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PubMed1976

Studies on the biological disposition of diethylstilbestrol in rats and humans.

Studies were conducted to elucidate the processes involved in the biological disposition of diethylstilbestrol (DES). The apparent biological half-life of [14C] DES decreased with increasing age in immature rats. The half-life of DES in adult rats (14 min) was reached between the 15th and 25th day after birth. Comparison of the intestinal absorption of [14C] DES and [14C]DES monoglucuronide showed the unconjugated drug to be absorbed much more rapidly. Hydrolysis of the conjugate took place in the lower intestine, and this permitted the drug to undergo enterohepatic cycling.

Age Factors↗

PubMed1976

Lack of effect of dietary diethylstilbestrol on reproductive performance.

Groups of male or female mice were pretreated for 2 wk and 1 wk, respectively, with flesh (liver or muscle) diets prepared from steers. In one experiment diethylstilbestrol (DES) was added to the diet at 0.5 or 5.0 ppb. In a second experiment diets prepared from DES-implanted steer flesh (liver or muscle) were fed. Tissues used in the control diet and DES-added diets were from DES-free steers. The animals were allowed to mate and diets continued until the first litter was delivered. Increasing DES levels in either liver or muscle diets or flesh from DES-implanted steers resulted in no significant differences either in litter size or in the number of fertile male or female mice between the control group and experimental groups. The offspring from each litter were mated and showed no significant difference in their reproductive performance. No abnormalities were noted in any offspring.

Animals↗

PubMed1977

Prenatal exposure to diethylstilbestrol in mice: toxicological studies.

The effect of prenatal exposure to diethylstilbestrol (DES) on the postnatal development of male and female genital tract function was studied. The placental transfer or radiolabeled (3H or 14C) DES was studied in pregnant mice. DES-associated radioactivity in the fetal plasma approximated that in maternal plasma 1/2 hr after intravenous administration of [3H]DES; 3H activity corresponding to DES in the fetal genital tract was about threefold higher. The decrease in reproductive capacity of female offspring from mice treated with DES during gestation was dose-related; a low incidence (10% or less) of cancer of the vagina, cervix, and/or uterus was also observed in these mice. Male offspring exposed prenatally to the highest dose (100 microng/kg) of DES in this study also had lower reproductive capacities. Lesions in the genital tract of these mice included epididymal cysts, inflammation, cryptorchidism, and nodular masses in the seminal vesicles and/or prostate gland. Such lesions and sterility were not observed at the lower DES doses. Histological studies with neonatal mice raise the possibility that Müllerian duct tissue may represent a site for the transplacental toxicity of DES in both the male and female fetus.

Abnormalities, Drug-Induced↗

PubMed1977

Biotransformation of diethylstilbestrol in the rhesus monkey and the chimpanzee.

Diethylstilbestrol (DES) is considered a teratogen and a transplacental carcinogen in humans. In order to compare its biotransformation in nonhuman primates to that in humans, a metabolic study was carried out in rhesus monkeys and chimpanzees. After an oral dose of 1 mg/kg [14C]DES, approximately 59% of the ingested radioactivity was found in the urine and 28% in the feces of two female rhesus monkeys after 4 days, while in male rhesus monkeys urinary radioactivity accounted for 43% and fecal radioactivity for 35%. In chimpanzees, 63% of a 0.5 mg/kg dose was excreted with the urine in a female and 47% in a male animal. In both species, urinary radioactivity was predominantly (greater than 70%) associated with glucuronides. Besides DES, three metabolites were found in the urinary glucuronide fraction of rhesus monkeys and chimpanzees by radio gas chromatography and were identified as dienestrol and omega-hydroxy derivatives of DES and dienestrol. Fecal radioactivity in rhesus monkeys was shown to consist exclusively of DES. Glucuronidation of DES appears to occur in neonatal and fetal rhesus monkeys.

Animals↗

PubMed1977

Strain differences in the response of the mouse to diethylstilbestrol.

