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PubMed1991

Clear cell adenocarcinoma of the vagina: a second primary in a diethylstilbestrol-exposed woman?

A clear cell adenocarcinoma of the vaginal remnant in a diethylstilbestrol (DES)-exposed woman developed 20 years after anterior exenteration for a histologically similar stage II vaginal cancer. Arguments favoring a new primary cancer over a late recurrence are presented. This case probably represents the first report of a second primary vaginal clear cell cancer after DES exposure in utero. The implications of a second vaginal primary and the need for long-term surveillance in DES-exposed women are discussed.

Adenocarcinoma↗

PubMed1982

Determination of hepatic uridine 5'-diphosphoglucuronic acid concentration by conjugation with diethylstilbestrol.

A sensitive and reliable assay for uridine 5'-diphosphoglucuronic acid (UDPGA) was developed that involved conjugation of diethylstilbestrol (DES) in vitro. This conjugation reaction is solely dependent upon UDPGA concentration. The assay uses 0.13 M Tris-HCl, pH 7.4, 6.7 mM MgCl2, 0.05% Brig 58, 0.25 mg guinea pig liver microsomal protein, 0.13 mM 3H-DES (0.2 microCi/ml), and 200 microliters of boiled 10% liver homogenate in a total volume of 0.5 ml. After a 60-min incubation at 37 degrees C, unconjugated DES is extracted into 5 ml of chloroform and the residual metabolized 3H-DES in the aqueous phase is determined by liquid scintillation spectrometry. After addition of beta-glucuronidase to the aqueous phase, about 90% of the radioactivity could be extracted into chloroform, demonstrating the DES-glucuronic acid is the primary metabolite. Thus, this method easily permits quantitation of UDPGA in rat liver in the 1-10 nmol range.

Animals↗

PubMed1984

Effects of subchronic exposure to diethylstilbestrol on humoral immune function in adult female (C3B6)F1 mice.

Adult female (C57BL/6 X C3H)F1 (B6C3F1) mice were treated with diethylstilbestrol for 14 days and assayed for the ability to produce antibody to a T-dependent antigen, a T-independent antigen, and to respond in vitro to stimulation by a polyclonal activator, bacterial lipopolysaccharide (LPS). No suppression of the in vivo antibody responses were observed. DES produced a subtle alteration in the response to the T-dependent antigen, sheep erythrocyte (sRBC), as treated groups maintained higher PFC values than vehicle groups after the peak day of the response. DES induced an enhanced response to the T-independent antigen, DNP-Ficoll. Spleen cells from DES-exposed animals were only marginally altered in their ability to produce antibody in vitro in response to LPS. Parallel experiments indicated a comparable reduction of LPS-induced blastogenesis. Serum immunoglobulin levels were determined following DES exposure, as a measure of baseline immunocompetence. DES only caused a reduction in the immunoglobulin M (IgM) isotype. DES exposure caused a significant enhancement of the activity of the reticuloendothelial (RES) system. Experiments were performed to assess the effects of enhanced RES function on concentrations of 51Cr labeled sRBC, which were optimal for antibody production. When sRBC were administered i.p., there was no effect on either the Ab response (as reported above) or on the number of sRBC localized in the spleen. In contrast, when sRBC were administered i.v., exposure to DES reduced (approximately 50%) both the Ab response and the number of sRBC localized in the spleen. Enhanced phagocytic function and alterations in antigen distribution must be considered in the interpretation of in vivo immune responses.

Animals↗

PubMed1984

Effects of diethylstilbestrol on human natural killer cells in vitro.

Exposure of human peripheral blood lymphocytes to diethylstilbestrol (DES) in vitro resulted in inhibition of Natural Killer (NK) cell activity. DES inhibited NK activity in a dose and time-dependent manner with maximal effect after an 18 h exposure time. Significant reduction in cytotoxicity was obtained at concentrations of DES equal to or above 1 microM. The DES-induced inhibition of NK activity was reversible and totally abrogated within 18 h of culture in the absence of DES. Studies at the single cell level revealed that DES impaired the lytic activity of NK cells without interfering with recognition of target cells. The presence of indomethacin or aspirin during exposure to DES completely reversed the DES-induced inhibition of NK activity, indicating that a product of the cyclooxygenase system mediated the suppression.

