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PubMed1997

Hydroperoxidative oxidation of diethylstilbestrol by lipoxygenase.

The oxidation of diethylstilbestrol (DES), a synthetic carcinogenic estrogen, by the hydroperoxidase activity of lipoxygenase was studied. Lipoxygenase catalyzes the oxidation of DES to its corresponding DES quinone to yield free radical species intermediates (DES semiquinone and DES quinone), which are associated with the adverse effects of this synthetic estrogen. The reaction was dependent on enzyme, DES, and hydrogen peroxide concentrations. Due to the low degree of water solubility of DES, the enzyme works in a range of DES concentrations below K(m). The enzyme presents a high affinity for hydrogen peroxide (5.7 microM), and produces substrate inhibition (Ksi = 2.5 mM). This study is the first demonstration that this reaction, which is known to be catalyzed by a variety of enzymes, including peroxidases, is also catalyzed by lipoxygenase.

Benzoquinones↗

PubMed1998

Abdominal B (AbdB) Hoxa genes: regulation in adult uterus by estrogen and progesterone and repression in müllerian duct by the synthetic estrogen diethylstilbestrol (DES).

Mice deficient for the Abdominal B (AbdB) Hox gene Hoxa-10 exhibit reduced fertility due to defects in implantation. During the peri-implantation period Hoxa-10 is sequentially expressed in the uterine epithelium and stroma. These observations, combined with the stringent regulation of uterine implantation by ovarian steroids, prompted us to test whether estrogen and progesterone directly regulate the expression of Hoxa-10 and other AbdB Hoxa genes. Here we show that Hoxa-10 expression in the adult uterus is strongly activated by progesterone. This activation is blocked by the progesterone receptor antagonist RU486 and is independent of new protein synthesis. In addition, Hoxa-10 expression is repressed by estrogen in a protein synthesis-independent manner. Analysis of adjacent AbdB Hoxa genes reveals that Hoxa-9 and a-11 are also activated in a colinear fashion by progesterone but differentially regulated by estrogen. These results suggest that the regulation of AbdB Hox gene expression in the adult uterus by ovarian steroids is a property related to position within the cluster, mediated by the direct action of estrogen and progesterone receptors upon these genes. We next examined whether the embryonic expression of Hoxa10 is regulable by hormonal factors. Previous work has demonstrated that perinatal administration of the synthetic estrogen diethylstilbestrol (DES) to mice and humans produces uterine, cervical, and oviductal malformations. Certain of these phenotypes resemble those in Hoxa-10 knockout mice, suggesting that Hoxa-10 gene expression might be repressed by DES during reproductive tract morphogenesis. Exposure of the developing female reproductive tract to DES, either in vivo or in organ culture, represses the expression of Hoxa-10 in the Müllerian duct. Thus, these data not only establish a direct link between ovarian steroids and AbdB Hoxa gene expression in the adult uterus, but also provide a potential mechanism for the teratogenic effects of DES on the developing reproductive tract.

Animals↗

PubMed2001

Estrogen receptor-alpha knockout mice exhibit resistance to the developmental effects of neonatal diethylstilbestrol exposure on the female reproductive tract.

Data indicate that estrogen-dependent and -independent pathways are involved in the teratogenic/carcinogenic syndrome that follows developmental exposure to 17beta-estradiol or diethylstilbestrol (DES), a synthetic estrogen. However, the exact role and extent to which each pathway contributes to the resulting pathology remain unknown. We employed the alphaERKO mouse, which lacks estrogen receptor-alpha (ERalpha), to discern the role of ERalpha and estrogen signaling in mediating the effects of neonatal DES exposure. The alphaERKO provides the potential to expose DES actions mediated by the second known ER, ERbeta, and those that are ER-independent. Wild-type and alphaERKO females were treated with vehicle or DES (2 microg/pup/day for Days 1-5) and terminated after 5 days and 2, 4, 8, 12, and 20 months for biochemical and histomorphological analyses. Assays for uterine expression of the genes Hoxa10, Hoxa11, and Wnt7a shortly after treatment indicated significant decreases in DES-treated wild-type but no effect in the alphaERKO. In contrast, the DES effect on uterine expression of Wnt4 and Wnt5a was preserved in both genotypes, suggesting a developmental role for ERbeta. Adult alphaERKO mice exhibited complete resistance to the chronic effects of neonatal DES exposure exhibited in treated wild-type animals, including atrophy, decreased weight, smooth muscle disorganization, and epithelial squamous metaplasia in the uterus; proliferative lesions of the oviduct; and persistent vaginal cornification. Therefore, the lack of DES effects on gene expression and tissue differentiation in the alphaERKO provides unequivocal evidence of an obligatory role for ERalpha in mediating the detrimental actions of neonatal DES exposure in the murine reproductive tract.

