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1.
Pregnant Lister Hooded rats were dosed orally with chlorocyclizine (60 mg/kg), promethazine (5 and 10 mg/kg) or doxylamine (500 and 750 mg/kg) (histamine H1 antagonists prescribed for nausea of pregnancy) over the period of organogenesis (days 7–13). Fetuses were removed by caesarian section on day 21 and stained with Alizarin Res S and Alcian Blue for calcified bone and cartilage respectively. There were no significant differences in fetal size with any of the treatments; however, all 3 antagonists caused dose-dependent loss of skeletal integrity and marked fragility compared to the controls. By dosing dams on selected days, skeletal fragility was seen in all fetuses; the most marked effects occurring after dosing on days 10–12. Prolonging the gestation period with progesterone (10 mg/dam orally) resulted in normal sekeletal calcification but fetuses were still very fragile. Therefore, histamine H1 antagonists may interfere with the development of rat fetal joints.  相似文献   

2.
本实验用频率36.11GHz、功率密度为10.0mW/cm~2的毫米波,在小鼠怀孕6~15d时进行2h/d的照射,在孕期终了用足孕期畸形学指标进行分析。结果显示,毫米波照射可导致足孕期孕鼠体重、体重增加数和胎鼠体重的明显降低,胎盘重明显减轻,足孕时胎仔身长及尾长均减短,照射未导致孕鼠脑、肝、肾、卵巢等脏器重量(右肾除外)及脏器/体重比值、活胎数、死胎数、吸收数等指标发生明显变化,亦未导致胎鼠外表发生畸形、内脏发生畸形,或骨骼畸形增多。  相似文献   

3.
The effects of methylnitrosourea (MNU) on the development of preimplantation mouse embryos were investigated in this study. ICR mice were treated intraperitoneally with single doses of 10, 20, and 30 mg MNU/kg body wt on day 0, 1, 2, or 3 of pregnancy. The uterine contents were examined on day 18 of pregnancy. The fetuses were examined for external and skeletal abnormalities. No significant differences were observed in the number of implantation sites between all the MNU-treated groups and controls. MNU treatment on day 2 or 3 of pregnancy caused dose-dependent significant increases in the incidence of abnormal fetuses over the control level, while treatment on day 0 or 1 failed to cause an increase of abnormalities. Cleft palate, exencephalus, and malformed vertebrae were the most common types of abnormalities. In the embryo transfer experiments, the frequency of fetal abnormalities induced when embryos were transferred from MNU-treated females to untreated pseudopregnant females was significantly higher than that induced when embryos were transferred from untreated females to MNU-treated or untreated pseudopregnant females. The results in the present study confirm and extend the previously proposed hypothesis that the direct effects of MNU on preimplantation embryos make a significant contribution to the induction of fetal malformations.  相似文献   

4.
The developmental toxicity of indium was examined in both rats and mice using comparable experimental protocols. Pregnant rats received a single intravenous administration of indium trichloride (InCl(3)) at 0.4 mg In/kg, on day 9, 10, or 11 of pregnancy and their fetuses were examined on day 20. Pregnant mice were treated in the same manner at 0.8 or 1.6 mg In/kg on day 7, 8, or 9 of pregnancy and their fetuses were examined on day 18. In rats, indium caused fetal weight decrease and fetal gross malformations, such as brachyury, kinked tail, cleft palate, and oligodactyly, most severely by the administration on day 10. In mice, however, indium did not cause fetal gross malformations, although it caused fetal weight decrease at 0.8 mg In/kg or more and fetal death at 1.6 mg In/kg, most severely by the administration on day 8. It was concluded from these results that rats and mice were susceptible to the embryotoxicity of indium at similar developmental stages in the early organogenetic period, but mice were less susceptible to the teratogenicity of indium than rats in terms of gross malformation. Toxicokinetic factors may be involved in this different susceptibility. Teratogenesis Carcinog. Mutagen. 20:219-227, 2000.  相似文献   

