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PubMed1994

Effects of RU486 on the ovarian response of immature rats to pregnant mare's serum gonadotrophin or diethylstilbestrol.

The purpose of this study was to further investigate the role of progesterone in follicular development induced by pregnant mare serum gonadotrophin (PMSG) or diethylstilbestrol (DES), in pre-pubertal rats, using RU486 to prevent the receptor-mediated actions of progesterone. Intact or hypophysectomized 26-day-old rats received either a single injection of 10 IU PMSG i.p., or 2 mg DES s.c. daily for 3 days, with or without 0.8 mg RU486 s.c. daily for 3 days. Groups of rats were killed 51-96 h after the first injection. RU486 significantly increased the ovarian weight gain, the ovarian and circulating concentrations of progesterone, the concentrations of immunoreactive and bioactive LH and the number of ovulated oocytes in intact rats. RU486 did not affect the ovarian weight increase induced by PMSG or the ovulatory response following PMSG plus human chorionic gonadotrophin (HCG) in rats hypophysectomized 24 h before initiating treatment or in intact rats where ovulation was blocked with chlorpromazine. The ovarian weight gain, the development of antral follicles and the increments in tissue and plasma progesterone concentrations and luteinizing hormone (LH) plasma concentrations elicited by DES in intact rats, were further increased by concomitant treatment with RU486, whereas the ovarian weight increase and antral follicle development induced by DES were completely inhibited by RU486 in hypophysectomized rats. Follicles stimulated to grow by DES plus RU486, but not by DES alone, were capable of ovulating in response to HCG.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed2000

Immunolocalization of progesterone and estrogen receptors in the sperm storage tubules of laying and diethylstilbestrol-injected immature hens.

The goal of this study was to determine whether sperm storage tubules (SST) in the uterovaginal junction (UVJ) contain receptors for progesterone and estrogen (PR and ER) and whether estrogenic stimulation induces activation of these receptors in the SST. Frozen sections of UVJ obtained from immature chicks treated with or without diethylstilbestrol (DES), which is an estrogenic substance, and those from laying hens were immunostained for PR and ER. In laying hens, immunoreactions for PR were observed in the SST cells and on the surface epithelium of UVJ; the strongest reactions appeared in the SST cells. In contrast, ER immunoreactions were localized in the SST cells but not in the other cells. Immunoreactions for PR and ER were negligible in the UVJ of control immature birds that received only the oil vehicle. However, in the DES-treated birds, PR immunoprecipitates were localized in the surface epithelium and SST cells, and there were ER in the SST cells. These results suggest that the SST cells in the UVJ contain PR and ER, and estrogenic stimulation may play a significant role in inducing activation of these receptors.

Animals↗

PubMed2002

Comparison of the developmental and reproductive toxicity of diethylstilbestrol administered to rats in utero, lactationally, preweaning, or postweaning.

