reaching than currently recognized and will harbor cancer implications in the face of known associations between teratogenesis and carcinogenesis; and 3) genetic heterogeneity will be a critical etiologic discriminant in DES associated cancer. This hypothesis embraces a prodigious body of data at the infrahuman level, as well as extant pharmacogenetic and ecogenetic observations in humans which signify heritable variations in response to environmental carcinogenic exposures. This hypothesis has important implications for drug testing with appropriate preventive strategies. Herein, particular restraints with monitoring through governmental legal channels must be employed. Past experience has clearly indicated negligence in shouldering this responsibility by both the pharmaceutical industry and government regulatory bodies.

Adenocarcinoma↗
PubMed1986

Long-term effects of diethylstilbestrol (DES) on genetically obese and non-obese female Zucker rats.

The long-term effects of diethylstilbestrol (DES) were studied in genetically obese and non-obese female Zucker rats. Experimental animals were implanted subcutaneously with a 15 mg pellet of DES at the beginning of the experiment, and again three months later. Weight-matched control animals received no treatment. Rats were sacrificed 6.5 months after the first implantation. The animals treated with DES had significantly lower body weights at sacrifice than the control rats; the percentage reduction was comparable for the obese and lean animals. Treatment was associated with significant reductions in body length, food intake, water intake and weights of an inguinal fat pad, heart, liver, kidneys and adrenals. In contrast, weight of the reproductive tract and pituitary gland were significantly higher in the treated rats. Effects of DES treatment were comparable in lean and obese rats.

Animals↗