Cell Line↗

PubMed1984

Exposure of neonatal female mice to diethylstilbestrol persistently impairs NK activity through reduction of effector cells at the bone marrow level.

Female NMRI mice neonatally treated with diethylstilbestrol (DES) show persistent impairment of various immune parameters, including NK activity. The present study demonstrated that NK activity was reduced in all lymphoid compartments and thus is not due to a simple redistribution of effector cells. Poly I:C was unable to augment NK activity in DES treated animals in vitro and in vivo. This defect was not attributable to inability to produce interferon in response to poly I:C since interferon-beta was also unsuccessful in augmenting NK activity in vitro. Moreover, the lack of response was not dependent on alterations in macrophage function, as evident from experiments showing that macrophages from DES-exposed animals resulted in a normal enhancement of NK activity in response to poly I:C when mixed with lymphocytes from control animals. Studies at the single cell level revealed that the reduced NK activity was the result of a reduced number of target-binding effector cells, and that the individual cells actually binding a target killed the target in an apparently normal fashion. Adoptive transfer of bone marrow cells between control and neonatally DES-treated animals showed that the reduced number of effector cells was determined at the bone marrow level.

Animals↗

PubMedDate not supplied

Murine macrophage activation with resorcyclic acid lactones (RALs): comparison with diethylstilbestrol and 17 beta-estradiol.

Zearalane, a resorcyclic acid lactone (RAL) derivative, activates murine macrophages (M phi) in vivo and in vitro. Mouse M phi incubated in vitro with different concentrations of zearalane released superoxide anion (O2-) on stimulation with either opsonized zymosan (Op-zym), phorbol myristate acetate (PMA), or Salmonella typhimurium. The levels of O2- released were similar to those released from M phi incubated in vitro with supernatants enriched in macrophage-activating factors from concanavalin A-stimulated mouse spleen cells. In contrast, 17 beta-estradiol (E2) or diethylstilbestrol (DES) induced little or no enhancement of O2- release. Zearalane, dideoxyzearalane, DES and E2 were tested for induction of host resistance to S. typhimurium infection in mice. Treatment of mice with zearalane (9 mg/kg) resulted in at least 65% survival 4 days post-infection, compared to 10% survival of mice with vehicle alone, DES, or E2. Peritoneal and alveolar M phi from the zearalane-treated mice released up to six times as much O2- on stimulation with Op-zym as M phi from the other treatment groups. M phi activation was observed for up to 7 days after intraperitoneal or subcutaneous administration of zearalane in either aqueous or organic vehicles. These results suggest that zearalane may enhance resistance to infection by increasing bactericidal activity due to increased release of toxic oxygen radicals by M phi and mononuclear phagocytes. These effects differ from the immunosuppressive effects reported for DES and E2.

Animals↗

PubMed1991

Increased risk of profound weight loss among women exposed to diethylstilbestrol in utero.

We surveyed 1711 women exposed to diethylstilbestrol in utero, and 919 women not exposed, concerning lifetime weight loss histories. The prevalence of a history of unexplained profoundly low body weight (weight less than or equal to 80% of expected weight for age, sex, and height) was 18.7 per 1000 in the exposed group compared to 3.3 per 1000 in the unexposed group; a 5.72 to 1 ratio of increased risk.

Adult↗

PubMed1979

Cytogenetic effects of diethylstilbestrol-diphosphate (DES-dp) on mouse bone marrow monitored by the micronucleus test.

6 dosages of diethylstilbestrol-diphosphate (DES-dp), ranging from 0.01 to 500 mg per kg of body weight were compared to saline and phosphate buffered saline (negative controls) and two dosages of cyclophosphamide (positive control) in the micronucleus test with 115 ICR mice. DES-dp failed to generate a significant increase in micronucleated polychromatic erythrocytes over negative controls. Cyclophosphamide produced a dose-related increase in micronuclei similar to previously published reports. Iit was therefore determined that the micronucleus test did not detect the types of chromosomal changes known to be generated by DES-dp and DES.

Animals↗

PubMed1985

Mutagenicity of methyl 2-benzimidazolecarbamate, diethylstilbestrol and estradiol: structural chromosomal aberrations, sister-chromatid exchanges, C-mitoses, polyploidies and micronuclei.

