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Termination of pregnancy and occurrence of abnormalities following estrone administration during early pregnancy
... The situation with estrogen, however, is quite different. Early work showed that administration of pharmacological doses of estrogens caused high levels of embryonic mortality [3,4], although, administered later in gestation, estrogens had less effect on survival but retarded fetal growth [5]. Furthermore, a reduction of estrogen concentrations by ovariectomy, with progesterone and partial estrogen replacement, elicited fetal and placental hypertrophy that was prevented when higher levels of estrogen replacement were used [6][7][8]. ...
... Both estrogen and progesterone are essential for fetal survival in the rat, as demonstrated by ovariectomy and selective hormone replacement [22,23]. However, pharmacological doses of estrogens [3,4] are highly lethal. The major finding of the present work was that even a minor elevation of maternal E 2 concentrations over mid-gestation can elicit fetal death. ...
High doses of estrogens cause embryonic mortality, and fetal and placental growth retardation in rats. This study addresses the physiological relevance of such findings. Estradiol benzoate (EB), by s.c. injection, or estradiol-17β (E2), delivered by a miniosmotic pump, raised maternal E2 concentrations from only slightly above control values to 5-fold. EB (1 μg/day) over Days 6–13, 8–13, and 11–13, and continuous infusion of E2 (15 ng/h; Days 10–13) reduced fetal survival to 0%, 0%, 22%, and 75%, respectively. Single injections of EB showed that its lethal effect declined rapidly over Days 9 (44% survival) to 13 (90% survival). Embryos died within 48 h, but death was not due to luteal failure since progesterone levels were maintained and progesterone administered with EB did not reduce mortality. Administration of EB at 1 μg/day (Days 14–21) or E2 at 40 ng/h (Days 13–16) retarded fetal and placental growth but did not affect survival. The rat embryo is highly sensitive to elevated maternal estradiol concentrations over much of gestation. The early lethal effect implies that endogenous E2 production is carefully regulated to maintain pregnancy; the latter growth-retarding effect suggests that E2 may have a role in the normal control of fetal growth.
... As reported by Tiboni et al. (2009), a preliminary study conducted by these authors to select ECP testing dosages revealed overt embryo lethal effects involving the majority of the litter following administration of 3 g/rat ECP. Other literature also confirms that high estrogen levels can increase embryonic mortality (Dreisbach, 1959;Haddad and Ketchel, 1969;Sarkar et al., 1986;Matsuura et al., 2004) Therefore, higher ECP doses were not tested in our study. ...
Epoxiconazole (CAS-No. 133855-98-8) was recently shown to cause both a marked depletion of maternal estradiol blood levels and a significantly increased incidence of late fetal mortality when administered to pregnant rats throughout gestation (GD 7-18 or 21); estradiol supplementation prevented this epoxiconazole effect in rats (Stinchcombe et al., 2013), indicating that epoxiconazole-mediated estradiol depletion is a critical key event for induction of late fetal resorptions in rats. For further elucidation of the mode of action, the placentas from these modified prenatal developmental toxicity experiments with 23 and 50 mg/kg bw/d epoxiconazole were subjected to a detailed histopathological examination. This revealed dose-dependent placental degeneration characterized by cystic dilation of maternal sinuses in the labyrinth, leading to rupture of the interhemal membrane. Concomitant degeneration occurred in the trophospongium. Both placentas supporting live fetuses and late fetal resorptions were affected; the highest degree of severity was observed in placentas with late resorptions. Placental degeneration correlated with a severe decline in maternal serum estradiol concentration. Supplementation with 0.5 and 1.0 μg of the synthetic estrogen estradiol cyclopentylpropionate per day reduced the severity of the degeneration in placentas with live fetuses. The present study demonstrates that both the placental degeneration and the increased incidence of late fetal resorptions are due to decreased levels of estrogen, since estrogen supplementation ameliorates the former and abolishes the latter. Birth Defects Res (Part B) 98:208-221, 2013. © 2013 Wiley Periodicals, Inc.