Abnormalities, Drug-Induced↗

PubMed2000

Effect of diethylstilbestrol on thyroid hormone binding to amphibian transthyretins.

Transthyretin (TTR) is responsible for a major part of the binding of thyroid hormone to proteins in the plasma in amphibian tadpoles. To characterize the binding properties of amphibian TTRs, the effects of 17 hydrophobic signaling molecules, including 6 endocrine disruptors, on 3,5,3'-l-[(125)I]triiodothyronine ([(125)I]T(3)) binding to plasma proteins were examined in bullfrog Rana catesbeiana tadpoles. T(3) was the most potent competitive inhibitor among the 11 natural biological ligands studied, with an ID(50) of 8 nM. Diethylstilbestrol (DES) was the most powerful inhibitor among the 6 endocrine disruptors studied, with an ID(50) of 20 nM. Similar inhibitions of [(125)I]T(3) binding by these compounds were obtained when purified recombinant Xenopus and Rana TTRs were analyzed. Scatchard analysis revealed that Xenopus and Rana TTRs each possessed a single class of binding site for T(3), with a K(d) of 262 and 1.9 nM, respectively, at 0 degrees C. DES, at a concentration of 200 nM, induced the uptake of [(125)I]T(3) into Rana red blood cells suspended in Rana plasma from prometamorphic stages XIII-XV, when TTR is present in plasma. DES induced the uptake of [(125)I]T(3) into red blood cells to a lesser extent when they were suspended in Rana plasma from metamorphic climax stage XXIV, in which the level of TTR was lower than in plasma from the prometamorphic tadpoles. These results indicate that amphibian TTRs have the ability to bind DES with similar affinity to T(3), the natural ligand, and raise the possibility that DES binding to TTR might induce the temporary elevation of the free concentration of plasma T(3) followed by acceleration of cellular T(3) uptake.

Animals↗

PubMed2000

Localization of immunoglobulin G gamma-chain mRNA-expressing cells in the oviduct of laying and diethylstilbestrol-treated immature hens.

The purpose of this study was to determine the synthetic sites of IgG in the chicken oviduct by localizing IgG gamma-chain mRNA (IgGgamma mRNA)-expressing cells and the effects of estrogen on their population. Paraffin sections of oviducal tissues from laying hens (approximately 57 weeks old) and immature hens (approximately 16 weeks old) with or without diethylstilbestrol (DES) treatment were hybridized by digoxigenin-labeled IgG riboprobes or immunostained for IgG gamma-chain (IgG). Immunoreactive IgG was present in some of the mucosal epithelial cells and the plasma cell-like cells in the stromal connective tissue in all segments of the oviduct. In contrast, IgGgamma mRNA expression was observed only in the plasma cell-like cells in the stromal connective tissues, but not in the cells of mucosal epithelium. In laying hens, the lower end of the oviduct, namely the vagina and uterovaginal junction, contained more IgGgamma mRNA-expressing cells than the other segments. Treatment of immature hens with DES for 3 or 6 days increased the population of both IgGgamma mRNA-expressing cells and IgG-containing cells in the oviducal stroma. These results indicate that IgG is locally produced by plasma cell-like cells in the stroma, but not by the cells of the mucosal epithelium, and estrogen may stimulate the infiltration of IgG-producing plasma cell-like cells into the oviducal stroma.

Animals↗

PubMed2001

Induction of gene expression in sheepshead minnows (Cyprinodon variegatus) treated with 17beta-estradiol, diethylstilbestrol, or ethinylestradiol: the use of mRNA fingerprints as an indicator of gene regulation.