The objective of the study was to determine which period of exposure produces the most marked effects on the reproductive capacity and sexual development of the rat, with particular emphasis on the relative sensitivity of in utero and postnatal exposures. The endocrine active chemical, diethylstilbestrol (DES) was used as an agent known to affect many of the endpoints examined. Hitherto, such comparisons have been made between studies, rather than within a study. Our data will be helpful in the interpretation of future multigenerational assay data. In preliminary studies, DES was shown to be active in the immature rat uterotrophic assay with a lowest detected dose of 0.05 mg DES/kg body weight by sc injection and 10 mg DES/l (1.6 mg DES/kg body weight) by administration in drinking water. A dose of 60 microg DES/l drinking water ( approximately 6.5mg DES/kg body weight/day) was selected for the main study since this represented the midpoint of the drinking water uterotrophic dose response and produced no overt maternal toxicity. The study used 10 groups of concomitantly pregnant animals, including 2 control groups. The first comparison was between the effects of exposure to DES in utero, and exposure from conception to weaning. Another group of animals was exposed to DES in utero and cross-fostered to untreated pregnant females to prevent lactational transfer of DES to pups. Two groups were exposed to DES neonatally, either from birth to postnatal day (PND) 10 (pups thus having only lactational exposure), or from birth until weaning (PND 21; pups thus having both lactational exposure and self-exposure via drinking water). In addition, a dose response study to DES was conducted on animals exposed from weaning to PND 100, when the first phase of the study was terminated. Pups exposed to DES in utero and pups exposed from weaning to PND 100 were bred to assess fertility of the F1 animals and the sexual development of F2 offspring. This last comparison was to determine the extent to which weanling rats could be used in endocrine toxicity studies to assess their potential to show activity in utero. The most sensitive period of exposure for inducing developmental effects in F1 animals was from weaning onwards. The neonatal to weaning period (PND 1-21) was the next most sensitive. Essentially no effects were induced in F1 animals exposed in utero. No effects of any kind were observed in animals only exposed over the early neonatal period of PND 1-10. The mean day of vaginal opening, testes descent, and prepuce separation was only altered in groups where postnatal exposure to DES continued beyond PND 10, or was started at weaning. No changes were observed in anogenital distance or caudal sperm counts. Some changes in organ weights were observed, but the interpretation of these was often confused by concomitant changes in body weight. In general, histopathological examination of tissues yielded no additional information. In breeding studies with animals exposed to DES in utero, or from weaning, reduced litter sizes and marginal advances in the day of vaginal opening were observed in the offspring, together with changes in organ weights. However, no unique sensitivity was noted for exposure in utero. Evaluation of the several exposure periods and the many markers monitored in this study may have individual strengths in individual cases, but when rigorously compared using the reference estrogen DES, many preconceptions regarding their absolute or relative value were not upheld. Further, each of these markers is subject to natural variability, as demonstrated by comparisons made among the 5 separate control groups available in parts of the present study. This variability increases the chance that small changes observed in endocrine toxicity studies employing small group sizes and a single control group, or no concomitant control group, may be artifactual. The most marked effects observed in this study were on the developmental landmarks in the F1 animals induced by exposures after PND 10. Some effects on developmental landmarks and organ weights were observed in F2 animals following exposure either in utero or postweaning. This study therefore does not establish a unique role for exposures in utero or during the early neonatal period.

Abnormalities, Drug-Induced↗

PubMed2003

Time- and dose-related effects of estradiol and diethylstilbestrol on the morphology and function of the fetal rat testis in culture.

UNLABELLED: The mechanisms underlying the action of estrogens in the fetal testis are still largely obscure. In particular, whether this action is direct or indirect remains largely unexplored. This study was aimed at investigating the effect of estradiol (E2) and diethylstilbestrol (DES) on the testis from 14.5-day-old rat fetuses in culture, at concentrations ranging from 4 x 10(-10) M (Kd of E2 for the estrogen receptors [ER]: 1-4 x 10(-10) M) to 4 x 10(-6) M (concentration previously shown in the literature to affect in vitro gonocyte proliferation). Exposure to DES and E2 decreased gonocyte number, the effects of DES being much more drastic than those of E2. Gonocyte number decreased in a concentration-dependent manner (day 3: -5%, -16%, and -80% at 4 x 10(-10) M, 4 x 10(-8) M, and 4 x 10(-6)M of DES, respectively), as well as in a time-dependent manner (at 4 x 10(-6) M DES: -31% on day 1, -60% on day 2, and -80% on day 3). This was due to a decrease in the gonocyte mitotic index and a dramatic increase in apoptosis. Importantly, in the presence of the anti-estrogen ICI 182.780 (ICI), the effect of DES was abolished. Sertoli cell number subsequently decreased (day 3), although the rate of apoptosis did not increase. These changes were less dramatic than those observed with gonocytes and were due to a decrease in Sertoli cell proliferation, which was not antagonized by ICI. Addition of 4 x 10(-6) M DES had no effect on basal Sertoli cell cyclic adenosine 5'-monophosphate (cAMP) levels or on follicle-stimulating hormone (FSH)-stimulated cAMP production after adjustment for Sertoli cell number. Finally, estrogens reduced both Leydig cell number (-26% on day 3, 4 x 10(-6) M DES) and basal and luteinizing hormone (LH)-stimulated testosterone production. The latter effects were antagonized by ICI. IN CONCLUSION: 1) E2 and DES induce alterations in the germ line and in somatic cells; 2) gonocyte alteration was the first event detected, and the action of estrogens at this level was mediated by ER, as is the case in Leydig cells; and 3) these data should help us to understand estrogen effects on the fetus and should be considered in the context of the debate on environmental estrogens.