... It is known that the administration of estrogen and synthetic estrogens, diethylstilbestrol causes a high rate of embryonic mortality in rats and mice (Dreisvach, 1959;Sarkar et al., 1986;Scott and Adejokun, 1980). The rat embryo is highly sensitive to elevated maternal estradiol concentrations over much of the gestation (Haddad and Ketchel, 1969). The early lethal effect implies that endogenous estrogen production is carefully regulated to maintain pregnancy; the latter growth-retarding effect suggests that estrogen may have a role in the normal control of fetal growth, but the cause of the estrogen-induced mortality is unknown (Bartholomeusz et al., 1999). ...
We examined the sequential histopathological changes in the placenta from rats exposed to estrogen. 17 β-estrogiol-3-benzoate was intraperitoneally administered at 100μg/animal/day during GD 6 to GD 8 (GD6-8 treated group), GD 9 to GD 11 (GD9-11 treated group) and GD 12 to GD 14 (GD12-14 treated group), and the placentas were sampled on GDs 11, 13, 15, 17, and 21. Fetal mortality rates were increased up to approximately 50% in the GD6-8 and 9-11 treated groups, but there was no change of fetal weight on GD 21. An increase in placental weight and a reduction in fetal/placental weight ratio were detected during GD 17 to GD 21 in the GD6-8 treated group. Histopathologically, hypoplasia of metrial gland was detected with defective development of spiral arteries in the GD6-8 and GD9-11 treated groups. A decrease in the thickness of metrial gland was observed from GD 11 onwards in the GD6-8 treated group and from GD 13 onwards in the GD9-11 treated group. The endovascular trophoblasts invaded into the spiral arteries in the deep part of metrial gland in these treated groups. The number of phospho-histone H3 positive cells was decreased on GD 11 or GD 13 in these groups. In the decidua basalis, transitory necrosis was observed with hemorrhage on GD 13 in the GD6-8 and GD9-11 treated groups. In the labyrinth zone, cystic dilatation of the sinusoid was observed with congestion in the GD6-8 treated group, resulting in an increased placental weight. Therefore, we consider that estrogen inhibits the proliferation of decidualized endometrial stromal cells in the metrial gland, and leads to metrial gland hypoplasia with less development of the spiral arteries. The reduced utero-placental blood flow is supposed to be one of the important factors for poor reproductive performance.
... It is worthwhile to remember that, as reported in the materials and methods section, a preliminary study conducted to select ECP testing dosages revealed overt embryo lethal effects involving the majority of the litter following administration of ECP at levels of 3 mg/rat. The concept that supraphysiological estrogen levels can increase embryonic mortality is also consistent with literature data (Dreisbach, 1959;Haddad and Ketchel, 1969;Sarkar et al., 1986;Matsuura et al., 2004). ...
The aromatase inhibitor, letrozole, exerts embryo toxic effects in rats, causing increased embryo lethality and anomalies of the axial skeleton at pharmacologically relevant doses. Letrozole acts by inhibiting estrogen biosynthesis. It may thus be feasible that estrogen deprivation is a crucial determinant of the elicited developmental toxic effects. In order to gain insight on this hypothesis, the present study tested the capacity of estrogen replacement in preventing letrozole-mediated embryopathy.
Pregnant Sprague Dawley rats were exposed to letrozole alone (0.04 mg/kg), or in combination with estradiol cyclopentylpropionate (ECP) at 0.5, 1 or 2 microg/rat. A control group receiving only the vehicles was also included. Animals were exposed during gestation Days 6-16 (corresponding approximately to 3-10 weeks of gestation in the human). Developmental end-points, including intrauterine mortality, fetal growth, placental weight and incidence of structural abnormalities, were evaluated near term gestation.
Exposure to letrozole alone was lethal for 41% of conceptuses, and caused minor axial skeletal anomalies in 51% of live fetuses. ECP co-administration effectively prevented letrozole-induced embryolethality, but failed to reduce the incidence of axial skeletal alterations.
The obtained results support the concept that inhibition of estrogen biosynthesis represents a critical determinant of letrozole-induced embryonic mortality. A mechanism other than estrogen deprivation appears to underlie the initiation of skeletal anomalies.