5.
Processes that might explain the hypocholesterolemia observed in pregnant rabbits were studied in animals fed a cholesterol-free chow diet. Excretion of endogenous steroids, measured after administration of a single intravenous dose of radioactive cholesterol, averaged 75 mg/day in controls and 96 mg/day in pregnant hypocholesterolemic rabbits. The mass of maternal plasma cholesterol transferred to the fetuses was measured in animals in which a constant plasma cholesterol specific activity was maintained. Placental transfer during the first 28 days of gestation ranged from 2 to 12 mg/day for mothers carrying litters of one to eight fetuses. It is concluded that loss of maternal plasma cholesterol due to placental transfer is small compared to loss by fecal steroid excretion. Because large decreases in plasma cholesterol concentration during pregnancy and increases at parturition were not accompanied by changes in the slopes of the specific activity-time curves, it appears most likely that cholesterol in isotopic equilibrium with plasma cholesterol is temporarily and reversibly sequestered in maternal tissues of the pregnant rabbit.  相似文献   

6.
Cyclophosphamide (CP) as an alkylating agent is used for treatment of cancer and to prevent rejection of tissue transplantation. There are many reports that the teratogenic effects of cyclophosphamide can be prevented by application of antioxidant drugs and stimulation of the maternal immune system. Also, there is some evidence that melatonin and carvedilol are antioxidant.Therefore, in this study, the prophylactic effects of melatonin and carvedilol on teratogenic effects of CP was compared. This study was performed on 31 pregnant mice that were divided into six groups. The control group received normal saline and test groups received CP (20 mg/kg), carvedilol (5 mg/kg), melatonin (10 mg/kg), CP (20 mg/kg) pluscarvedilol (5 mg/kg) and CP (20 mg/kg) plus melatonin (10 mg/kg) intraperitoneally on the 10th day of gestation, respectively. Fetuses were collected on the 19th day of gestation and after determination of weight and length; they were stained by Alizarin red-Alcian blue method. Cleft palate, spina bifida and exencephalyincidence were 62.79%, 62.79% and 30.23% in fetuses of mice that received only CP. Cleft palate,spina bifida, exencephaly, and incidence were 45.45%, 9.09% and 0% in group which received CP plus carvedilol (5 mg/kg), respectively.However, cleft palate, spina bifida and exencephalyincidence were 62.5%, 45.83% and 4.16% range in the group which received CP plus melatonin (10 mg/kg), respectively. In addition, theincidence of skeletal anomalies including limb, vertebral, and sternaldefects were decreased by melatonin and carvedilol. The mean weight and length of animal fetuses that had received melatonin and carvedilol were significantly greater than those receiving only CP. It is concluded; carvedilol has a significant effect in preventing CP-induced malformations and in cases like CP-induced exencephaly, cleft palate and spina bifidahas better prophylactic effect than melatonin, but this improvement is not significant.  相似文献   

7.
Pregnant rats were injected im with 0.5 mg/kg triamcinolone acetonide (TAC) on day 12, 13, or 14 of gestation and the fetuses were examined for cleft palate on day 20. All three TAC-treated groups showed an increased proportion of fetuses with cleft palate compared to an untreated control group. Only the group treated on day 13 showed a significant increase in the proportion of litters affected. This indicates that day 13 of gestation is the most sensitive day for cleft palate induction by TAC in the rat. Pregnant rats were then treated on day 13 of gestation with either TAC, triamcinolone (TA), or cortisol. TAC was 59 times as potent as TA in inducing cleft palate, with ED50 values of 1.1 mg/kg and 65 mg/kg respectively. Cortisol induced a significant increase in cleft palates at 500 mg/kg, but the efficacy of this compound was too low to calculate an ED50 and relative teratogenic potency value. Other developmental abnormalities including umbilical hernias, resorption, and fetal death resulted from TAC treatment. Fetal growth retardation was produced by all three compounds. The rank order of teratogenic potency was determined to be TAC greater than TA greater than cortisol.  相似文献   