Animals↗

PubMed2006

Effects of neonatal exposure to 4-tert-octylphenol, diethylstilbestrol, and flutamide on steroidogenesis in infantile rat testis.

Exposure of neonatal testis, populated by fetal-type Leydig cells, to endocrine-active compounds may have far-reaching consequences. Our aim was to resolve the sensitivity of testosterone synthesis of infant rat (Sprague-Dawley) testis to diethylstilbestrol (DES; 0.1-1.0 mg/kg), 4-tert-octylphenol (OP; 10-100 mg/kg), and Flutamide (FLU; 2.0-25 mg/kg) given by daily sc injections from birth to postnatal day 4. Testes and serum were collected on day 14 when body and testis weight, testicular histology, circulating testosterone, LH and FSH levels, and steroidogenic acute regulatory protein (StAR) and 3beta-hydroxy-steroid-dehydrogenase (3beta-HSD) protein levels were determined. DES at each dose and FLU at 25 mg/kg dose reduced testis weight and the diameter of seminiferous cords. FLU caused some Leydig cell hyperplasia. Plasma testosterone was reduced in all DES animals, LH elevated in DES 0.5 mg/kg and FLU 25 mg/kg animals, and FSH reduced in the DES 1.0 mg/kg group. Basal testicular ex vivo progesterone and human chorionic gonadotropin (hCG)-stimulated testosterone production were decreased in DES animals. Despite a decrease in hCG-induced cyclic adenosine-3',5'-monophosphate (cAMP) production, intratesticular testosterone was increased in the FLU 10 and 25 mg/kg groups. OP 100 mg/kg elevated hCG-induced progesterone production only. No changes were seen in 3beta-HSD protein levels in any treatment group. StAR levels were reduced in DES animals. The results indicate the sensitivity of postnatal fetal-type Leydig cells to endocrine-active compounds. Suppression of StAR expression level was an early sign of the DES-induced steroidogenic lesion. FLU-induced changes suggest the importance of androgen receptor-mediated regulation of testosterone synthesis in the postnatal rat testis. Octylphenol appeared less effective in bringing about acute steroidogenic changes.

Androgen Antagonists↗

PubMed2002

Inhibin a increases apoptosis in early ovarian antral follicles of diethylstilbestrol-treated rats.

The purpose of this study was to evaluate the role of inhibin A in follicular development and apoptosis-related mechanisms in preantral and early antral follicles from prepubertal diethylstilbestrol (DES)-treated rats. Granulosa cells isolated from the ovaries of 23- to 25-day-old rats were cultured in serum-free medium containing FSH (20 ng/ml), transforming growth factor beta (5 ng/ml), and estradiol (50 ng/ml) in the presence or absence of different concentrations of recombinant human inhibin A. (3)H-Thymidine incorporation was decreased in the presence of Inh, but no significant changes were observed in progesterone and estradiol levels in culture medium. An increase in low molecular weight DNA fragmentation indicative of apoptosis and an increase in the levels of Bax protein with no changes in Bcl-2 protein levels were evident in early antral follicles incubated for 24 h with Inh. For each animal, Inh (0.5 micro g/ovary) was injected intrabursally in one ovary, and the contralateral ovary served as a control. Ovarian histology revealed an inhibitory effect of Inh treatment on the follicular development induced by DES. At 24 h after Inh injection, the number of preantral follicles was increased compared with controls, whereas the number of early antral follicles was decreased. In addition, in vivo Inh treatment caused an increase in the percentage of apoptotic cells in preantral and early antral follicles. These results suggest that inhibin produced by the dominant follicle may act as a paracrine factor inhibiting the growth of neighboring follicles, thus participating in the mechanism of follicular selection.

Animals↗

PubMed2004

Diethylstilbestrol versus estradiol as neonatal disruptors of the hamster (Mesocricetus auratus) cervix.