... Disturbance of the normal oestrogen/progesterone stimulation could lead to termination of pregnancy. Thus, preimplantation treatment of the intact rat with high doses of oestrogen interrupted pregnancy (Haddad & Ketchel, 1969); however, physiological doses of oestrogen (Haddad & Ketchel, 1969), and relatively high doses of progesterone (up to 16 mg/day—see Sammelwitz, Dziuk & Nalbandov, 1956; Cochrane & Meyer, 1957) did not have adverse effects on the pregnancy. Morulae degenerated subsequent to their transfer into the uteri of ovariectomized, progesterone (2 mg/day)-treated rats (Dickmann, 1970); apparently, progesterone unopposed by endogenous oestrogen has toxic effects (either direct, indirect, or both) on the morula. ...
Pregnant rats were injected subcutaneously with either 1 μg oestrone, 12·5 mg Depo-medroxyprogesterone acetate (MPA), or both. Oestrone injected on Day 3 had no effect on pregnancy. Injection of MPA on Day 1 caused delayed implantation, which was abolished when, in addition, oestrone was injected on Day 4. Injection of MPA on Day 1 followed by oestrone on Day 3 destroyed the eggs during the morula—blastocyst transformation period. The contraceptive effect of the latter treatment suggests a general guide-line for postcoital contraceptive trials in women.
... With regard to progesterone, growth and development of the embryo and fetus are unaffected over a wide range of progesterone concentrations in maternal plasma [7]. On the other hand, pharmacological doses of estrogens cause high levels of embryonic mortality [8] , although administration later in pregnancy causes retarded fetal growth with less effect on survival [9]. In order for estrogens to exert their biological effects, they need to bind to the ER which then undergoes a conformational change allowing it to interact with chromatin and to modulate transcription of target genes [10]. ...
High levels of estrogens during pregnancy not only retard placental and fetal growth but can lead to reproductive tract abnormalities in male progeny. Estrogens act through estrogen receptors (ER) to modulate the transcription of target genes. These ER exist in two isoforms, ER alpha and ER beta and recently several variants of these isoforms have been identified.
The expressions of ER isoforms and variants have been studied in rat placenta at 16, 19 and 21 days gestation (dg). Gene expression was assessed using RT-PCR and real time PCR while protein expression was studied using Western blotting followed by immunodetection. Placental homogenates were probed with: a monoclonal antibody raised against the steroid binding domain of the ER alpha (ER alpha -S), a monoclonal antibody raised against the hinge region of ER alpha (ER alpha -H) and a polyclonal antibody raised against the amino terminus of ER beta.
ER alpha and ER beta mRNA and protein were detected from as early as 16 dg. Two PCR products were detected for ER alpha, one for the wild type ER alpha, and a smaller variant. Real time PCR results suggested the presence of a single product for ER beta. The antibodies used for detection of ER alpha protein both identified a single 67 kDa isoform; however a second 54 kDa band, which may be an ER alpha variant, was identified when using the ER alpha -H antibody. The abundance of both ER alpha bands decreased significantly between 16 and 19 dg. As for ER beta, four bands (76, 59, 54 and 41 kDa) were detected. The abundance of the 59 and 54 kDa bands decreased significantly between 16 and 19 dg.
This study shows that both ER protein isoforms and their variants are present in rat placenta. The decrease in their expression near parturition suggests that the placenta may be relatively unresponsive to estrogens at this stage.
Background: To clarify the effect of estradiol benzoate on placental structure and its consequences for fetal survival and fetoplacental growth. Study design: Estradiol benzoate (0, 0.1, 1, 10, 100 μg/day) was infused intraperitoneally into pregnant Wistar rats from 12 to 19 days' gestation. Survival rate, weight of pups and placentas at 20 days' gestation, and plasma levels of estrogen and progesterone were measured. Pathological changes in the placenta were also examined. Results: Estradiol benzoate reduced fetal survival (1 μg/day: 100%, 10 μg/day: 70%, 100 μg/day: 14.6%) and the weights of the pups and placentas in a dose-dependent manner. Maternal estradiol concentration was raised 23-fold with 100μg/day of estradiol benzoate. Trophoblast degeneration, including apoptosis and destruction of placental labyrinth was induced but the structures of the maternal kidney and liver were not affected. Conclusions: In pregnant rats, estradiol benzoate causes fetal mortality at a pharmacological dose (more than 10 μg/day) and fetoplacental growth retardation via trophoblastic degeneration and destruction of the placental labyrinth even at a physiological dose (1 μg/day).