8.
Groups of pregnant rabbits were given cyclophasphamide (Endoxan Asta®) in single intravenous doses of 30 mg/kg on different days from the 6th day to the 14th day of gestation. On the 28th day (shortly before term) the foetuses were removed by caesarean section. Administration of cyclophosphamide about the time of implantation led to an increase in the number of early embryonic deaths. Injection of cyclophosphamide at the later stages resulted in an increased number of foetal deaths. About 10% of the foetuses from dams treated on the 7th day of pregnancy exhibited malformations, in particular disturbances of ventral closure. When cyclophosphamide was administered on the 11th day of pregnancy more than 30% of the foetuses were found to have median cleft palates and other malformations of jaws and lips. All the foetuses from dams treated on the 12th day showed oligodactylia and brachydactylia. The latter type of malformation was also present when treatment was given on the 13th day. The embryotoxic effect of cyclophosphamide administration was particularly evident in the early periods of embryonic development. In contrast, the teratogenic action was more confined to the later periods of organogenesis. Teratogenicity occurred in two peaks corresponding to characteristic phaenocritical phases of development. The first and lower peak coincided with the period of histiotrophic nutrition and the second and higher peak corresponded to the heamotrophic phase. It is concluded that embryotoxicity and teratogenicity are largely independent phenomena.  相似文献   

9.
The teratogenic and cytogenetic effects of two drugs with antihistaminic properties, Pipethiadene and Pizotifen maleate, were investigated. Three groups of pregnant mice were treated daily with oral doses (0.24, 0.6 and 1.2 mg/kg) of these drugs from day 4 to day 16 of gestation. The following parameters were investigated: reproductive health of the dams, external, skeletal and visceral malformations of fetuses and frequencies of micronuclei and chromosome aberrations in bone marrow cells of dams. Oral administration of Pipethiadene or Pizotifen maleate produced no teratogenic effects. No elevation was observed in the frequencies of micronuclei and chromosome aberrations. However, the significant reduction of fetal weight after all doses of Pipethiadene or Pizotifen maleate was found to correlate well with the decreased values of the mitotic indices of bone marrow cells of mice, suggesting a potential embryotoxic effect of the tested substances.  相似文献   

10.
The present study was undertaken to determine histopathologic differences in the ribs of Wistar-albino rat fetuses prenatally exposed to valproic acid (VPA), folic acid (FA) and vitamin E (Vit E), and to compare their differential developmental susceptibility and morphological association with skeletal anomalies. VPA (300 mg/ kg), FA (300mg/kg) and Vit E (250mg/kg) were administered to rats on each of gestation days (GD) 7-9. Fetuses were collected on GD 21 and their ribs were examined for malformations. The fetuses were divided into four groups: blind-trial group, VPA group (vpa), VPA and Vit E group (vpa+vit e), valproic and FA group (vpa+fa). In each group; drug procedure, surgical procedure and histological methods were performed. Later, weights and lengths of fetuses in each group were compared and analyzed by one-way Anova test. As a result, maLformations in fetuses were determined and photographed by Nikon SMZ-2 steromicroscopy, using 2 x objective. Administration of single doses of VPA (300 mg/kg) resulted in weight and length loss between blind-trial and vpa group. However, length and weight differences between the other groups were not significant. The objective of the present study is to analyze morphological and histopathologic changes which may occur in a high-risk experimental model after the administration of VPA. In addition, protective roles of the administration of FA and Vit E are assessed.  相似文献   

11.
Embryolethal and teratogenic effects of carbendazim in rats.   总被引:5,自引:0,他引:5  
This study was performed to evaluate the effects of prenatal development of rats. Females were exposed to carbendazim by gavage every day on days 6-15 of gestation at doses 8, 35, 160 mg/kg b.w. Carbendazim administered at doses of 35 and 160 mg/kg was associated with significant maternal toxicity, embryonal lethality, congenital defects, and retarded fetal development. It produced encephalocele, umbilical hernia, missing or shorter tail, and internal malformations of brain, kidneys, and skeletal malformations of ribs, arch, and vertebrae. NOEL for the dam and fetus in our study was 8 mg/kg/day.  相似文献   