Methyl 2-benzimidazolecarbamate (MBC), diethylstilbestrol (DES) and estradiol were tested with regard to their ability to induce C-mitoses, polyploidies, micronuclei, structural chromosomal aberrations and sister-chromatid exchanges (SCE) in human peripheral lymphocytes in vitro. The compounds did not induce structural chromosomal aberrations either in the presence or absence of metabolic activation. MBC and estradiol were negative in the SCE test. DES induced SCE rates which were not even twice the control level and which were independent of dose and of metabolic activation. All compounds induced C-mitoses, polyploidies and micronuclei. The micronuclei are interpreted as resulting from errors in the anaphase distribution of chromosomes by spindle disturbances rather than from structural chromosomal aberrations.

Benzimidazoles↗

PubMed1989

Nonrandom karyotypic changes in immortal and tumorigenic Syrian hamster cells induced by diethylstilbestrol.

Treatment of Syrian hamster embryo cells with diethylstilbestrol (DES) resulted in the induction of immortal cell lines that progressed and formed tumors in nude mice. Four independently treated cell lines were analyzed cytogenetically at several passages during neoplastic progression. The immortal cell lines at the early passages had no structural abnormalities but did have numerical changes. For example, gain of chromosome 11 was found in all immortal cell lines, and gain of chromosome 19 was found in two of four cell lines. Tumorigenic cells showed not only a variety of numerical abnormalities but also structural abnormalities. Loss of a sex chromosome and gain of chromosome 19 were found in six of seven tumors. Gain of chromosome 11, which was found in all immortal cell lines, disappeared in five of seven tumors. Structural abnormalities involving chromosomes 2 and 3 were found in three of seven tumors. Many marker chromosomes were also found in the tumors. These results support our hypothesis that DES-induced nondisjunction is important in its ability to induce cell transformation and suggests that gain of chromosome 11 and/or 19 may play a role in DES-induced neoplastic progression. Furthermore, these results indicate that for the acquisition of tumorigenicity, additional numerical or structural changes are needed, suggesting that multiple genetic events are required in the multistep process of carcinogenesis.

Animals↗

PubMed1994

Cytogenetic analysis of murine cell lines from diethylstilbestrol-induced uterine endometrial adenocarcinomas.

Treatment of female CD-1 mice with the synthetic estrogen diethylstilbestrol (DES) on days 1 through 5 after birth results in a 90% incidence of endometrial adenocarcinomas by 18 months of age Three cell lines were established from DES-induced uterine carcinomas and studied for specific chromosomal changes. Each cell line exhibited numerical decreases in chromosomes 9, 11, 13, and X as common abnormalities. Structural alterations involving chromosomes 3, 6, 11, and 19 occurred nonrandomly among the three cell lines. Every cell line showed a rearrangement in the long arm of chromosome 3 (3q+), a translocation between chromosomes 3 and 19 [t(3;19)], isochromosome of chromosome 11 [i(11)], and a marker chromosome (M2) either as common abnormalities or recurrent abnormalities. t(3;19), i(11), and M2 were observed also in the primary colonies from which the cell lines arose. The changes were not observed in a cell line derived from the uterus of one untreated control mouse, suggesting that these chromosomal alterations may have occurred during DES-induced neoplastic transformation. The chromosomal alterations found in the present study may prove useful in investigating the genetic changes involved in DES carcinogenesis.

Adenocarcinoma↗

PubMed1990

Aneuploidy assay on diethylstilbestrol by means of in situ hybridization of radioactive and biotinylated DNA probes on interphase nuclei.

Aneuploidy tests by means of in situ hybridization with chromosome-specific DNA probes on interphase nuclei have been carried out on human lymphocytes treated with diethylstilbestrol (DES). A DNA probe specific for chromosome Y (Y97), either radioactive or biotinylated, was used for the assays. Autoradiography or FITC-conjugated antibiotin antibodies were employed to visualize the hybridization sites. A significant increase of hyperdiploid nuclei was obtained with both procedures and a dose-related effect was revealed using the biotinylated probe. The results obtained, while giving further support to the evidence that DES is able to induce aneuploidy in cultured human cells, also indicate that the sensitivity of the assay can be improved by using biotinylated probes coupled with fluorescent antibodies.