The recent interest in hormonally active environmental contaminants has sparked a drive to find sensitive methods to measure their effects on wildlife. A molecular-based assay has been developed to measure the induction of gene expression in sheepshead minnows (Cyprinodon variegatus) exposed in vivo to the natural and pharmaceutical estrogens 17beta-estradiol, ethinylestradiol, and diethylstilbestrol. This method used differential display reverse transcriptase polymerase chain reaction assays to compare the expression of individual mRNAs from control and estrogen-exposed fish. Forty-eight differentially expressed cDNAs were isolated by this method, including cDNAs for vitelline envelope proteins and vitellogenin. The mRNA expression patterns for fish injected with a pharmacological dose of estradiol (5 mg/kg) were identical to those obtained in fish receiving constant aqueous exposure to 212 ng estradiol/liter. Further, the cDNA "fingerprint" pattern observed in the estradiol-treated fish also matched that obtained in fish receiving continuous-flow aqueous exposures to 192 ng ethinyl estradiol/liter and a nominal concentration of 200 ng diethylstilbestrol/liter. The results demonstrate a characteristic expression pattern for genes upregulated by exposure to a variety of natural and anthropogenic estrogens and suggest this approach may be valuable to examine the potential effects of environmental contaminants on other endocrine-mediated pathways of reproduction, growth, and development.

Amino Acid Sequence↗

PubMed1994

Influence of in utero diethylstilbestrol exposure on the prognosis and biologic behavior of vaginal clear-cell adenocarcinoma.

Most young women with clear-cell adenocarcinoma (CCA) of the vagina have a history of prenatal exposure to diethylstilbestrol (DES). Some, however, develop vaginal CCA without a prior history of DES exposure. We hypothesized that the natural history of DES-exposed vaginal CCA and DES-unexposed vaginal CCA may differ. Cases were identified from the Registry for Research on Hormonal Transplacental Carcinogenesis which maintains information on cases of CCA of the lower genital tract occurring in women born after 1940. Four hundred and thirty-one cases satisfied FIGO criteria for primary vaginal carcinoma of which 318 had prenatal, hospital, obstetrician, or pharmacy records available for review. Of these, 80% (255/318) had written documentation of prenatal exposure to DES (DES+) and 20% (63/318) had no evidence of DES exposure (DES-) in their medical records. DES exposure was undetermined in 113 cases due to lack of appropriate medical records. Among cases with documentation, DES exposure was not associated with mean age at diagnosis, (DES+, 20.3 years, DES-, 21.1 years), stage (stage I: DES+, 59%, DES-, 54%; stage II: DES+, 32%, DES-, 33%; stage III: DES+, 7%, DES-, 11%; stage IV: DES+, 2%, DES-, 2%, mean tumor diameter or surface area, grade, histology, cell type, or initial therapy. Among cases which underwent pelvic and paraaortic lymph node sampling (DES+, 63%; DES-, 56%; P = NS) the prevalence of pelvic node involvement was similar (DES+, 18.6%; DES-, 17.1%). However, only 1.2% (2/161) of DES+ cases had positive paraaortic lymph nodes compared to 8.6% (3/35) of DES- cases (P = 0.041). Survival differed significantly between the two groups. Probability of survival at 5 and 10 years for DES+ cases was 84 and 78%, respectively, compared to 69 and 60%, respectively, for DES- cases (5 years, P = 0.007, and 10 years, P = 0.008). Presently, 21% (53/255) of DES+ cases are known to have died, compared to 37% (23/63) of DES- cases (P = 0.008). Sites of disease recurrence also differed. DES- cases were more likely than DES+ cases to present with or to later develop distant tumor to the lungs (24% vs 9%; P = 0.002) or metastases to supraclavicular lymph nodes (8% vs 1.6%; P = 0.017). Among the 113 cases with an uncertain history of DES exposure, survival was intermediate between the well-documented cases (79% at 5 years and 65% at 10 years with 35/113 or 31% known dead), as was frequency of metastases to the lungs (13%) or supraclavicular lymph nodes (5.3%).(ABSTRACT TRUNCATED AT 400 WORDS)

Adenocarcinoma, Clear Cell↗

PubMed1996

Sexual differentiation of cognitive abilities in women exposed to diethylstilbestrol (DES) prenatally.