BALB/c StCrlfC3Hf/Nctr, C57BL/6/, C57BL/6 X BALB/c F1 hybrid (B6CF1), and monohybrid-cross offspring from the breeding of B6CF1 mice were examined with respect to uterine, vaginal, and thymus responses to diethylstilbestrol (DES). About 400 mice of each genetic population were used. Weanling mice were fed DES at dietary concentrations of 2.5 to 1,000 ppb (microgram/kg feed) for 6 days and were killed by cervical dislocation about 20 hr after removal of the feed. C57BL/6, B6CF1, and the monohybrid-cross offspring did not differ in the uterine-weight response to DES, but the slope of the dose-response line was shallower for the BALB/c than for the other strains. Dietary DES concentrations of 250 ppb or more inhibited the uterotrophic response in all populations. Vaginal cornification occurred at lower concentrations of DES in the C57BL/6 strain than in the B6CF1 animals. BALB/c and monohybrid-cross offspring were indistinguishable from each other in their vaginal response to Des and were less sensitive to DES than the other mouse populations. The use of ethanol or corn oil as the solvent for mixing DES into the diet had no apparent effect on the uterine weight or vaginal response in any of the mice. DES depressed thymus weight in a dose-related fashion at dietary concentrations of 100 ppb and above in all genetic populations.

Animals↗

PubMed1979

Evaluation of the transplacental toxicity of diethylstilbestrol with the scanning electron microscope.

Exposure in utero to the synthetic estrogen diethylstilbestrol (DES) is associated with reproductive tract lesions in male and female CD-1 mice. The scanning electron microscope was used to evaluate the luminal surface of the vagina, cervix, and uterus following prenatal exposure to DES. Abnormalities that have been observed include urethral openings in the cervicovaginal area, squamous metaplasia of the uterus, glandular elements in the vagina, and abnormal cell surface features in the vaginal epithelium.

Animals↗

PubMed1979

Mammary tumorigenesis in the rat following prenatal exposure to diethylstilbestrol and postnatal treatment with 7,12-dimethylbenz[a]anthracene.

Pregnant rats were injected with vehicle or 1,2 microgram diethylstilbestrol (DES) during wk 2 or 3 of gestation; their female offspring ( approximately 50 d old) were fed 7,12-dimethylbenz[a]anthrocene (DMBA). The survivors (27 per group) were sacrificed 30 wk later. The three groups did not differ in the number of tumor-bearing animals; however, significantly more palpable mammary tumors arose in both DES-exposed groups than in controls. When DES was given during the second trimester, palpable tumors appeared earlier than in the other two groups. Thus, transplancental exposure to DES potentiated the action of a known carcinogen (DMBA) on rat mammary tissue. These results raise the possibility that, for young women, DES exposure in utero may have affected tissues other than the vagina. Further investigation is warranted, with special emphasis on the effects of DES on mammary and other estrogen-sensitive tissues.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1980

Ovarian influence on mitogen responsiveness of lymphocytes from mice neonatally exposed to diethylstilbestrol.

Treatment of neonatal female mice with diethylstilbestrol (DES) resulted in a reduced response of spleen lymphocytes to concanavalin A (Con A) and lipopolysaccharide (LPS). Ovariectomy or ovariectomy plus estradiol treatment had no influence on the response to Con A in either control or DES-treated females. Ovariectomy reduced the response to LPS in control animals and eliminated the difference between control and DES-treated females. Estradiol treatment enhanced the response of ovariectomized control females to LPS and restored the difference between control and DES-treated animals. Comparison of the mitogen responsiveness during various stages of the estrous cycle showed a tendency for the response to be augmented at proestrus and metestrus, although the differences were not significant.

Animals↗

PubMed1981

Influence of prenatal exposure to diethylstilbestrol on estrogen and progestin binding proteins in uteri and dimethylbenzanthracene- induced mammary tumors of the rat.

Various characteristics of steroid binding proteins from mammary tumors and uteri of rats exposed prenatally to diethylstilbestrol (DES) were examined. Pregnant rats were treated with no hormone (group A) or with a total dose of 1.2 micrograms DES during the second (group B) or third (group C) trimester of gestation. Female offspring received 7,12-dimethylbenz[a]anthracene (DMBA) at d 50 +/- 1. Animals with large mammary tumors were subjected to bilateral ovariectomy. Seven months after carcinogen treatment, the experiment was terminated. High-affinity binding sites for [3H] estradiol-17 beta and [3H]R5020 were found in all mammary tumors assayed. On sucrose gradients of low ionic strength both 8S and 4S forms of the estrogen receptor were identified in mammary tumors, regardless of prenatal treatment. In addition, progestin receptors sedimenting at 4S were identified in these tumors. However, the 7-8S form of the progestin receptor was found only in tumors from intact animals. Levels of progestin receptors were diminished after ovariectomy, both in mammary tumors and in uteri; ovariectomy also resulted in a significant reduction in uterine wet weight in the hormone exposure groups, as expected. Unlike groups A and B, rats exposed to DES during the third trimester had uterine progestin binding capacities and uterine wet weights that did not decrease proportionally ater ovariectomy. Furthermore, progestin binding capacities in mammary tumors from group C ovariectomized rats were higher than those in the other two groups. In intact rats from group C, cytosol from mammary tumors also had elevated levels of progestin binding; however, no differences in progestin binding were observed in the uteri from these animals. Small differences in estrogen binding capacities in tumor tissues were observed among the three groups; uterine estrogen binding capacities did not vary significantly. Prenatal exposure to DES during the third trimester appeared related to persistent biochemical alterations in rat mammary tumors and uteri; earlier exposure did not have this effect.