12.
Summary Treating mice of strain C57BL/6Ffm on day 9 of gestation with 10 mg/kg of 5-fluoro-2-deoxycytidine (FCdR) resulted in malformations of the thoracic vertebral column (ThVC) in 98% of near-term fetuses (Degenhardt et al., 1968). The spectrum of malformations was broad: fusion, dysplasia, cleft, aplasia and hypoplasia were all produced. Fusions of two or more segments represented more than half of all malformations (Bosse, 1978).The alterations in embryonic precartilage and cartilage after FCdR-treatment were followed from day 11 to day 15 in a biochemical and histological study. Biochemically, the 35S-uptake into embryonic mucopolysaccharides (MPS) and the content of total MPS and seven fractions of MPS in embryos or isolated ThVCs were analyzed. The histological variables studied were the types and incidence of malformations of the ThVC, 35S-autoradiography of the ThVC, and the amount of alcian blue-stained cartilaginous matrix. The results showed that on day 11 the synthesis of embryonic MPS was not affected, on day 12 the synthesis of MPS was greatly reduced, on day 13 the synthesis of MPS was slightly reduced while the MPS-content was not affected. On day 13 aplasias were seen in the same percentage as at term, but no fusions were detected. By day 14 the MPS-content was greatly reduced; hyaluronate, condroitin 4-sulfate, and chondroitin 6-sulfate being principally involved; the first fusions were seen. On day 15 the MPS-content was slightly reduced (chondroitin 6-sulfate and heparan sulfate were involved), fusions were complete. The results are discussed in terms of disturbance of structure and function of the notochord and intervertebral discs with the production of fusions, the main type of vertebral malformation in these experiments.  相似文献   

13.
N-(4-hydroxyphenyl)-all-trans-retinamide (HPR) has potential efficacy in the treatment of dermatologic, arthritic, and neoplastic disorders. The teratogenicity of such a compound is of special concern in light of the known adverse effects of retinoids, in general, on the developing conceptus. In these studies, Sprague-Dawley rats and New Zealand White rabbits were treated orally from gestation days 6 to 15 and 6 to 18, respectively, with 0, 20, 125, or 800 mg/kg/day of HPR. In rat fetuses, low incidences of hydrocephaly (mid- and high-dosage groups) were observed. Fetal tissue (ng/g) and maternal plasma (ng/ml) concentrations of HPR, its major metabolite (N-[4-methoxyphenyl] retinamide [MPR]) and retinol were determined in separate groups of similarly-treated rats 3 h following the last dose on gestation day 15. Fetal tissue concentrations of HPR and MPR were approximately one-half maternal plasma concentrations. A dose related reduction in maternal plasma and fetal tissue concentrations of retinol were also observed. In mid- and high-dosage rabbit fetuses, a dose-related increase in the incidence of dome-shaped head was observed. Subsequent skeletal evaluation revealed delays in skull bone ossification and a widening of the frontal and frontoparietal sutures. Microphthalmia was also observed in two high-dosage fetuses. A dose-dependent and statistically significant reduction in maternal plasma retinol levels was observed across all dosage groups.  相似文献   

14.
Indole-3-acetic acid (IAA), known as natural auxin, induces cleft palate in rodents. However, there has been no report about the neurodevelopmental toxicity of IAA in rats. In the present study, we found microencephaly in the fetuses from the rats exposed to IAA. The purpose of this work was to examine the effects of IAA administration in pregnant rats on neuroepithelial cells in the embryos/fetuses. IAA was administered at 500 and 1,000 mg/kg on gestation days (days) 12, 13, and 14, and then embryos/fetuses were harvested on days 14.5, 15, 16, and 21. Cleft palate was induced at 1,000 mg/kg. The brain in treated groups exhibited reduction in the size and weight on day 21 in a dose-dependent manner. Histopathologically, apoptotic cells were observed mainly in the medial and dorsal layer of the neuroepithelium at 500 and 1,000 mg/kg on day 14.5. On day 15, they were observed in the medial and dorsal layer of the neuroepithelium, and preplate at 1,000 mg/kg. On day 16, they existed in the dorsal layer of the neuroepithelium and intermediate zone in the embryos from 1 dam at 1,000 mg/kg. On day 21, an increase in cell proliferative activity was observed in the neuroepithelium at 500 and 1,000 mg/kg. The reduction of the cortical plate, the enlargement of the neuroepithelium and a slight increase in neuron density in the intermediate zone were observed at 1,000 mg/kg. These findings indicated IAA might induce the neuronal apoptosis in the S phase and lead to microencephaly.  相似文献   