In nonhuman animals, prenatal exposure to androgens or estrogens enhances development of male-typical characteristics (masculinizes) and impairs development of female-typical characteristics (defeminizes). We investigated the hypothesis that prenatal exposure to the synthetic estrogen, diethylstilbestrol (DES), similarly masculinizes or defeminizes cognitive development in women. Forty-two DES-exposed women and 26 of their unexposed sisters were studied. No group differences were seen for abilities at which females excel on average (verbal fluency, perceptual speed and accuracy, and associative memory), for abilities at which males excel on average (visuospatial abilities), or for abilities that do not show sex differences (vocabulary, nonverbal intelligence). The time of prenatal exposure to DES correlated with visuospatial performance with later exposure associated with better performance. However, the subgroup of women exposed to DES late in gestation did not differ from unexposed women on these measures. Results support the conclusion that prenatal exposure to DES has little or no influence on cognitive development in women. However, they do not preclude other types of early hormonal influences on human cognition, such as prenatal influences of androgen or influences of androgens or estrogens during the early postnatal period.

Adult↗

PubMed1996

The effects of diethylstilbestrol (DES) before birth on the development of masculine behavior in juvenile female rhesus monkeys.

Eight pregnant rhesus monkeys were injected with 100 microg diethylstilbestrol dipropionate (DESDP) from the 40th day of gestation until term, a long-term treatment. Male (n = 3) and female (n = 5) offspring were obtained. Five other pregnant females were injected with DESDP beginning on the 115th day of gestation and continuing until either the 140th day or term--a relatively short-term treatment. Five female infants were obtained from these short-term treatments. Monkeys from the treated pregnancies were assigned randomly to mother-infant social groups containing untreated male and female infants the same age. They were observed in their peer groups each weekday from 3 to 12 months of age, and the display of mounting and play behavior was recorded for each subject. Results showed that DESDP significantly increased the frequency of display of these juvenile behaviors only in long-term-treated females. However, one of the aspects of mounting that is characteristic of males (the ratio of complete to abortive mounts) was unaffected even by the long-term treatment. Thus, DESDP-treated females displayed a limited behavioral masculinization. Whether this limitation was due to dosage and/or timing or to a selective action of DESDP was not determined. DESDP-treated males were not altered in any measurable way compared to untreated males.

Animals↗

PubMed1994

Vasoactive intestinal polypeptide antiserum affects rat prolactin mRNA in 40-day but not 110-day diethylstilbestrol-induced prolactinoma tissue.

Experiments were designed to examine whether vasoactive intestinal polypeptide (VIP), a known stimulator of basal prolactin (PRL) secretion, regulates PRL gene expression in the rat diethylstilbestrol (DES)-induced prolactinoma model. The VIP-induced increase in PRL release could result from increased PRL synthesis and/or decreased PRL degradation. Male Fischer 344 rats were implanted with 10 mg DES pellets 40 or 110 days prior to obtaining the anterior pituitary glands for cell dispersal. Cells were incubated in 1:10 normal rabbit serum or VIP antiserum (AVIP). After incubation, cells were pelleted, washed, and pooled for total nucleic acid extraction. The rat PRL (rPRL) mRNA abundance was quantitated using a solution hybridization/ribonuclease protection assay. Supernatant was collected and analyzed for PRL content using radioimmunoassay. Results from this experiment reveal partial immunoneutralization of intrapituitary VIP significantly decreased PRL secretory rate by rapid reduction in rRPL mRNA in the 40-day tumors. However, in the 110-day tumors the rPRL mRNA steady-state levels were unchanged but the basal release of PRL continued to be decreased by AVIP. These results indicate VIP exerts its effects on PRL secretion through at least two mechanisms.

Animals↗

PubMed1999

Comparative activities of p-nonylphenol and diethylstilbestrol in noble rat mammary gland and uterotrophic assays.