9,10-Dimethyl-1,2-benzanthracene↗

PubMedDate not supplied

Nonneoplastic changes induced in female C3H mice by chronic exposure to diethylstilbestrol or 17 beta-estradiol.

The long-term nonneoplastic effects of estrogenic diets were studied in female C3H/HeJ and C3HeB/FeJ mice. C3H/HeJ mice received diets containing 0, 10, 100, or 500 ppb diethylstilbestrol (DES) or 100, 1000, or 5000 ppb 17 beta-estradiol (E2) from 6 to 110 wk of age. C3HeB/FeJ females were fed diets containing nominal concentrations of 0, 10, 100, or 500 ppb DES from 6 to 136 wk of age. Responses of both strains to DES were qualitatively identical. Histological changes in the reproductive tract induced or increased by DES in both strains and by E2 in C3H/HeJ mice included stromal mucoid changes in the vagina and cervix, epithelial keratinization in the vagina, and glandular hyperplasia in the uterine horns. Increasing doses above 10 ppb DES or 100 ppb E2 increased the prevalence and, in some cases, severity of these responses. Dose-responses to DES for these endpoints were virtually indistinguishable in the two strains. At 10 ppb DES or 100 ppb E2 there were minimal or no observable effects. When the nonneoplastic dose-response data were compared with neoplastic dose-response data previously reported, no consistent relation between doses causing neoplastic and nonneoplastic responses was seen for the two estrogens.

Animals↗

PubMed1983

Steroid-hormone-binding proteins in normal and neoplastic mammary tissues from C3H mice fed diethylstilbestrol.

Mammary tumors develop earlier and in greater numbers in C3H mice fed diets containing up to 1000 ppb diethylstilbestrol or 5000 ppb estradiol-17 beta. We have analyzed the steroid-hormone-binding proteins in cytosols of normal target tissues and in neoplastic mammary tissues of control and estrogen-fed mice to determine whether the capacity for hormone response was altered by dietary estrogens. Using estradiol-17 beta as a ligand, estrogen-binding proteins were measured with Kd = 10(-11)-10(-10) M and sedimentation constants of 8 and 4 S. The binding capacity (per mg cytosol protein) of uterus exceeded that of normal mammary gland 10-20-fold, while mammary tumors only contained half the binding capacity of virgin mammary gland. Binding proteins for the glucocorticoid, triamcinolone acetonide, exhibited a sedimentation constant of 7-8 S and Kd = 10(-9)-10(-8) M. The glucocorticoid binding capacity of mammary tumors exceeded that of virgin mammary gland. Binding proteins for progestins were measured using the synthetic ligand R5020. Mammary gland contained progestin-binding proteins with 4 S sedimentation constants and Kd = 10(-9)-10(-8) M. Not all mammary tumors contained progestin-binding proteins, and the binding capacities varied considerably among those that did. The molecular characteristics of the steroid receptors in tumors were the same as those found in normal target tissues. There was nothing to suggest that dietary estrogens altered the characteristics of the three steroid-binding proteins.

Animals↗

PubMed1984

Neoplastic and nonneoplastic responses to chronic feeding of diethylstilbestrol in C3H mice.