The last 40 years have seen many reports that man-made chemicals and environ- mental pollutants cause adverse effects in humans and wildlife; however, actually linking an exposure with a mechanism and an effect has yet to be done for endocrine disruption. Certainly, studies in experimental animals have shown that sufficient doses of select com- pounds can disrupt the endocrine system and produce the attendant adverse outcomes. The purpose of this contribution is to evaluate some of the recent reports of the adverse effects on reproduction and development, the immune system, and the nervous system that have been observed in experimental animals after treatment with man-made chemicals and environ- mental pollutants. Space limitations prevent us from presenting a comprehensive review of all reported endocrine active chemicals and their effects. Instead, we have focused on draw- ing conclusions as to the scope and etiology of the adverse effects in experimental animals using examples from the scientific literature, and on suggesting a path forward for further work.
Placental growth and function are of biological significance in that placental tissue promotes prenatal life and the maintenance of pregnancy. Exposure to synthetic estrogens causes embryonic mortality and placental growth restriction in mice. The aim of the present study was to examine the effects of diethylstilbestrol (DES) on placenta in mice. DES at 1, 5, 10 or 15 µg kg(-1) day(-1) , or 17β-estradiol (E(2) ) at 50 µg kg(-1) day(-1) , was administered orally to ICR mice on days 4 through to 8 of gestation. Expression of ERα, ERβ, ERRβ or ERRγ mRNA in the junctional or labyrinth zone of the placentas on day 13 was assessed using RT-PCR, as well as the embrynic mortality, embryonic and placental weight, histological changes of labyrinth and ultrastructural changes of the trophoblast giant cells (TGCs). Embryo mortalities in the DES 10 and 15 µg kg(-1) day(-1) groups were markedly increased. No significant changes in embryonic and placental weight were observed in any DES- or E(2) -exposed groups. Expression of ERα mRNA in the junctional zone with male embryos in the 5 µg kg(-1) day(-1) group was significantly higher than that in the control, whereas expression was not determined in the 15 µg kg(-1) day(-1) group. Histological observation revealed that the placentas exposed to DES at 10 µg kg(-1) day(-1) lacked the developing labyrinth. Ultrastructural observation of the TGCs showed poor rough-surfaced endoplasmic reticulum in the DES 10 µg kg(-1) day(-1) group. The present data suggest that developmental changes induced by DES may be related to interference with the nutrition and oxygen exchange between mother and embryo or decreased protein synthesis, resulting in a high frequency of embryo mortality. Copyright © 2012 John Wiley & Sons, Ltd.
Females from two strains of mice were treated orally for 4 weeks daily with norethisteroneacetate (N). C3H-inbred females received 10 mg or 1 mg N per day and NMRI random-bred females only 1 mg per day. The effect on the oocytes of N-treat inent was measured by two methods: (1) Dominant lethal assay with C3H and NMRI-females; (2) Chromosome analysis of spontaneously ovulated metaphase-II oocytes from C3H mice. The analysis was carried out in two steps: immediately after stopping the application and after a longer interval without any treatment during weeks 7, 8 and 9. The increase of aneuploid oocytes ovulated during the first 2 weeks was significant only after the extremely high dosage of 10 mg N per day. Only a slight but not significant increase of non-disjunction was found after 1 mg N immediately after treatment as well as after the longer interval without N application. The frequency of pre- and postimplantation loss was significantly increased in those C3H females fertilized within the first two weeks. Only a slight increase (P ≈ 0.05) however, was observed in NMRI mice and. only during the first week after treatment.Conclusions: (r) The frequency of non-disjunction during the first meiotic division in C3H females depended on the gestagen dose applied. (2) Diploidy was not the pre-dominating type of abnormality. (3) No significant increase of aneuploidies was observed with the low dose-group. (4) The findings with the dominant lethal assay proved to be strain-specific.