Colerangle and Roy (1996, Endocrine 4, 115-122) have described the apparent ability of both diethylstilbestrol (DES) and p-nonylphenol (NP) to cause extensive cell proliferation and lobular development in the mammary glands of young adult Noble rats. The chemicals were administered over 11 days via subcutaneously implanted minipumps. The dose level of DES used (0.076 mg/kg/day) was about 70 times higher than its minimum detection level in rodent uterotrophic and reproductive toxicology studies. In contrast, the lowest active dose level of NP (0.073 mg/kg/day) in the Noble rat mammary gland study was about 600 times lower than its minimum detection level in rat uterotrophic and multigeneration studies. The apparent enhanced sensitivity of the Noble rat mammary gland to the estrogenic activity of NP was considered worthy of further study. Ovariectomized Noble rat uterotrophic assays with NP (minimum detection level approximately 40 mg/kg/day, 3 or 11 days, oral gavage) revealed similar assay sensitivity to that observed for earlier immature and ovariectomized Alderley Park (AP) rat uterotrophic assays of this chemical. The response of the ovariectomized Noble rat uterotrophic assay to DES and estradiol was also as expected from earlier immature AP rat assays. It is concluded that the general sensitivity to estrogens of the Noble rat and the AP rat is similar. A repeat of the Noble rat mammary gland study with DES (11 x 0.076 mg/kg/day) and NP (11 x either 0.073 or 53.2 mg/kg/day), as originally reported by Colerangle and Roy (1996), revealed a strong positive response to DES and no response to NP. It is concluded that the minimum detection level of NP as a weakly estrogenic material in the rat should be based on the results of rat uterotrophic and multigeneration studies and therefore be set at approximately 40 mg/kg/day. It is also concluded that induced S-phase in the rodent mammary gland is best monitored using BRDU, as opposed to PCNA staining, and that use of subcutaneously implanted minipumps/pellets is inappropriate for risk/hazard assessment studies of chemicals already established as estrogenic in vitro and in vivo, as are NP and DES.

Animals↗

PubMed1999

Lack of effects for low dose levels of bisphenol A and diethylstilbestrol on the prostate gland of CF1 mice exposed in utero.

vom Saal et al. (Proc. Natl. Acad. Sci. 94, 2056-2061, 1997) have reported that low dose exposure (0.02-2 microg/kg/day) of CF1 mice to diethylstilbestrol (DES) in utero led to increases in the prostate gland weight when the pups reached 8 months of age. Nagel et al. (Environ. Health Perspect. 105, 70-76, 1997) reported similar effects in CF1 mice at 6 months of age after exposure in utero to low dose levels (2 and 20 microg/kg/day) of bisphenol A (BPA). vom Saal et al. (Toxicol. Indust. Health 14(1/2) 239-260, 1998) subsequently reported reduced sperm efficiency (daily sperm production per gram testes) in a subset of the BPA animals for which enlarged prostates had been observed. These three experiments have been repeated in a single experiment that was terminated when the offspring reached 6 months of age. No statistically significant effects on prostate weight or sperm efficiency were recorded for offspring of animals exposed to either DES (0.2 microg/kg/day) or BPA (2 and 20 microg/kg/day) in utero. Significant dam effects were seen for several of the assay parameters indicating that the litter, as opposed to the individual, should be considered as the statistical unit in such experiments. A statistically significant increase in body weight was recorded for the low dose BPA male offspring. Females from the study underwent normal sexual maturation and showed no significant differences in reproductive tissue weights at termination and the mean day of vaginal opening. The possible reasons for this failure to confirm the earlier reported effects for DES and BPA at these low doses are discussed.

Animals↗

PubMed1998

2,3,7,8-Tetrachlorodibenzo-p-dioxin and diethylstilbestrol affect thymocytes at different stages of development in fetal thymus organ culture.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and estrogen induce thymic atrophy and alter thymocyte development. In the present study we investigate whether TCDD and the synthetic estrogen diethylstilbestrol (DES) alter intrathymic development by the same or different mechanisms. We compared the effects of TCDD and DES on thymocyte development in fetal thymus organ culture (FTOC) and found that both compounds caused a reduction in cell yield. TCDD- and DES-treated FTOCs yielded fewer CD4 + CD8+ double-positive cells. However TCDD treatment also led to a greater percentage of cells in the CD8+ single-positive compartment. At lower dioxin concentrations, our results demonstrated an actual increase in CD8+ cells, whereas DES-treated fetal thymocytes were mainly enriched in CD4-CD8- double-negative cells. More alpha beta-TCR+ positive cells were seen in TCDD- but not in DES-exposed cultures. Furthermore, in this study we found that TCDD and DES also alter intrathymic development at different stages in the CD4-CD8- double-negative compartment. TCDD induced a relative increase in c-kit + CD44 + CD25-HSA-thymocytes, while DES induced an relative increase in c-kit-CD44-CD25 + HSA+ cells. RT-PCR revealed that TCDD reduced RAG-1, RAG-2, and TdT gene expression in the CD4-CD8- double-negative thymocytes. Co-treatment by TCDD and DES in FTOC yielded a mixture of effects induced by each agent. Taken together, our results demonstrate that TCDD and DES affect thymocytes at different stages of development, suggesting distinct mechanisms for induction of thymic atrophy.