Over 3000 female C3H/Hen-MTV+ mice continuously received graded dietary levels (0, 2.5, 5, 10, 20, 40, 80, 160, 320, and 640 ppb) of diethylstilbestrol (DES) beginning at weaning. Mice were scheduled to be killed after 3 or 26 wk of exposure and were palpated weekly and removed for histological evaluation when subcutaneous masses reached 1 cm diameter. Mammary tumors were more prevalent than in controls only at 320 and 640 ppb DES. However, palpable mammary tumors appeared significantly earlier than in controls in mice fed 80 ppb and above. Mice killed at 3 wk and later showed a dose-response for several nonneoplastic endpoints. At 3 wk, moderate to severe uterine glandular hyperplasia, lack of corpora lutea, and vaginal keratinization were more prevalent than in controls at 80 ppb; cervical adenosis was more prevalent than in controls at 160 ppb and above. Generally, the prevalence of other nonneoplastic responses such as uterine fibrosis, stromal mucoid changes, and bony trabecular proliferation were increased above control levels only later than 3 wk at 160 ppb and greater. This study demonstrated neoplastic and nonneoplastic responses to DES at and above 80 ppb, but gave no clear evidence of either type of response below this level. Conclusions are, (1) dietary levels of DES causing nonneoplastic effects also cause neoplastic effects when fed chronically, and (2) neoplastic levels of DES may be predicted from a 3 wk feeding study in C3H/HeN-MTV+ female mice based on nonneoplastic responses.

Animals↗

PubMed1985

Hepatic presystemic elimination of diethylstilbestrol by rats and effect of pretreatment with inducers of UDP-glucuronosyltransferase.

In order to determine if the synthetic estrogen diethylstilbestrol (DES) undergoes hepatic presystemic elimination, male Sprague-Dawley rats were administered [3H]DES (0.005, 0.05, 0.5 mg/kg) into either the ileocolic (portal administration) or femoral (systemic administration) vein. Plasma and bile samples were collected and the concentrations of both DES and DES glucuronide fractions were determined. The concentration of the DES fraction was lower and the proportion of glucuronides was higher after portal than after systemic administration of all three doses. Comparison of the areas under the curve (AUC) of plasma concentration versus time for the DES fraction indicates that the liver diminishes this fraction by 50-70%. Biliary excretion of DES also showed route-dependent differences, in that it was higher for 10-20 min after portal than after systemic administration. To determine if these effects could be enhanced by induction of UDP-glucuronosyltransferase, rats were pretreated for 4 d with phenobarbital, 3-methylcholanthrene, or pregnenolone-16 alpha-carbonitrile and then administered DES (0.5 mg/kg) by the portal or systemic route. 3-Methylcholanthrene and pregnenolone-16 alpha-carbonitrile enhanced the plasma disappearance of the DES fraction to a greater extent after portal than systemic administration and thus further increased the apparent hepatic presystemic elimination. This effect does not appear to involve increased glucuronidation or biliary excretion. These data provide evidence that hepatic presystemic elimination of DES occurs in rats, and this effect can be enhanced by some microsomal enzyme inducers.

Animals↗

PubMed1992

Steroid synthesis in ovarian homogenates from hypophysectomized adult female mice treated with diethylstilbestrol in neonatal life.

Eight-week-old female NMRI-mice treated with 5 micrograms diethylstilbestrol (DES) or vehicle (olive oil) from d 1 to 5 after birth were hypophysectomized or sham operated. Thirty days after the operation, homogenates were prepared from the ovaries and incubated at 37 degrees C in the presence of [3H]pregnenolone for 1 h. In parallel experiments ovaries were taken for histology. In control ovaries regressing corpora lutea were still present 4 wk after hypophysectomy (Hx). Ovaries from DES females had no corpora lutea, but showed degeneration of the pre-Hx hypertrophic interstitial tissue. Steroids synthesized during the incubation were extracted and separated in a two-dimensional thin-layer chromatography system. After Hx, the amount of extractable [3H]testosterone, [3H]progesterone, and [3H]androstenedione recovered from homogenates of vehicle-treated females increased, but the amount of recovered [3H]-17 alpha-hydroxyprogesterone was not significantly altered. In contrast, in DES-treated females Hx significantly decreased levels of [3H]androstenedione and [3H]-17 alpha-hydroxyprogesterone, but did not affect [3H]progesterone or [3H]testosterone. The persistent difference in steroid synthetic activity after Hx could be linked to the difference in morphology between different ovarian tissue compartments of control and DES-treated females.

Animals↗

PubMed1995

Histone nuclear proteins are irreversibly modified by reactive metabolites of diethylstilbestrol.