Recently, a 5-hydroxytryptamine (5-HT) receptor has been described, whose pharmacology was distinct from that of the already known serotonergic receptors, so that it has been called 5-HT4. Because the lack of a high affinity radioligand, the identification of this receptor depends entirely on functional pharmacological analysis. Its stimulation leads to an increase in cyclic AMP accumulation in mouse embryo colliculi neurons, in guinea pig hippocampus and in human heart. We studied the effect of two indoleamines, 5-HT and 5-methoxytryptamine (5-MeO-T), and a benzimidazolone derivative, BIMU 8, in stimulating basal adenylyl cyclase activity in human frontal cortex, and characterized the receptor subtype involved. In membranes prepared from this tissue, 5-HT, 5-MeO-T and BIMU 8 dose-dependently stimulated (13–25 %) the basal enzyme activity (220 pmoles cyclic AMP/min/mg protein). 5-MeO-T behaved as a full agonist, BIMU 8 elicited about 60 % of the maximal 5-HT effect. The selective 5-HT1A agonist 8-OH-DPAT, was devoid of any stimulating activity. ICS 205–930, a low affinity 5-HT4 receptor antagonist, completely reversed the effect of all three agonists at high concentrations. Therefore, the present data are consistent with the 5-HT-mediated stimulation of adenylyl cyclase in human frontal cortex resulting by the activation of a 5-HT4 receptor subtype.
The oral activity of a new synthetic estrogen [3-(2-propynyloxy)-estra-1,3,5(10)-trien-17β-ol trimethylacetate], AY-20,121, was studied in a battery of tests in ovariectomized and intact rats. Its activity was compared to the activity of ethynylestradiol (EE) and its 3-cyclopentyl ether (EECPE). In the vaginal cornification test in ovariectomized rats AY-20,121 was less potent as an estrogen than EECPE, but was slightly more potent than EE. However, at higher dose levels the duration of estrogenicity of AY-20,121 and EECPE was significantly longer than that of EE. A single dose (5 mg/rat = 20 mg/kg) of AY-20,121 had a longer duration of effect in preventing conception than the same dose of EE and EECPE. Possible mechanisms of such actions are discussed.
Two sex steroid compounds which have been used clinically for parenteral supportive therapy of pregnancy were examined for embryotoxic effects in rhesus and cynomolgus macaques. Hydroxyprogesterone caproate (HPC) alone or in combination with estradiol valerate (EV) were administered intramuscularly (i.m.) to pregnant monkeys at 7-day intervals between 20 and 146 days of gestation and fetuses were examined following cesarean section at 150 +/- 2 days. HPC alone was tested in both species at doses ranging from 0.01 X to 10 X the human dose equivalent (HDE); only rhesus monkeys were exposed to the HPC + EV combination at 0.1 X to 10 X HDE. Total embryolethality resulted following the administration of HPC alone and combined with EV at 1 X and 10 X HDE in rhesus monkeys; the level of abortions in cynomolgus monkeys exposed to HPC (0.1 X to 1 X HDE) was comparable to controls. A small number of nonspecific malformations and developmental variations observed in cynomolgus fetuses after HPC exposure were considered to be incidental findings. No anomalies were found in surviving rhesus monkey fetuses treated with HPC + EV. The results indicate that long-term in utero exposure to the progestin, HPC, alone or in combination with EV in rhesus and cynomolgus monkeys, is embryolethal but not teratogenic at doses up to ten times the human therapeutic dose.
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Although a previous study (Kramen, 1969) demonstrated normal uterine decidual sensitivity in young female rats which had been given low (50 μg) doses of testosterone propionate (TP) shortly after birth, it is not known if uterine sensitivity to blastocyst implantation is normal in such rats. The present study was undertaken to determine if the uteri of adult rats treated neonatally with TP could support implantation.