15.
Mercury is a major environmental pollutant and a proven teratogen in man and animals. Its teratogenicity and effects on fetal chromosomes were investigated in mice. Various dose levels of methylmercuric chloride (MMC) were administered via an intragastric tube to pregnant ICR Swiss/Webster mice on day 9 of gestation. On day 18 of gestation the animals were killed and the fetuses were removed. Fetal lung and liver tissues were processed for cytogenetic studies. Fetuses were also fixed in Bouin's solution for subsequent teratological examination by using Wilson's technique. Mercury levels were determined in maternal blood and randomly selected fetuses. One fetus from each litter was processed for skeletal staining with Alizarin Red S. A significant increase in embryonic deaths and resorptions was observed at all dose levels. The incidence of fetal anomalies was significantly increased following maternal treatment with 10, 15, or 20 mg/kg of MMC. Maternal weight between day 9 and day 18 of gestation decreased significantly. The LD50 of MMC in pregnant mice was determined to be 20 mg/kg of body weight; the LD100 was 30 mg/kg. A significant difference was observed between the mean fetal weights at the various dose levels. Levels of mercury were found to be significantly higher in treated animals and fetuses, and increased in a dose-related manner. The levels of mercury were significantly higher in the fetuses than in the mothers at the same dosage, indicating a correlation between the levels of mercury in maternal mice and corresponding higher levels in their fetuses. Cytogenetic studies revealed significant clumping of chromosomes in metaphase at all dose levels and the frequency of clumping increased as dosage increased. The euploidy number (2n = 40) of chromosomes per cell did not vary between the treatment groups and control groups. The frequency of nucleolus-organizing regions per cell did not change significantly between the treatment groups and the control. The frequency of sister chromatid exchanges increased significantly as the dosage increased.  相似文献   

16.
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) causes a high percentage of cleft palate in fetuses when administered during organogenesis in certain strains of mice including the C57BL/6J, but not in certain other strains (AKR/J). The purpose of the present study was to examine various biochemical and morphological aspects of TCDD-induced changes in the developing palatal shelves. Our results indicate that when TCDD (100 micrograms/kg) was given on individual days between days 8 and 10 of gestation, a high percentage of cleft palate was observed. Receptors specific for TCDD were detected in the C57BL/6J but not AKR/J palatal shelves. The amount of TCDD receptors is highest in the palatal shelves on day 13 as compared to other embryonic tissues including the liver. Examination of cryostat sections taken from embryos during the time of palatal elevation and fusion demonstrated that TCDD does not interfere with growth, elevation, or initial contact of the palatal shelves, but does interfere with firm adhesion and/or degeneration of the medial epithelial cells. Our results suggest that TCDD exerts a direct effect on the embryonic palatal shelves which results in formation of cleft palate.  相似文献   

17.
Cell cycle alterations and cell death in cyclophosphamide teratogenesis   总被引:3,自引:0,他引:3  
Litters of pregnant mice treated with cyclophosphamide (CP) exhibit malformations of the limbs ranging from oligodactyly to amelia. Previous studies have indicated that cell death occurs in limb buds shortly after maternal exposure. We have investigated the relationship of cell death, cell cycle perturbation, and embryo/fetal toxicity in the mouse using vital staining and flow cytometry (FCM). CP (20, 30, and 40 mg/kg) was investigated via intraperitoneal administration to Swiss-Webster mice on day 10 of gestation. At 4, 8, or 28 hours later, embryos were removed. Cell death was identified with Nile blue sulphate (NBS). Two embryos per litter were stained with NBS, and the remaining embryos were frozen at -70 degrees C prior to FCM analysis. After thawing, the forelimb buds were removed for the isolation of nuclei. Tissues were dissociated through a wire mesh followed by cytolysis with 0.1% nonidet P-40 in PBS with 0.5 mg/ml RNase. Nuclei were stained with the fluorescent nucleic acid probe propidium iodide and analyzed (10,000 nuclei per sample) for propidium iodide fluorescence by FCM. NBS revealed a dose-related increase in cell death by 8 hours after dosing. CP-induced cell death was greatest in areas of rapid cell proliferation (DNA synthesis). FCM analysis revealed retardation of progression through the S-phase of the cell cycle by 4 hours post-exposure at all doses. This retardation occurred earlier in S-phase with increasing dose and persisted through 8 hours. At 28 hours, cell cycle histograms were normal in the low-dose embryos, but remained perturbed in the intermediate- and high-dose embryos. On day 17 of gestation, the last group of dams was killed. A high incidence of fetal malformations, including limb defects, occurred at the 20 mg/kg dose, and fetal mortality was observed at 30 and 40 mg/kg. The pattern and magnitude of cell death correlated with cell cycle perturbation and fetal toxicity at term, suggesting a relationship between cell cycle perturbation, cell death, and malformations produced by CP.  相似文献   