The synthetic estrogen diethylstilbestrol (DES) is an established, estrogenic endocrine disruptor (ED). The Syrian golden hamster (Mesocricetus auratus) offers some unique advantages as an experimental system to investigate the perinatal ED action of DES and other estrogenic EDs. Previous analyses regarding the consequences of neonatal administration (100 microg) of DES versus estradiol-17beta (E2) showed that DES had a more potent disruptive effect on morphogenesis and gene expression in the uterus, oviduct, and ovary as well as in the testis and male accessory organs. The objectives of the present study were to describe the histopathological consequences of the two neonatal treatment regimens in the hamster cervix and to compare them with our previous observations in the hamster uterus. As previously found in the hamster uterus, DES was more potent than E2 as a neonatal disruptor of the hamster cervix in prepubertal animals and in ovarian-intact adult animals. However, the cervix-versus-uterus scenario diverged in animals that were ovariectomized prepubertally and then chronically stimulated with natural estrogen (E2). We confirmed previous observations that neonatal exposure to DES, but not to E2, permanently alters estrogen responsiveness in the adult hamster uterus, but neither neonatal treatment regimen affected estrogen responsiveness in the adult hamster cervix. These results suggest that an unidentified ovarian factor influences the extent of neonatal DES-induced disruption of the cervix, but not of the uterus, in hamsters.

Aging↗

PubMed2004

Abnormal morphology of the penis in male rats exposed neonatally to diethylstilbestrol is associated with altered profile of estrogen receptor-alpha protein, but not of androgen receptor protein: a developmental and immunocytochemical study.

Objectives of the study were to determine developmental changes in morphology and expression of androgen receptor (AR) and estrogen receptor (ER)alpha in the body of the rat penis exposed neonatally to diethylstilbestrol (DES). Male pups received DES at a dose of 10 microg per rat on alternate days from Postnatal Day 2 to Postnatal Day 12. Controls received olive oil vehicle only. Tissue samples were collected on Days 18 (prepuberty), 41 (puberty), and 120 (adult) of age. DES-induced abnormalities were evident at 18 days of age and included smaller, lighter, and thinner penis, loss of cavernous spaces and associated smooth muscle cells, and increased deposition of fat cells in the corpora cavernosa penis. Fat cells virtually filled the entire area of the corpora cavernosa at puberty and adulthood. Plasma testosterone (T) was reduced to an undetectable level, while LH was unaltered in all treated groups. AR-positive cells were ubiquitous and their profile (incidence and staining intensity) did not differ between control and treated rats of the respective age groups. Conversely, ERalpha-positive cells were limited to the stroma of corpus spongiosus in all age groups of both control and treated rats, but the expression in treated rats at 18 days was up-regulated in stromal cells of corpora cavernosa, coincident with the presence of morphological abnormalities. Hence, this study reports for the first time DES-induced developmental, morphological abnormalities in the body of the penis and suggests that these abnormalities may have resulted from decreased T and/or overexpression of ERalpha.

Aging↗

PubMed2004

Effects of neonatal exposure to diethylstilbestrol, tamoxifen, and toremifene on the BALB/c mouse mammary gland.

In this study, we compared the long-term effects of neonatal exposure to diethylstilbestrol (DES, 0.0125-50 microg), tamoxifen (TAM, 0.0125-50 microg), and toremifene (TOR, 53 microg) on mammary gland development and differentiation. Allometric growth of the mammary ducts was stimulated by neonatal DES exposure (12.5 microg) and impaired by exposure to TAM (25 microg). Neonatal treatment with high doses of DES resulted in mammary ducts that displayed extensive dilatation and precocious lactogenesis in postpubertal, nulliparous females. Initiation of this precocious differentiation coincided with the absence of corpora lutea, increased levels of serum prolactin (PRL), and the induction of Prl mRNA expression within the mammary glands. Neonatal exposure to 1.25 microg TAM increased alveolar development in postpubertal, nulliparous females similar to that recorded in females treated with low doses of DES. Lower doses of TAM did not affect alveolar development, whereas branching morphogenesis and alveolar development were impaired by higher doses. Increased alveolar development in females exposed to 1.25 microg TAM was associated with elevated serum progesterone (P) and increased alveolar development in response to exogenous P. Taken together, our findings demonstrate that neonatal exposure to both DES and TAM exerts long-lasting effects on the proliferation and differentiation of the mammary glands in female BALB/c, primarily as the result of endocrine disruption.