Female Holtzman rats were treated on Day 5 of life with 50 μg TP as previously described (Kramen & Johnson, 1971). Various hormonal treatments were used to induce implantation in 100- to 120-day-old TP-treated rats which were mated after ovulation had been induced. In one group, the progesterone necessary to maintain pregnancy was supplied by supporting corpora ultea with a normal female pituitary implanted beneath the kidney capsule (Nikitovich-Winer
The influence of various steroids upon placental size in the intact, castrate, and hypophysectomized pregnant rat was studied. Pregnancy maintenance utilizing estrone and progesterone injections resulted in an increase in placental weight, but maintenance of pregnancy with progestagens alone did not. Adequate amounts of Provera, a potent progestational agent, inhibited estrone-induced placental hypertrophy. The presence of the anterior pituitary gland was not necessary for the placental hypertrophy in response to estrogen injection in the castrate, and enlarged placentae could not be induced by estrone administration to the intact pregnant rat.
Pregnant mice were injected with 12.5 micrograms DES/kg body weight or 25 micrograms DES/kg body weight daily from gestation day 9 through day 12 or 16 and sacrificed on day 13 or 17. Placentas of DES treated animals were smaller than controls, the effect being dose dependent. Histologic changes in 13 gestation day placentas regional thinning of the labyrinth associated with an apparent inhibition of trophoblast maturation and development of fetal blood vessels. Knots of mononuclear cells form in the labyrinthine region of 13 day placentas exposed to the higher dose of DES. By 17 days gestation, coagulative necrosis is common in the decidua basalis, being most severe in those animals receiving 25 micrograms DES/kg. In many placentas the labyrinthine region is absent. The only remaining elements are trophoblast cells, giant cells and glycogen-containing cells. Fetal deaths associated with the lower dose of DES increased with time whereas 100% fetal mortality was associated with the higher dose.
Pregnant mice were treated with a single subcutaneous injection of either cyproterone acetate (CA) or medroxyprogesterone acetate (MPA). In the first experiment the animals received 5–900 mg/kg of the hormone before implantation (day 2 of pregnancy). CA treatment on day 2 caused a dose-dependent decrease in fetal weight and a significant dose-dependent increase in the rates of cleft palate and urinary tract abnormalities. Exencephaly and heart abnormalities were also significantly more frequent, but this increase was not dose-dependent. MPA treatment on day 2 was followed by sporadic increases in dead and resorbed fetuses, a decrease in fetal weight and an increase in the rates of cleft palate and malformed or abnormally developed fetuses. None of these effects, however, was dose-dependent.
In the second experiment the mice were given one single injection (30 mg/kg) of CA or MPA on any one of days 1–12 of gestation. Treatment with CA on one day between days 1 and 12 revealed that the specific sensitivity for abnormalities of the urinary tract was on days 5 and 6, for the respiratory tract on days 8 and 9, and for cleft palate on days 10 and 11. Treatment with MPA on one day between days 1 and 12 only revealed a high rate of respiratory and urinary tract abnormalities on day 9. After treatment with MPA cleft palate was again significantly more frequent in all treated groups, however, days of peak sensitivity were not detected.
The long half-life of CA (60 hours) explains the teratogenic effect of high doses of this progestin after treatment on day 2 and also the pattern of abnormal development found after treatment with a single dose of CA on one of the days between day 1 and day 12.