18.
Mirex is a pesticide that is environmentally stable, accumulates in body tissues, and is embryo- and feto-toxic at high concentrations in vivo. This study is the first to evaluate the effects of mirex on organogenesis-stage embryos in vitro. Mouse embryos were exposed on gestation day 8.5 for 24 h in whole-embryo culture to mirex at 100, 200, or 400 microg/ml dissolved in xylene and compared with xylene-treated controls (1, 2, or 4 microl/ml, respectively) and untreated controls. Embryos were evaluated for malformations, somite number, total protein content, and visceral yolk sac circulation. Potential embryotoxic mechanisms were evaluated by using PCNA stain for cell proliferation and the TUNEL assay for apoptotic cell death. Mirex-exposed embryos demonstrated increased malformation rates and decreased total embryonic protein contents at > or =200 microg/ml mirex, and decreased somite numbers and VYS circulation at > or =100 microg/ml mirex, compared with xylene-treated controls. There was no difference in PCNA levels or TUNEL staining in mirex-treated embryos compared with xylene-treated controls or untreated controls. Thus, mirex is embryotoxic in vitro to early organogenesis stage mouse embryos at concentrations > or =100 microg/ml, but the effects do not appear to be mediated by changes in cell proliferation or apoptotic cell death.  相似文献   

19.
Rabbits given acute serum sickness (ASS) and treated with cyclosporin A (CyA) developed glomerular capillary thrombosis and cortical infarction, lesions not seen in unmodified ASS. Thirty-three NZW rabbits received a single intravenous injection of 250 mg/kg bovine serum albumen (BSA) with or without endotoxin (5 micrograms/kg) on day 0. Groups of rabbits were given intramuscular CyA as follows: 15 mg/kg from day -2 to +8, or 25 mg/kg/day from day -20 to +3 or day 0 to 5. Signs of this renal injury were haematuria, transient proteinuria, glycosuria and oliguria and they occurred during the rapid phase of antigen elimination when immune complexes were being formed. Seventeen of the 33 rabbits developed glomerular capillary thrombi and 11 of 17 also had glomerular and tubular infarction. Electron microscopic examination showed that these lesions were associated with severe endothelial injury and platelet-fibrin-leucocyte thrombi. These changes were more severe in the groups given 25 mg/kg. The lesions were not seen in untreated rabbits and ASS, nor in normal rabbits given equivalent doses of CyA alone. A strikingly similar renal lesion has been seen in patients receiving CyA following bone marrow transplantation, and also in the haemolytic uraemic syndrome. The model we describe may be valuable for the study of the mechanisms of endothelial injury and thrombosis in the kidney.  相似文献   

20.
The potential of oral exposure to dolomite, a natural product that contains calcium and magnesium, to initiate teratogenesis was analyzed in Wistar rats. Animals received dolomite oral dosages of 500 and 1500mg/kg during the period of gestation from day 6-15 post conceptionem (p.c.). Maternal, embryo and fetal toxicity were evaluated. Dolomite exposure did not produce maternal toxicity assessed by clinical observations, body weight gain, hematology parameters and relative organs weight. Signs of embryo-fetal toxicity were not observed. Skeletal malformations and visceral variations were similar in control and dolomite-treated groups. On the other hand, slight increase was observed in fetal body weight in the dolomite-treated group. Treatment with dolomite resulted in significantly decreased incidences of unossified xiphisternum, incomplete ossification of xiphisternum and sternebrae. These effects could be caused by a beneficial influence of calcium and magnesium salts present in dolomite on ossification process. In conclusion, in this study we found that the oral exposure to rats of up to 1500mg/kg of dolomite during organogenesis did not induce significant maternal and embryo-fetal toxicity.  相似文献   

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