Aging↗

PubMed1983

Exposure to diethylstilbestrol during pregnancy permanently alters the ovary and oviduct.

To determine the effects of transplacental exposure to diethylstilbestrol (DES) on the ovary and oviduct of the CD-1 mouse, timed pregnant mice were injected subcutaneously with DES (100 micrograms/kg) on Days 9 through 16 of gestation and female offspring sacrificed from 4 weeks to 10 months of age. Following DES exposure, ovarian alterations such as inflammation, a prominent interstitial compartment composed of medullary tubule-like structures, and intra- and para-ovarian cysts from mesonephric remnants were observed. In addition, there were oviductal abnormalities including malformation. As reported previously, the oviduct was closely adherent and coiled around the ovary in a similar position to that seen in the fetal mouse. This malformation was termed developmental arrest of the oviduct (DAO) and was a consistent finding in female offspring exposed prenatally to DES (100 micrograms/kg). Increased prevalence of salpingitis and microscopic alterations in the oviduct were also observed. Oviductal epithelium was mostly secretory type with basal vacuoles. In some cases, oviductal epithelium was hyperplastic and formed mucosal folds resembling glands which extended through the muscularis (diverticulosis). The extent of the adenomatous mucosal folds and the degree of extension through the muscularis increased with the age of the animal (100% at 10 months). Some characteristics of this abnormality resembled salpingitis isthmica nodosa, a lesion described in women which is associated with ectopic pregnancies and subfertility. Gross and microscopic changes in the oviduct were more consistent than were the changes among other portions of the reproductive tract of DES-treated mice previously reported. Since subfertility has been described in this mouse model as well as in prenatally DES-exposed women, the data presented in this report may help in evaluation of the reported reduced fertility in exposed patients as well as other infertility patients.

Animals↗

PubMed1984

Molecular differentiation of the mouse genital tract: altered protein synthesis following prenatal exposure to diethylstilbestrol.

Exposure in utero to the synthetic estrogen diethylstilbestrol (DES) has been associated with the subsequent development of reproductive tract lesions in both women and experimental animals. Using the techniques of organ culture and two-dimensional (2-D) gel electrophoresis, the effects of DES on protein synthetic patterns were studied during fetal and neonatal development of the CD-1 mouse. The protein patterns, analyzed by comparing 2-D fluorograms after [35S] methionine incorporation at different developmental stages, were correlated with the histology at the same age. Several qualitative and quantitative changes in protein synthesis were observed after prenatal DES exposure. A protein, apparent by Day 14 of gestation, with molecular weight approximately 70,000 and pI of 5.8, was observed to be greatly diminished in all reproductive tract tissues exposed to DES during prenatal development. This alteration, induced in utero, persists through the early postnatal differentiation of the genital tract (17 days old). This protein may provide an early marker for alterations in normal reproductive tract function.

Animals↗

PubMed1984

Prenatal diethylstilbestrol exposure in the mouse: effects on ovarian histology and steroidogenesis in vitro.

The effect of prenatal diethylstilbestrol (DES) exposure on ovarian morphology and steroid production in vitro was evaluated in the mouse. Pregnant mice were injected with 100 micrograms DES per kg maternal body weight on Days 9 to 16 of gestation and the female offspring sacrificed from 3 to 14 months of age. Ovaries of DES-exposed animals weighed significantly less than controls at 3 months of age (9.4 +/- 0.79 mg vs. 17.54 +/- 0.69 mg, mean +/- SEM). Histologically, the DES animals had an apparent increase in the size of the interstitial compartment with cells showing uniform vacuolization and tubular architecture. In addition, the lipid content of the interstitial compartment, as assessed by oil-red-O staining, was markedly increased in the treated animals as compared to controls and corresponded to the vacuolization. Ovarian steroidogenesis in vitro was determined by excising ovaries of animals from 3 to 14 months of age, placing them in tissue culture for 24 h, and measuring media steroids by radioimmunoassay. Estrogen, progesterone and testosterone production per mg of tissue was increased in DES-exposed animals at all ages studied. To correct for changes in the relative sizes of the ovarian compartments secondary to DES exposure, steroid production was calculated on a "per ovary" basis. Only testosterone production remained elevated "per ovary" in the DES-exposed animals which is consistent with androgens being the primary secretory products of the enlarged interstitial compartment. These data indicate that in the mouse, prenatal DES exposure is associated with an enlargement of the ovarian interstitial compartment, increased lipid content of the individual interstitial cells, and increased interstitial compartment testosterone production in vitro throughout the reproductive life span of the animal.