Adjuvants, Immunologic↗

PubMed2000

Differential effects of diethylstilbestrol and 2,3,7,8-tetrachlorodibenzo-p-dioxin on thymocyte differentiation, proliferation, and apoptosis in bcl-2 transgenic mouse fetal thymus organ culture.

Both the estrogenic drug diethylstilbestrol (DES) and the pervasive environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) inhibit thymocyte development. The mechanisms by which either agent induces thymic atrophy are still undetermined. We previously found that TCDD and DES inhibited C57BL/6 murine fetal thymocyte organ cultures (FTOC) at different stages of development. Now, using bcl-2 transgenic (TG) mice, we have further investigated their effects on FTOC proliferation, differentiation, maturation, and apoptosis. As with C57BL/6 mice, thymocyte development in C3H/bcl-2 FTOCs was inhibited by either TCDD (10 nM) or DES (20 microM) in both bcl-2 TG- and TG+ littermates. However, the percentage reduction of cell number induced by DES in bcl-2 TG+ FTOCs was significantly less than the level of inhibition in TG- FTOCs. There was no difference in the level of reduction from TCDD-exposed TG+ or TG- FTOC. Whereas TCDD increased production of mature CD8 cells in either strain, DES mainly yielded cells in the CD4(-)CD8(-)(DN) stage in TG- mice. The anti-apoptotic bcl-2 transgene overcame some DES blocking of DN thymocyte development, allowing more cells to differentiate into CD4 single-positive cells. Analysis of cell cycle showed that TCDD inhibited entry into S phase, whereas DES blocked cell cycling in the G2/M phase. TCDD did not induce detectable apoptosis in FTOC. However, unlike the effects of 17 beta-estradiol (E2) in vivo, DES induced apoptosis in the TG- FTOC, and these apoptotic cells were mainly in the DN subpopulation. This apoptosis could be prevented by the overexpression of bcl-2 in the TG+ mice. Our results demonstrate that, in addition to inhibition of fetal thymocytes at different stages of development by TCDD and DES, DES also induces thymic atrophy by both bcl-2-inhibitable apoptosis and by inducing cell cycle arrest in G2/M in the latest stage in the stem cell compartment. TCDD, on the other hand, does not induce apoptosis, but inhibits entry into cell cycle in the earliest stage in the stem cell compartment.

Animals↗

PubMed2002

Uterine responsiveness to estradiol and DNA methylation are altered by fetal exposure to diethylstilbestrol and methoxychlor in CD-1 mice: effects of low versus high doses.

We examined the effects on female CD-1 mice of fetal exposure to low doses of the drug diethylstilbestrol (DES) (0.1 microg/kg/day) and the insecticide methoxychlor (MXC) (10 microg/kg/day) as well as 1000-fold higher doses: 100 microg/kg/day DES and 10,000 microg/kg/day MXC. Pregnant females were administered these chemicals on gestation days 12-18. At 7-8 months of age, female offspring were ovariectomized and implanted for 7 days with a Silastic capsule containing estradiol. Relative to controls, females exposed to the 0.1 microg DES dose showed significantly heavier uteri, while females exposed to the 100 microg DES dose showed significantly lighter uteri. Females exposed prenatally to the 10 microg/kg dose of MXC had significantly heavier uteri relative to females exposed to the 10,000 microg/kg dose of MXC, but neither group differed significantly from controls. Liver weight for females exposed to both doses of DES was significantly greater than controls. Using a microarray approach to analyze DNA methylation, an increase in ribosomal DNA (rDNA) methylation was observed. Sequence data and Southern analysis indicate an increase in 18S rDNA and 45S pre-rDNA methylation in uterine samples exposed prenatally to low and high doses of DES. We thus found opposite effects of fetal exposure to a low and a high dose of DES on the uterine response to estradiol (inverted-U dose-response relationship). In contrast, there was a monotonic dose-response relationship found for prenatal DES exposure on both liver weight and ribosomal DNA hypermethylation.

