摘要:

AbstractPhenytoin (diphenylhydantion, Dilantin®, PHT), an anticonvulsant and antiarrhythmic drug, is teratogenic to A/J mice, producing an increased incidence of cleft lip with or without cleft palate [CL(P)] and cardiac defects. Although its mechanism of teratogenic action remains unclear, one possibility may involve uterine ischemia resulting from an exaggerated depressant effect on maternal cardiovascular function. To test this hypothesis, the heart rate response of susceptible A/J and resistant C57B1/6J mice was monitored following intraperitoneal injection of doses of PHT of known teratogenic potential.Heart rate (HR) was obtained electrocardiographically from unanesthetized, pregnant mice on day 10 of gestation via previously implanted subcutaneous electrodes. The HR of A/J mice was significantly depressed relative to vehicle‐injected controls following doses of 40, 60, and 75 mg/kg, with the greatest effect occurring in the high‐dose group. In C57B1/6J mice, the HR response of the group treated with 75 mg/kg was not different from that of the vehicle‐treated controls. At the same dose level, the depression of HR of A/J mice was significantly greater in magnitude and duration than that of C57B1/6J mice.A proposed maternally mediated mechanism of CL(P) in A/J mice involving low placental/embryonic oxygen delivery is discussed. The results of the present study indicate the potential significance that changes in maternal physiology may have on embryonic devel

ISSN:0040-3709    

DOI:10.1002/tera.1420280102

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1983

数据来源: WILEY

摘要:

AbstractIt has been documented that activation of the β1‐adrenergic receptor mechanism is directly related to cardiovascular malformations associated with the heart and great vessels of the embryonic chick. These adrenergic receptors are believed to be present and functional in the innervated and noninnervated embryonic heart at early stages of development. The present study examined the effects of four sympathomimetic cardioactive amines on chick cardiovascular morphogenesis at Hamburger and Hamilton stage 24. Special attention was directed toward understanding dopamine teratogenicity. In order of decreasing potency at the maximum teratogenic dose (dopamine>isoproterenol>epinephrine>norepinephrine) each drug was found capable of producing aortic arch anomalies of the third, fourth, and sixth aortic arches and ventricular septal defects (VSD). A new specific β1‐adrenergic antagonist, metoprolol tartrate, was employed in an attempt to lower the incidence of these cardiovascular malformations. Pretreatment with this selective β1‐blocker profoundly reduced the incidence of malformations within any aminetreated group. These experiments demonstrate that dopamine, as well as the other sympathomimetic amines, is a potent teratogen and most likely produces these cardiovascular malformations by primarily stimulating the β1‐adrenoreceptor in the embr

ISSN:0040-3709    

DOI:10.1002/tera.1420280103

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1983

数据来源: WILEY

摘要:

AbstractPrevious studies have indicated that serotonin and acetylcholine stimulate palate shelf reorientation. The present studies were undertaken to determine whether γ‐aminobutyric acid (GABA) functions as an inhibitory neurotransmitter in the palate and whether diazepam mimics GABA to inhibit shelf reorientation and cause cleft palate. First, it was shown that 10−4M GABA inhibits palate shelf reorientation in day 14.5 AJ embryos cultured for 2 hours. Anterior palate reorientation stimulated by 10−5M serotonin was decreased by GABA; 10−5M picrotoxin (GABA antagonist) stimulated anterior shelf reorientation and reversed the effect of GABA. Diazepam (10−4M) partially inhibited palate shelf reorientation and that stimulated by 10−5M serotonin. Diazepam (400 mg/kg) was administered to AJ mice at day 13.5 of gestation and embryos were cultured at day 14.5. The inhibition produced by diazepam was significantly reduced by 10−5M picrotoxin. The teratogenic effect of diazepam was compared with AJ and Swiss‐Webster Vancouver (SWV) inbred strains. Diazepam produced greater clefting in SWV mice (57% net) than in the AJ (18% net) when compared to their water‐ and food‐starved controls. The greater sensitivity of the SWV strain than the AJ strain to diazepam, as well as to GABA, was also observed in embryo culture. GABA (10−5M) markedly inhibited posterior palate reorientation and reversed the stimulation produced by bethanechol in SWV mice. The inhibitory effects of GABA on the posterior palate were partially reversed by picrotoxin. Furthermore, diazepam inhibited palate reorientation either when administereted to the pregnant dam or added in embryo culture. Picrotoxin significantly antagonized these effects. Thus both GABA and diazepam inhibited palate reorientation. The SWV strain was more sensitive to both agents than the AJ; the posterior end was preferentially affected in SWV while the anterior was more sensitive in the AJ mouse. These results suggest that (1) GABA may function as an inhibitory neurotransmitter to regulate palate reorientation, (2) diazepam may cause cleft palate by mimicking GABA to inhibit shelf reorientation, and (3) these events are genetically regulated i

