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External Malformations (external + malformation)
Selected AbstractsCombined exposure to anti-androgens causes markedly increased frequencies of hypospadias in the ratINTERNATIONAL JOURNAL OF ANDROLOGY, Issue 2 2008S. Christiansen Summary The incidence of hypospadias is increasing in young boys, but it remains unclear whether human exposure to endocrine disrupting chemicals plays a role. Risk assessment is based on estimation of no-observed-adverse-effect levels for single compounds, although humans are exposed to combinations of several anti-androgenic chemicals. In a mixture (MIX) study with three androgen receptor antagonists, vinclozolin, flutamide and procymidone, rats were gavaged during gestation and lactation with several doses of a MIX of the three chemicals or the chemicals alone. External malformations of the male reproductive organs were assessed on PND 47 using a score from 0 to 3 (normal to marked) for hypospadias. Markedly increased frequencies were observed after exposure to a MIX of the three chemicals compared to administration of the three chemicals alone. Anogenital distance at PND 1, nipple retention at PND 13, and dysgenesis score at PND 16 were highly correlated with the occurrence of hypospadias, and MIX effects were seen at doses where each of the individual chemicals caused no observable effects. Therefore, the results indicate that doses of anti-androgens, which appear to induce no hypospadias when judged on their own, may induce a very high frequency of hypospadias when they interact in concert with other anti-androgens. [source] Developmental toxicity evaluation of inhaled tertiary amyl methyl ether in mice and ratsJOURNAL OF APPLIED TOXICOLOGY, Issue 6 2003Frank Welsch Abstract This evaluation was part of a much more comprehensive testing program to characterize the mammalian toxicity potential of the gasoline oxygenator additive tertiary amyl methyl ether (TAME), and was initiated upon a regulatory agency mandate. A developmental toxicity hazard identi,cation study was conducted by TAME vapor inhalation exposure in two pregnant rodent species. Timed-pregnant CD®(Sprague-Dawley) rats and CD-1® mice, 25 animals per group, inhaled TAME vapors containing 0, 250, 1500 or 3500 ppm for 6 h a day on gestational days 6,16 (mice) or 6,19 (rats). The developmental toxicity hazard potential was evaluated following the study design draft guidelines and end points proposed by the United States Environmental Protection Agency. Based on maternal body weight changes during pregnancy, the no-observable-adverse-effect level (NOAEL) was 250 ppm for maternal toxicity in rats and 1500 ppm for developmental toxicity in rats using the criterion of near-term fetal body weights. In mice, more profound developmental toxicity was present than in rats, at both 1500 and 3500 ppm. At the highest concentration, mouse litters revealed more late fetal deaths, signi,cantly reduced fetal body weights per litter and increased incidences of cleft palate (classi,ed as an external malformation), as well as enlarged lateral ventricles of the cerebrum (a visceral variation). At 1500 ppm, mouse fetuses also exhibited an increased incidence of cleft palate and the dam body weights were reduced. Therefore, the NOAEL for the mouse maternal and developmental toxicity was 250 ppm under the conditions of this study. Copyright © 2003 John Wiley & Sons, Ltd. [source] ,-Lipoic acid reduces congenital malformations in the offspring of diabetic miceDIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue 3 2009Y. Sugimura Abstract Background The mechanism of diabetes-induced congenital malformation remains to be elucidated. It has been reported that ,-lipoic acid (LA) prevents neural tube defects (NTDs) in offsprings of rats with streptozotocin-induced diabetes. Here, we evaluate the protective effect of LA against diabetic embryopathy, including NTDs, cardiovascular malformations (CVMs), and skeletal malformations, in mice. Methods Female mice were rendered hyperglycemic using streptozotocin and then mated with normal male mouse. Pregnant diabetic or non-diabetic mice were treated daily with either LA (100 mg/kg body weight) or saline between gestational days 0 and 18. On day 18, fetuses were examined for congenital malformations. Results Plasma glucose levels on day 18 were not affected by LA treatment. No congenital malformations were observed either in the saline-treated or LA-treated non-diabetic group. In the saline-treated diabetic group, 39% of fetuses had external malformations and 30% had NTDs. In the LA-treated diabetic group, the corresponding proportions were 11 and 8%, respectively. LA treatment also decreased the incidence of CVMs from 30,3% and of skeletal malformations from 29,6%. Conclusions We conclude that LA can reduce NTDs, CVMs and skeletal malformations in the offspring of diabetic mice at term delivery. Copyright © 2009 John Wiley & Sons, Ltd. [source] Non-invasive tracking of avian development in vivo by MRINMR IN BIOMEDICINE, Issue 4 2009Bianca Hogers Abstract Conventional microscopic techniques, to study embryonic development, require large numbers of embryos and are invasive, making follow-up impossible. We explored the use of in vivo MRI to study embryonic development, in general, and cardiovascular development in particular, over time. Wild-type quail embryos (n,=,11) were imaged at embryonic days 3, 5, 7, 9, and 11, covering the main time course of embryonic heart development. On each imaging day cardiac morphology was evaluated and embryonic length was measured. MRI-embryos as well as control embryos (n,=,11) were sacrificed at day 11 and scored for external malformations, while embryonic wet weight and stage were determined. In addition, venous clipped embryos (n,=,4), known to develop cardiovascular malformations, were scanned at regular intervals and sacrificed at day 9 for histological analysis ex vivo. We were able to follow heart development of individual quail embryos inside their shell non-invasively over time, with sufficient detail to study cardiac morphology in vivo. We did not find any adverse effect of the repeated MRI examinations on morphology, length, or weight. Prenatally diagnosed malformations, like ventricular septal defects and aortic arch interruptions were confirmed by histology. In conclusion, micro-MRI can be used to evaluate in vivo early embryonic development and to diagnose cardiovascular malformations prenatally. Copyright © 2008 John Wiley & Sons, Ltd. [source] Effects of Subchronic versus Acute in utero Exposure to Dexmedetomidine on Foetal Developments in RatsBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 2 2008Mohammad Tariq This study was undertaken to investigate the effects of in utero exposure of dexmedetomidine on foetal development and postnatal behaviour in the offspring. Pregnant Sprague-Dawley rats were chronically treated with dexmedetomidine (0, 5, 10 and 20 µg/kg, subcutaneously) daily from gestation day 7 to day 19. Another group of animals received only a single acute dose of dexmedetomidine (20 µg/kg) on gestational day 19 to mimic a model for systemic analgesia during labour. Administration of dexmedetomidine did not affect the frequency of implantations. Chronic administration of 10 and 20 µg/kg of dexmedetomidine significantly reduced the body weight and crown-rump length of pups, whereas a single acute dose (20 µg/kg) did not affect these parameters. None of the pups exhibited any external malformations or skeletal abnormalities irrespective of treatment assigned. All the pups showed a normal postnatal weight gain during the developmental phase. No significant differences were observed among any of the groups with respect to behavioural performances of offspring in beam balance, grip strength and inclined plane tests as well as motor activity. In conclusion, acute exposure to dexmedetomidine at the anticipated delivery time does not exert any adverse effects on perinatal morphology of pups, their birth weight, crown-rump length, physical growth and postnatal behavioural performances. Since this study was conducted in rats, its clinical relevance in human beings remains to be unclear and warrants further studies. [source] Tetramethylcyclopropyl analogue of the leading antiepileptic drug, valproic acid: Evaluation of the teratogenic effects of