An adult superovulated rat model has been developed and is characterized by high ovulation rates, early morphological degeneration of embryos, complete embryo loss within 48 hours of conception and elevated peripheral estradiol(E2)/progesterone(P4) ratios. In this study, three trials were conducted using the superovulated adult rat model. First, control naturally cycling rats were compared with superovulated rats supplemented with 1 mg P4 on days 0-3 of pregnancy. A sperm positive vaginal smear is designated as day 0 of pregnancy. The P4 treated rats demonstrated improved embryo retrieval on day 1 of pregnancy, continued embryo recovery with a decrease in normal morphologic characteristics of integrity on day 2, with nearly total embryo loss by day 3. On each day, P4 levels were elevated 2-3 times over control. The second trial compared 3 groups of rats, 1) naturally cycling, 2) superovulated unsupplemented and 3) superovulated rats supplemented with 1 mg P4/rat/day and the aromatase inhibitor, 4-hydroxyandrostenedione (4-OHA), 12.5 mg/rat/day. The superovulated unsupplemented rats had no embryo recovery after day 2 of pregnancy, while the P4 and 4-OHA treated rats showed a variable ability to maintain normally developing embryos through day 4 of pregnancy. E2 levels were elevated in both superovulated groups on days 1-4 of pregnancy as were P4 levels on days 2-4. The E2/P4 ratio was significantly lowered only on day 1 of pregnancy in the P4 and 4-OHA treated group. The third trial demonstrated implantation in 50% of the superovulated rats supplemented with P4 and 4-OHA. In conclusion, implantation in the superovulated adult rats can occur with P4 and 4-OHA supplementation, however, this biologic phenomenon could not be explained by obvious changes in peripheral E2 and P4 levels.
Estrogens can have a variety of physiological effects, especially on the reproductive system. Chemicals with estrogenic activity that are present in the environment may thus be considered potentially hazardous to development and/or reproduction. Methoxychlor is one such chemical, a chlorinated hydrocarbon pesticide with proestrogenic activity. Metabolism of the chemical either in vivo or using liver microsomes produces 2,2-bis(p-hydroxyphenyl)- 1,1,1-trichloroethane (HPTE), the active estrogenic form, and the delineation of this mechanism is reviewed herein. When administered in vivo, methoxychlor has adverse effects on fertility, early pregnancy, and in utero development in females as well as adverse effects on adult males such as altered social behavior following prenatal exposure to methoxychlor. Effects of methoxychlor on the female have been studied extensively, whereas reports on the chemical's effects on males are less common. From the studies reviewed here, the reproductive toxicity of methoxychlor is evident, but the significance of this toxicity with respect to human health remains to be determined.
To clarify the effect of estradiol benzoate on placental structure and its consequences for fetal survival and fetoplacental growth.
Estradiol benzoate (0, 0.1, 1, 10, 100 microg/day) was infused intraperitoneally into pregnant Wistar rats from 12 to 19 days' gestation. Survival rate, weight of pups and placentas at 20 days' gestation, and plasma levels of estrogen and progesterone were measured. Pathological changes in the placenta were also examined.
Estradiol benzoate reduced fetal survival (1 microg/day: 100%, 10 microg/day: 70%, 100 microg/day: 14.6%) and the weights of the pups and placentas in a dose-dependent manner. Maternal estradiol concentration was raised 23-fold with 100microg/day of estradiol benzoate. Trophoblast degeneration, including apoptosis and destruction of placental labyrinth was induced but the structures of the maternal kidney and liver were not affected.
In pregnant rats, estradiol benzoate causes fetal mortality at a pharmacological dose (more than 10 microg/day) and fetoplacental growth retardation via trophoblastic degeneration and destruction of the placental labyrinth even at a physiological dose (1 microg/day).
Endocrine-disrupting compounds are synthetic and natural compounds in the environment that can alter endocrine-governed developmental processes. Among these are the natural estrogens genistein, a plant isoflavone, and 17beta-estradiol (E2), which is present in dietary animal products, such as eggs and meat. In addition, natural and synthetic steroids are administered to beef cattle to promote growth, and low levels of the estrogens can persist in the beef. Most previous work using E2 has involved injection; however, oral administration results in a different suite of hormone products following first-pass metabolism in the liver.
Low doses of E2 were administered orally to pregnant dams to determine embryonic effects. As end points of effects, we examined whether embryonic exposure produced hypospadias, an endocrine-linked abnormality of the male genitalia, and we assessed fetal mass.
Male fetuses from the two highest dosage groups were significantly smaller than their control male counterparts, and males from the highest dosage group were also significantly smaller than control females. Control males were significantly larger than all females, and there was no difference in mass among control and treated females. Additionally, the E2 dose was inversely correlated with mass overall. No effect of these doses of E2 on hypospadias was seen.
These results indicate a sex-specific fetal effect of low-dose, orally administered E2, which appears to exert androgen-inhibiting effects on mass in males.
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