ISSN:0040-3709    

DOI:10.1002/tera.1420280104

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1983

数据来源: WILEY

摘要:

AbstractThe toxicity of methyl mercury (mHg) in the developing chick embryo was investigated. The relationship of dose, time of administration (i.e., days 4–9 of development), and body levels of mercury was examined. The LD50for mHg injected into the yolk sac on day 5 of incubation was 40–50 μg. Embryos dying within 24 hours showed increased total body mHg levels when compared to survivors (219 ± 67 vs. 105 ± 41 μg/gm, mean ± SD). Absorption was dose‐related, with a good correlation between mortality and body, blood, and brain levels. Daily analysis of body mHg levels after injection on day 5 showed continued mHg accumulation (0.88 ± 0.35 μg/embryo/day). However, the rate of embryo growth exceeded the rate of mHg absorption, resulting in a progressive decrease in mHg in concentration in tissues (from 94.5 ± 34.2 μg/gm on day 6 to 45.3 ± 13.4 on day 9). Administration after day 5 resulted in a significant reduction in levels of mHg in the brain on day 18 (from 11.4 ± 2.1 μg/gm when given on day 5 to 8.4 ± 2.3 when given on day 9) and in mortality (from 64% to 33%). Because blood mHg levels remained unchanged, the increased brain levels and higher mortality early in embryogenesis may reflect facilitated transfer of mHg across a poorly developed blood‐brain barrier. Later in development, the reduced mortality and lower brain mHg levels correspond to the formation of specialized interendothelial junctions and a more effective

ISSN:0040-3709    

DOI:10.1002/tera.1420280105

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1983

数据来源: WILEY

摘要:

AbstractTeratogenic to subteratogenic doses of x‐ray, mitomycin C, MNNG, thio‐TEPA, cyclophosphamide, and chlorambucil were administered to pregnant ICR mice together with caffeine at doses of 12.5, 25, or 50 mg/kg on day 11 of gestation. Fetuses were examined for gross malformations on day 18 of gestation. The teratogenicity of mitomycin C was significantly potentiated by caffeine at a dose as low as 12.5 mg/kg. The teratogenicity of chlorambucil was also significantly potentiated by caffeine at 50 mg/kg, but similar potentiation was not observed for x‐ray, MNNG, thio‐TEPA, and cyclophos

ISSN:0040-3709    

DOI:10.1002/tera.1420280106

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1983

数据来源: WILEY

摘要:

AbstractThis study further defines the craniofacial malformations induced by triamcinolone acetonide in the rhesus monkey. Ten timed‐mated pregnant rhesus monkeys (Macaca mulatta) received intramuscular injections of 10 mg/kg TAC on days 23, 25, 27, 29, and 31 of gestation. Results of previous experiments with rhesus and bonnet monkeys and baboons indicated that specific craniofacial and brain malformations could be induced with TAC during this period of pregnancy (Hendrickx et al., '80). Stage‐matched TAC‐treated and control embryos (stages 17–18 and 22) and age‐matched TAC‐treated and control fetuses (50, 60, and 70 days gestation) were removed by hysterotomy. Stage 17–18 TAC embryos appeared grossly normal but histologic evaluation revealed a shortened anlage of the posterior cranial base. Stage 22 TAC embryos and all TAC fetuses exhibited craniofacial dysmorphia and encephalocele. The developing sphenoid was the earliest affected and most severely malformed bone. Its defects included reduced anterioposterior and transverse dimensions, reduced orbitosphenoid and alisphenoid, abnormal pituitary fossa, and reduced dorsum and tuberculum sellae. In addition, shortening of the posterior cranial base and decreased cranial base angle was a consistent finding in the treated embryos and fetuses. Decreased ossification and remodeling in the facial bones and abnormal position due to the malformed sphe

ISSN:0040-3709    

DOI:10.1002/tera.1420280107

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1983

数据来源: WILEY

摘要:

AbstractA skeletal variant assay system (SVAS) consisting of a group of 88 spontaneously occurring qualitative variations of the adult mouse skeleton was applied to CD‐1 animals that had been exposed in utero to 0, 200, or 1,000 mg/kg/day of the sodium salt of acetazolamide dissolved in distilled water, presented by SC injection of the dam during day 8 or days 9–11 of gestation. Two separate series of experiments were performed, and skeletons were examined at postnatal 62 ± 2 days.Variation occurred in 62 and 67 characters in the two series. Frequencies of occurrence differed from untreated (UNTD) and vehicle‐treated (VEH) values of substantial numbers of variants in a dose related manner for both series in both treatment regimes as did the number of variants which showed significantly different frequencies (P<.01) in comparisons of experimental with either UNTD or VEH. At the high doses 12 and 16 variants occurred with significantly different frequencies from UNTD in day 8 treatments in the two series, and 15 and 19 variants differed in the days 9–11 treated group. Contrasting high‐dose animals with appropriate vehicle controls revealed differences in 13 and 12 variants in day 8 treatment groups and in 18 and 15 variants in days 9–11 groups.Agreement between the two series was good, especially in the D9–11 treatments. Several variants differed significantly from both UNTD and VEH in both series of experiments. Among these were a number which appeared more or less specific to acetazolamide exposure. They include: day 8 treatments–accessory parietal, frontal extension, and 27 presacral vertebrae; day 9–11 treatments—sacral fusions in dorsal processes and vertebral bodies, and caudal fusions and malformations; both sets of treatments—lumbar fusions, and fusions of the transverse processes of the sacral vertebrae. Other importantly affected variants, also seen in exposure to other compounds include: day 8 treatments—abnormal metoptic roots; day 9–11 treatments—accessory mental foramen, foramina transversaria imperfecta of the atlas, arch foramen of the fifth cervical (C) vertebra, malformed sternebrae, fossa olecrani perforata, and fewer than 30 caudal vertebrae; both treatment regimes—parted frontals, accessory transverse foramina in C3–C6, reduced articular processes on the thoracic vertebrae, and 14 ribs.By all criteria applied, the SVAS is able to detect prenatal exposure to acetazolamide in adult skeletons even in the absence of any g

ISSN:0040-3709    

DOI:10.1002/tera.1420280108

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1983

数据来源: WILEY

摘要:

AbstractVarious characteristics were compared among mothers of 99 singleton male live births (in Upstate New York, 1970–1974) with hypospadias and mothers of 99 singleton male live births, matched for maternal age, race, and residence. Maternal (and paternal) education, maternal height and weight, and the frequency of maternal diseases did not differ between cases and controls. Mean age at menarche was significantly later, but delayed menarche (16 years) was not more frequent, in case vs. control mothers. In the latest year during which the mother was neither pregnant nor taking oral contraceptives, menstrual cycles were significantly more often asymptomatic in case vs. control mothers, implying a higher frequency of anovulatory cycles in case mothers. This suggests the need for further studies on menstrual symptoms. Among case‐control pairs with a previous pregnancy, the first pregnancy was less likely to have resulted in a male fetus in case vs. control mothers. Maternal use of exogenous sex hormones (oral contraceptives, hormone therapy, and hormone pregnancy tests) during the index pregnancy did not differ significantly between cases and controls, but the relative risk of 3.50 for hormone pregnancy tests (seven cases vs. two controls) was noteworthy in view of the results of previous stud

ISSN:0040-3709    

DOI:10.1002/tera.1420280109

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1983

数据来源: WILEY

摘要:

AbstractPrenalterol (levo‐1‐[4‐hydroxyphenoxy]‐3‐isopropyl‐amino‐2‐propanol), a new stimulant of cardiac β‐adrenergic receptors in man, induces cardiovascular malformations when topically administered to 2½‐through 5½‐day chick embryos (Hamburger‐Hamilton stages 17–27). Ventricular septal defects (VSD) located in the middle portion of the conal septum and classified as the simple, punched‐out type VSD without septal malalignment were the predominant malformations observed throughout the developmental period tested. Arch malformations of the aortic circulation were also observed throughout the test interval, while anomalies of the pulmonary system were observed only at Hamburger‐Hamilton stages 17 and 26–27. At stage 25 prenalterol demonstrated an acute toxicity significantly less than (1/50–1/20) epinephrine (P = .035 at concentrations of 8–10 mM) but was relatively equipotent with epinephrine in producing cardiovascular malformations. The effective median concentrations of the two agents were comparable (0.5–1.0 mM). The spectra of malformations induced by prenalterol and epinephrine were qualitatively similar. Malformations included absence of the right and/or left third aortic arch (innominate arteries), persistent remnant of the left fourth aortic arch, and VSD. These results support a previously proposed theory by these investigators that hyperstimulation of cardiac β‐adrenergic receptors in the chick e

ISSN:0040-3709    

DOI:10.1002/tera.1420280110

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1983

数据来源: WILEY

摘要:

AbstractThe consequences of CO‐induced hypoxia to the forebrain of seven‐day‐old chick embryos were investigated. Exposure of embryos to CO for three hours caused hemorrhages in developing forebrain areas. Carboxyhemoglobin levels reached about 50% in the embryos. Two weeks later, about one day prior to hatching, morphology of large neurons in the paleostriatum primitivum was evaluated. In Golgi‐stained sections examined under the light microscope, the CO‐exposed chicks were found to have reduced branching of the dendritic tree. In addition, the nuclear size of the paleostriatum primitivum neurons was reduced in the CO‐exposed chicks. These findings in chick embryos are comparable to results in previous experiments with

ISSN:0040-3709    

DOI:10.1002/tera.1420280111

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1983

数据来源: WILEY