We demonstrate for the first time that diethylstilbestrol (DES), a synthetic estrogen, is converted by nuclei to histone-binding metabolite(s). Reaction of [3H]DES with nuclei in the presence of cumene hydroperoxide or NADPH revealed binding of [3H]DES to histone nuclear proteins. Gel electrophoresis experiments revealed that all five histones, 1, 2A, 2B, 3, and 4, were irreversibly bound to [3H]DES. Histones 1 and 3 were more susceptible to the attack by [3H]DES quinone, a metabolite of DES, than histones 2A, 2B, or 4. The kinetic constants, Km and Vmax, of this binding reaction in the presence of cumene hydroperoxide were 10 microM and 750 pmol/mg protein/30 min, respectively. This binding was significantly inhibited by cytochromes P-450 inhibitors. Low-molecular-weight thiols, such as glutathione and cysteine, or thiol modifiers, such as n-ethylmaleimide, dithionitrobenzoic acid, and hydroxymercuric benzoate, drastically inhibited binding of [3H]DES quinone to histone 3. The binding of [3H]DES metabolites to both transcriptionally active and inactive chromatin histone proteins was observed. We conclude that DES is metabolized to histone-binding metabolites, presumably by nuclear cytochrome P-450. DES quinone may be one of the histone-binding DES metabolites. These data suggest that an analogous in vivo modification in the transcriptionally active chromatin histones by DES metabolites may influence gene function.

Animals↗

PubMed1995

Neonatal exposure to xenobiotics alters adult hepatic protein kinase C alpha levels and testosterone metabolism: differential effects by diethylstilbestrol and phenobarbital.

Hepatic enzymes that metabolize endogenous and xenobiotic compounds have been shown to be altered in adult rats that had been exposed to xenobiotics as neonates. Protein kinase C (PKC) is important in intracellular signaling and has been implicated in the regulation of hepatic monooxygenases. Therefore, we examined the effects of neonatal exposure to diethylstilbestrol (DES) and phenobarbital (PB) on hepatic microsomal testosterone metabolism and on the alpha form of protein kinase C (PKC alpha) in adult rats. In adult males, neonatal exposure to DES altered adult testosterone metabolism such that 7 alpha-hydroxylation was increased by 58% but 2 alpha-, 16 alpha-, and 6 beta-hydroxylations and conversion to androstenedione were decreased 31-44%. In contrast, adult males neonatally exposed to PB showed increased (20-27%) testosterone 2 alpha- and 16 alpha-hydroxylations and androstenedione formation, but no effect was observed in the rate of 6 beta- or 7 alpha-hydroxylations. Western blot analyses indicated that cytosolic PKC alpha levels in male rats neonatally exposed to PB were decreased by approximately 63% relative to the vehicle control group but were not significantly altered in the DES males. The PKC alpha levels generally correlated (r = -.75) with 16 alpha-hydroxytestosterone formation in all samples. These results show that neonatal treatment with DES or PB differentially alters hepatic monooxygenase enzyme activities and PKC alpha levels in adult rats.

Animals↗

PubMedDate not supplied

Rapid action of testosterone and diethylstilbestrol on enzymes of osmoregulation in a freshwater fish Oreochromis mossambicus.

The rapid action of sex steroids on enzymes of osmoregulation has not been studied in teleosts. In vivo administration of 0.1 microg/g body wt. of testosterone and diethylstilbestrol (DES) significantly enhanced branchial Na+-K+ ATPase, Ca2+ ATPase, and Na+, K+, and Ca2+ ions as early as 30 minutes in a freshwater teleost Oreochromis mossambicus. Treatment with 10(-6) M testosterone significantly stimulated Na+-K+ ATPase as early as 5 minutes in vitro. The same dose of DES also stimulated Na+-K+ ATPase activity within 10 minutes of incubation in a gill culture study. Administration of the transcriptional inhibitor, actinomycin D (0.1 microg/g body wt. in vivo and 10(-6) M in vitro), prior to hormone treatment, did not prevent the steroid-induced ATPase activity both in vivo and in vitro. It seems that stimulation of Ca2+ ion may be responsible for the hormonal effects to increase enzyme activity. A possible nongenomic mode of action for testosterone and DES is suggested in Oreochromis.

Animals↗

PubMed1979

Glandular dysplasia in diethylstilbestrol-associated vaginal adenosis. A case report and review of the literature.

A case of diethylstilbestrol-associated vaginal adenosis in which dysplastic glands were identified and examined by light and electron microscopy is reported. Transitions between normal and dysplastic glands were documented in subserial sections. These alterations may characterize an intermediate phase in the development of clear-cell adenocarcinoma of the vagina.

Adenocarcinoma↗