Animals↗

PubMed1988

Diethylstilbestrol-induced cervical and vaginal adenosis using the neonatal mouse model.

The relevance of diethylstilbestrol (DES) administration to neonatal mice as a model for human pathology attributed to the use of DES in high-risk pregnancies has been investigated, particularly with respect to cervical and vaginal changes in female offspring. Neonatal DES treatment of mice results in tonic pituitary gonadotropin release and continuous estrogen secretion by the ovary. Studies were designed to determine the effect of this altered ovarian endocrine activity on cervical and vaginal histopathology. Ovariectomy of DES-treated mice, with or without estradiol replacement, did not eliminate the lesions, nor did estrogen and progesterone administered in a regimen intended to mimic estrous cycle changes. Induction of the constant estrus state by neonatal estradiol benzoate or testosterone propionate administration or by exposure to constant light did not produce the type of vaginal or cervical changes seen in DES mice. Thus, altered ovarian function is apparently not required for the vaginal and cervical changes appearing in later life. A role for endogenous (or exogenous) ovarian hormones in the developmental progression toward normality is suggested.

Animals↗

PubMed1990

Ovarian reproductive function after exposure to diethylstilbestrol in neonatal life.

Inbred and random-bred NMRI mice were treated with diethylstilbestrol (DES, 5 micrograms per day) or vehicle (olive oil) on Days 1-5 after birth. At the age of 8 wk, females were treated with saline or eCG and hCG to induce ovulation. Ova never occurred in the ampulla of the uterine tube of saline-treated, DES-treated females when these mice were not mated. After gonadotropin treatment, ova were found in the ampulla of all olive oil-treated females and in approximately 80% of DES-treated females. The number of ovulated ova was similar in both groups. Twenty percent of gonadotropin-treated, DES-treated females had ova in the ampulla and a vaginal plug after being caged with males but none became pregnant. Ovaries from inbred control or DES-treated females were grafted to the ovarian bursa of control or DES-treated ovariectomized hosts. DES-treated hosts, carrying control or DES-exposed ovaries, never became pregnant. Control females, with control ovaries or DES-exposed ovaries, became pregnant; pregnancy rate and litter size were similar for control mice regardless of whether they were supporting DES-exposed or control ovaries. Oocytes from ovaries exposed neonatally to DES can thus give rise to apparently normal offspring. The results also indicate DES-induced nonovarian disturbances, e.g. tubal and/or endometrial function, both of which are important for fertility. In the grafting experiments, a high mortality rate was found in inbred DES-exposed females caged with males. All deaths were associated with vaginal concrements (vaginal stones) and intestinal complications.

Animals↗

PubMed1990

Polyovular follicles in mouse ovaries exposed neonatally to diethylstilbestrol in vivo and in vitro.

In 35-day-old C57BL/Tw female mice given daily injections of 1 microgram diethylstilbestrol (DES) for 5 days from the day of birth, a significantly higher incidence of polyovular follicles (PF) were found in the ovaries than in those of age-matched control mice. Ovaries of prepubertal mice treated neonatally with oil or DES (DES mice) showed an enhancement of ovulation and luteinization following a combined treatment with eCG and hCG. Tubal ova in DES mice treated with eCG plus hCG were surrounded by many granulosa cells. Incidence of PF in control mice was not changed by eCG plus hCG treatment. In contrast, PF incidence in DES mice was reduced by prepubertal injections of eCG plus hCG. A high incidence of PF was also found in newborn mouse ovaries transplanted for 30 days into ovariectomized adult hosts given DES injections, but not in ovaries transplanted into intact or ovariectomized DES-untreated hosts. When neonatal ovaries were cultivated in a serum-free medium containing DES for 5 days and then transplanted into ovariectomized hosts, PF were formed in the grafts, but not in DES-unexposed grafts. Oocytes from PF in DES mice were found to have a smaller capacity for fertilization when examined in vitro. The present study also demonstrated that neonatal ovaries exposed to estrogen in vivo or in vitro (which produces PF in prepubertal hosts) are capable of responding to gonadotropins given later, resulting in a reduction of PF incidence, and that exogenous estrogen acts directly on neonatal ovaries to induce PF.