its amide derivatives in NMRI mice,BIRTH DEFECTS RESEARCH, Issue 9 2008Akinobu Okada Abstract BACKGROUND: Although valproic acid (VPA) is used extensively for treating various kinds of epilepsy, it causes hepatotoxicity and teratogenicity. In an attempt to develop a more potent and safer second generation to VPA drug, the amide derivatives of the tetramethylcyclopropyl VPA analogue, 2,2,3,3-tetramethylcyclopropanecarboxamide (TMCD), N -methyl-TMCD (MTMCD), 4-(2,2,3,3-tetramethylcyclopropanecarboxamide)-benzenesulfonamide (TMCD-benzenesulfonamide), and 5-(TMCD)-1,3,4-thiadiazole-2-sulfonamide (TMCD-thiadiazolesulfonamide) were synthesized and shown to have more potent anticonvulsant activity than VPA. Teratogenic effects of these CNS-active compounds were evaluated in Naval Medical Research Institute (NMRI) mice susceptible to VPA-induced teratogenicity by comparing them to those of VPA. METHODS: Pregnant NMRI mice were given a single sc injection of either VPA or TMC-amide derivatives on gestation day 8.5, and then the live fetuses were examined to detect any external malformations on gestation day 18. After double-staining for bone and cartilage, their skeletons were examined. RESULTS: In contrast to VPA, which induced NTDs in a high number of fetuses at 2.4,4.8 mmol/kg, TMCD, TMCD-benzenesulfonamide, and TMCD-thiadiazolesulfonamide at 4.8 mmol/kg and MTMCD at 3.6 mmol/kg did not induce a significant number of NTDs. TMCD-thiadiazolesulfonamide exhibited a potential to induce limb defects in fetuses. Skeletal examination also revealed that fetuses exposed to all four of the tetramethylcyclopropanecarboxamide derivatives developed vertebral and rib abnormalities less frequently than those exposed to VPA. Our results established that TMCD, MTMCD, and TMCD-benzenesulfonamide are distinctly less teratogenic than VPA in NMRI mice. CONCLUSIONS: The CNS-active amides containing a tetramethylcyclopropanecarbonyl moiety demonstrated better anticonvulsant potency compared to VPA and a lack of teratogenicity, which makes these compounds good second-generation VPA antiepileptic drug candidates. Birth Defects Research (Part A), 2008. © 2008 Wiley-Liss, Inc. [source] Aortic and ventricular dilation and myocardial reduction in gestation day 17 ICR mouse fetuses of diabetic mothersBIRTH DEFECTS RESEARCH, Issue 6 2007J. Claudio Gutierrez Abstract BACKGROUND: Maternal diabetes mellitus is associated with increased fetal teratogenesis, including cardiovascular defects. Information regarding cardiovascular changes in late-gestation fetal mice, related to maternal hyperglycemia, is not present in the literature. METHODS: Late-gestation fetal heart and great vessel morphology were analyzed in fetuses from control and diabetic mice. Female ICR mice were injected with streptozocin (200 mg/kg IP) prior to mating to induce diabetes (n = 8). Nonhyperglycemic females were used as controls (n = 8). At day 17 of gestation, females were euthanized and one fetus was arbitrarily selected per litter to analyze the heart and great vessels. Six additional fetuses from different litters, showing external malformations (spina bifida and/or exencephaly), were also evaluated from the diabetic group. Fetal thoraxes were processed using routine histopathologic techniques, and 7-,m transversal sections were stained with hematoxylin-eosin. Digital images of sections were made and analyzed using NIH Image J software to compare regional cardiac development. Student's t tests for means were performed to determine differences between groups (p < .05). RESULTS: Maternal hyperglycemia caused a dilation of late-gestation fetal ventricular chambers, a reduction of total ventricular myocardial area, and an increase in transversal ascending thoracic aortic area. Three of six fetuses that displayed external malformations showed an overt cardiac defect, beyond the ventricular and myocardial changes. CONCLUSIONS: Maternal hyperglycemia altered morphology of the late-gestation fetal mouse heart. Postnatal persistence or consequences of late-gestation heart chamber dilation and myocardial reduction are not yet known. Birth Defects Research (Part A) 2007. © 2007 Wiley-Liss, [source] | ||||||||||