Adult↗

PubMed1988

Neutrophil involvement in effects of diethylstilbestrol and strontium 89 on macrophage activation by Propionibacterium acnes.

We have recently demonstrated that diethylstilbestrol (DES) significantly suppresses macrophage (M phi) activation by Propionibacterium acnes. Because the initial activation of M phi by P. acnes appears to involve the close interaction of the killed bacteria with inflammatory neutrophils (PMN) and resident M phi in the peritoneal cavity, we investigated whether the DES inhibition of M phi activation was associated with inhibition of the PMN response. Our data demonstrate that treatment of mice with DES did not interfere with the acute inflammatory peritoneal PMN influx 5 h after P. acnes injection. DES treatment also did not affect development of the early (day 4) tumor cytotoxic activity of P. acnes activated M phi; this M phi activity has been shown to be mediated by the acute PMN influx. DES treatment, however, did reduce M phi activation as evidenced by alterations in other markers typically associated with M phi activation by P. acnes, including the characteristic reductions in alkaline phosphodiesterase (APD) ectoenzyme activity and the total RNA synthesis, as well as the characteristic persistence of the peritoneal PMN response seen on days 4 and 7 after P. acnes injection. In addition, M phi activity 7 days after P. acnes injection was inhibited in DES treated mice, as evidenced by reduced antitumor activity, and alteration of the markers mentioned above. As a second approach to elucidate the involvement of the acute and persistent PMN response in the M phi activation process, we depleted mice of circulating PMN by treatment of mice with 89Sr before administration of P. acnes.(ABSTRACT TRUNCATED AT 250 WORDS)

Agranulocytosis↗

PubMed1984

Diethylstilbestrol and other estrogens in the environment.

Many environmental agents of diverse chemical structure possess estrogenic activity. Other hormonal activities do not seem to be so widespread through different chemical classes. Some compounds such as the mycotoxin, zearalenone, are metabolized from weakly active to more estrogenic forms and may thus be considered proestrogens. Metabolism of potent xenobiotics, such as diethylstilbestrol (DES), may result in relatively less hormonally active compounds as well as reactive intermediates associated with long-term toxicities. Weakly estrogenic xenobiotics may be physiologically significant if they persist in the body or when there is continuous exposure; some compounds with no apparent estrogen-receptor-binding affinity may exert estrogenic effects through indirect mechanisms. Estrogenic materials as part of the environment derive from natural (e.g., plant estrogens or mycotoxins) and synthetic (e.g., DES or DDT) sources. In some cases, environmental compounds may be potent estrogens which are used for their hormonal activity, or in other cases, they are weak estrogens in which hormonal activity is an inadvertant function; an example of the former case is DES as a growth-promoting agent for cattle, an example of the latter, kepone. Elucidation of the structural basis of estrogenic activity is the critical step awaited in this area.

Animals↗

PubMed1987

Glutathione protection against irreversible binding of diethylstilbestrol in the hamster renal cortex.

Hamster renal cortical slices bioactivated the synthetic estrogen, diethylstilbestrol (DES), to reactive metabolites that bound irreversibly to cellular proteins. Incubation of the slices for 30 min at 37 degrees C with 5 mM diethyl maleate prior to the addition of 50 nM [3H]DES for 60 min increased the nonextractable binding of [3H]DES metabolites to cellular protein by 150%, whereas addition of 5 mM glutathione (GSH) decreased the irreversible binding of [3H]DES by 17%. The addition of the 5 mM GSH to the incubation medium caused a 24% increase in tissue nonprotein sulfhydryl (NP-SH) content as estimated by reaction with Ellman's reagent after 30 min at 37 degrees C, while the addition of diethyl maleate for the same time period depleted tissue NP-SH levels by 54%. Kidneys from hamsters treated with the GSH synthesis inhibitor L-buthionine-(S,R)-sulfoximine at a dosage of 1 mmol/kg body wt for 2 hr had 45% of the NP-SH content as compared with kidneys of saline-treated controls. The irreversible binding of [3H]DES metabolites was increased by 60% in renal cortical slices from L-buthionine sulfoximine-treated hamsters. Non-extractable binding of [3H]DES metabolites to renal DNA was not observed. These results suggest that GSH, the predominate NP-SH in the cell, protects against the irreversible binding of DES metabolites to cellular macromolecules.