Animals↗

PubMed1991

Diethylstilbestrol-induced perinatal lethality in the rat. I. Relationship to reduced maternal weight gain.

An analysis was performed to determine the mechanism of depressed maternal weight gain and its effect on perinatal lethality following prenatal exposure to diethylstilbestrol (DES). Pregnant Sprague-Dawley rats were dosed orally by gavage with DES or corn oil (control) during various intervals of gestation. The maternal weight-gain patterns of control and treated dams and the number of live offspring were recorded. The amounts of feed and water intake and feces and urine output in pregnant dams were measured, and metabolic rate and thyroid hormone levels were also determined. DES (at 45 micrograms/kg/day) was embryo- and fetolethal during implantation and parturition, and there was an accompanying decline in maternal weight. Growth of adult males, nonpregnant females, and weanlings of both sexes was also depressed. During pregnancy, the net intake of feed and water was not altered by the drug, but maternal serum thyroxine and metabolic rate were significantly elevated. Reduced metabolic efficiency, then, is the likely mechanism for weight depression. Reduction of maternal weight gain during pregnancy by DES is a diagnostic indicator of fetolethality, but is probably not causally related to it.

Animals↗

PubMed1991

Diethylstilbestrol-induced perinatal lethality in the rat. II. Perturbation of parturition.

Evidence is presented suggesting that the fetolethal properties of diethylstilbestrol (DES) are indirect, mediated maternally through a perturbation of the normal mechanisms of parturition. Oral administration of the compound to Sprague-Dawley rats near Day 18 of pregnancy was shown to delay the onset of parturition, prolong labor, and induce dystocia, with a concomitant large increase in perinatal mortality. Exposure during Days 8-16 was without effect, whereas treatment in the Day 18-20 interval resulted in preterm delivery. Inability to initiate labor at term, accompanied by fetal death, also resulted from the administration of hCG on Days 16-18. The relative incidence of stillbirths in DES-exposed pups was markedly decreased by Caesarean delivery. The average weight of the maternal pituitary gland was not affected by treatment, whereas maternal adrenal glands were 30% larger. Maternal blood levels of corticosterone were not significantly elevated, however. The average number of follicles on Day 21 was significantly reduced by DES, and a histological analysis failed to demonstrate a luteotropic effect of the compound. In dams treated on Days 8-18, serum progesterone was reduced by as much as 60%, and total estrogens were 32% lower than in controls. We conclude that DES acts in the rat to depress the preterm levels of steroid hormones, which leads to a failure of uterine contraction accompanied by placental detachment and fetal death.

Animals↗

PubMed1991

Effects of neonatal exposure to diethylstilbestrol on early mouse embryo development in vivo and in vitro.

Eight-week-old female mice of the NMRI strain that had been treated neonatally with diethylstilbestrol (DES, 5 micrograms/day for five days) or not (controls) were treated with gonadotropins to induce ovulation and then were artificially inseminated. Ova or young embryos were recovered from the oviducts on the morning after insemination and on Days 2, 3, and 4. In other experiments, ova were obtained from inseminated females on the morning after ovulation and cultured in vitro. In DES-treated females, a few zygotes developed to the 4-cell stage, but no more advanced stages were seen. Under in vitro conditions, zygotes from DES-treated females developed into blastocysts and to the implantation stage, but the incidence of these stages was lower than with zygotes from controls. Our results point to an abnormal oviductal function in DES-treated females that is not compatible with early embryo survival, even though an additional zygote factor contributing to degeneration of early cleavage stages cannot be excluded.

Animals↗