Analysis of Variance↗

PubMed1979

Physiological mechanisms of diethylstilbestrol organotropic carcinogenesis.

Treatment of pregnant women with diethylstilbestrol (DES) during pregnancy has been demonstrated to be associated with an increased risk in the female offspring for development of an otherwise very rare type of malignancy: clear-cell adenocarcinoma of the vagina and cervix. The present knowledge about this association is reviewed. In experimental animals, many different types of malignancy can be induced by DES administered in large doses and during long periods. For the human situation there are as yet no indications that exposure to DES during fetal life has resulted in any generally increased incidence of malignant tumors. By injecting neonatal mice with DES for the first five days after birth, histologically malignant changes develope in the uterine cervix of the animals when more than one year old. A comparison is made between this animal model and development of tumors in the human female offspring of DES treated mothers. In the female mice, neonatal DES treatment results in a disturbed epithelial differentiation process in the upper part of the vagina and the uterine cervix, a disturbed development of the hypothalamic-pituitary gland control system as well as a disturbance in the normal development of the lymphoid system. The abnormal epithelial differentiation process results in development of adenosis and within these areas the malignant changes later appear. We do no know whether adenosis is a pre-cancerous condition or not, in the meaning that it contains dormant malignant cells. Other factors could act upon adenosis to result in cancer. The reasons for DES being called a "carcinogen" are reviewed. The possibility for factors in the environment acting as potential transplacental carcinogens in the human fetus should not be excluded.

Animals↗

PubMed1979

Diethylstilbestrol metabolic transformation in relation to organ specific tumor manifestation.

Oxidative biotransformation of the synthetic estrogen diethylstilbestrol (DES) gives rise to several reactive compounds. Two mechanisms are proposed concerning the possible involvement of reactive metabolites in the organotropic tumorigenesis of DES. The first mechanism suggests an affinity of the metabolite to the estradiol receptor present in estrogen target organs. This has been shown for the olefinic epoxide of DES. The second mechanism is based on the organ specific oxidation of DES by peroxidase. The intermediates of this reaction were found to bind to nucleic acid and protein in a manner characteristic of chemical carcinogens.

Animals↗

PubMed1985

The role of the estrogen receptor in diethylstilbestrol toxicity.

The site and specificity of the tissue response to a toxicant are of central importance; it is in this area of diethylstilbestrol (DES) toxicity that the estrogen receptor would appear to play its primary role. Compilation of the various sites of DES toxicity in humans and experimental animals indicates that lesions appear predominantly in estrogen responsive target tissues suggesting that the presence of the estrogen receptor in such target tissues may help govern the tissue specificity of the toxic insult. DES and many of its oxidative metabolites interact with high affinity with the estrogen receptor. Such an interaction may be responsible for localizing DES to target tissues. Autoradiographic and biochemical studies have supported the localization of radiolabeled DES in susceptible tissues. The intracellular mechanism of receptor binding of DES and certain metabolites could then result in mobilization of these compounds to the nucleus. Experimental evidence has shown that DES and a number of its metabolites are able to translocate receptor to the nucleus of uterine cells. Such an action by the receptor results in an increased probability of potential chemical interactions with the genome. The actual induction of a chemical lesion in the target cell may, at this point, proceed by non-receptor mediated mechanisms. For example, studies using in vitro cell culture systems which contain no estrogen receptors have shown that DES can induce neoplastic cell transformation, mutagenesis, irreversible binding to DNA and protein and unscheduled DNA synthesis. These results raise the possibility that a part of DES toxicity may follow pharmacologic principles established for chemical carcinogens. Following induction of the molecular lesion, the role of the receptor continues in this process by mediating increased protein synthesis and mitogenesis in responsive target tissues which ultimately permits a more extensive expression of the toxic effects. It has been demonstrated that DES is a potent mitogen in vivo in both uterine and pituitary tissues, subsequently, the lesion will perpetuate itself through this receptor mediated biological response. This is particularly important since a number of DES induced reproductive tract tumors are expressed only after additional estrogen exposure. While other tumors have been shown to be estrogen sensitive and will regress without continued estrogen stimulation. Therefore, it should be considered that the presence of the estrogen receptor and the estrogen receptor mediated biological responsiveness of a particular tissue are most important in explaining the specificity of DES toxicity.

Adenocarcinoma↗