Animals↗

PubMed1988

Uterine abnormalities in rats exposed neonatally to diethylstilbestrol, ethynylestradiol, or clomiphene citrate.

The toxicity of the synthetic estrogens diethylstilbestrol (DES), and ethynylestradiol (EE), and the antiestrogen clomiphene citrate (CC) was evaluated by assessing postnatal uterine growth and development prior to the onset of puberty in the rat. Both DES and EE, administered during the neonatal period (postnatal days 1-5), initially increased uterine weight and luminal epithelium hypertrophy. However, uterine weight declined in both DES- and EE-treated animals and fell below controls beyond day 11. Luminal epithelium stimulation generally paralleled uterine weight changes. Precocious development of uterine glands occurred after estrogenization (compared to untreated controls), but subsequently gland numbers were approximately 60% of control levels. Neonatal CC exposure induced only slight uterine weight gain but caused prolonged luminal epithelium hypertrophy and inhibited uterine gland genesis. Luminal epithelium hypertrophy appears to be a useful measure of antiestrogen activity. These data demonstrate the toxicity of DES and EE as assessed by altered prepubertal uterine gland development. Additionally, the inhibition of uterine gland genesis after neonatal CC exposure occurs in conjunction with prolonged luminal epithelium hypertrophy.

Animals↗

PubMed1996

Prenatal exposure to diethylstilbestrol and the mother-daughter relationship.

The psychological consequences resulting from the exposure to diethylstilbestrol (DES), a non-steroidal oestrogen, on the mother-daughter relationship are studied using semi-directive interviews with 43 daughters and 7 mothers treated with DES during their pregnancies. These women referred to gynaecological consultation for DES-related problems. The daughters, exposed to DES during their foetal life, learned about DES after a pregnancy mishap (35% of the cases), or by accident (65% of the cases). All of them were shocked when the existence of DES and its side effects were revealed to them. Consequences on the mother-daughter relationship were absent in 60% of the cases, favourable in 20%, and negative in 20%. Five percent of the women showed hostility towards the medical practice, but 65% were not suspicious of the drugs administered to them during their pregnancies. For 64% of them, administration of DES to their mother had been kept secret. In 7 out of 50 cases, parents alone came for medical assistance in order to manage the secret. Exposure to DES may reveal pre-existing difficulties not only between the mother and the daughter, but sometimes beyond from generation to generation.

Adaptation, Psychological↗

PubMed1988

Effects of bromocriptine on prolactin cellular hypertrophy, proliferation and secretory activity in diethylstilbestrol-induced pituitary tumors.

Pituitary tumors induced by chronic diethylstilbestrol (DES) treatment in female F344 rats were treated subsequently with bromocriptine (BC). Effects of BC on separable subpopulations of lactotrophs were examined. Enzymatically dissociated cells from individual pituitaries were assessed regarding total number, relative lactotroph population, intracellular prolactin (PRL) content, PRL release in primary culture, and density alterations by separation in Ficoll-Hypaque or after sedimentation at unit gravity. In addition to the treatment and analysis of in situ tumors, the effects of BC treatment in vitro were assessed, using tumor cells which were first separated on Ficoll-Hypaque. Cell proliferation was assessed by cell cycle analysis, using DNA measurement by laser flow cytometry. BC treatment of tumors reversed the effects of DES on pituitary weight, PRL content and in vitro PRL release. Total cell recovery was not affected by BC, but cell separation showed that BC reduced the number of larger PRL-containing cells. Cell cycle analysis showed a decrease in numbers of cells in S and G2 cycle phases after BC in only one of four experiments. BC had an effect on proliferation in only the upper gradient fractions, containing the smallest cells. Culture of Ficoll-separated tumor cells revealed greater PRL release among lighter/smaller cells. BC treatment inhibited PRL release from both light and dense cells. The results establish that PRL cell hypertrophy, as well as hyperplasia, results from DES treatment. Bromocriptine treatment reverses this hypertrophy concomitant with inhibiting PRL synthesis and release. Reversal of proliferation in tumor cells is not a major effect of bromocriptine treatment.

Animals↗