bluuebunny/crossref_metadata_2025_split huggingface dataset:
Teratogenic effects of retinoic acid in pigtail monkeys (Macaca nemestrina) II. Craniofacial features
Authors: Newell‐Morris Laura , Sirianni Joyce E. , Shepard Thomas H. , Fantel Alan G. , Moffett Benjamin C. 
Published: June 2005

AbstractThe teratogenic effects of retinoic acid, the alcohol‐soluble acid form of vitamin A, on the craniofacial complex of 11 macaque (Macaca nemestrina) whose mothers had received the compound from days 20 to 44 are described. The fetuses ranged in gestational age from 81 to 185 days and exhibited features of the so‐called retinoic acid syndrome (RAS). The syndrome includes both craniofacial defects and postcranial anomalies of the musculoskeletal and urogenital systems. The craniofacial anomalies were described with reference to gross external appearance and radiographic observations. The most frequent findings were cleft palate, malformed ears, hypertelorism, exophthalmos, hypoplasia of the bone of the mid‐face and mandible, a curvature of the inferior border of the mandible, retrognathia, and distortion of the cranium. Lateral cephalograms on nine animals of the RAS sample were measured using six linear dimensions which define the cranial base, face height, palatal length, and mandibular length. The measurements were plotted relative to normal curves which describe growth of the dimensions through the macaque fetal period. For their age, the abnormal animals were small in the craniofacial region. The same measurements were then plotted relative to the size of the fetus, to investigate the possibility of a differential response of the various craniofacial areas to the teratogen. Mandibular length and anterior cranial base were the most reduced dimensions, followed by anterior and posterior face height, with palatal length the least affected. Comparison of the features of the RAS syndrome in the macaque fetus with those reported for various human mandibulofacial dysostosis syndromes yields similarities, but there are enough differences to indicate that the syndromes are not identical in the two species. The utility of the approach used, wherein several craniofacial dimensions of the abnormal are assessed relative to normal growth curves and relative to body size, is emphasized.
Gene‐teratogen interaction in insulin‐induced mouse exencephaly
Authors: Cole Wendy A. , Trasler Daphne G. 
Published: June 2005

AbstractHeterozygotes for the mutant genes crooked (Cd) or rib fusion (Rf), crossed to either strain A/J or SWV produce mutant F1 offspring with minor skeletal defects. If the mothers are also treated with teratogenic doses of insulin, the mutant Fl heterozygotes develop exencephaly significantly more often than nonmutants. That the heterozygous mutant gene increased the embryo's sensitivity to insulin‐induced exencephaly was also demonstrated by dose‐response curves. For A/J and SWV crosses, probit regression lines for the mutant crosses were fitted to common slopes that were significantly different from those of probit regression lines for the nonmutant crosses. The nonparallelism of the mutant versus the nonmutant groups of lines indicated the presence of a gene‐teratogen interaction. Early exencephalic embryos showed delayed turning in one‐third of treated mutant crosses and less than a quarter of treated nonmutant crosses. Another one‐third of exencephalics, in treated mutant crosses only, had abnormally twisted hindbodies and appeared to be phenocopies of untreated homozygotes. Insulin treatment significantly slowed the rates of embryo turning and neural tube closure but did not affect somite number. Histologically, insulin did not appear to cause cell death, and mitotic index of mesoderm was unaffected. Only exencephalic embryos showed a significant reduction in neurectoderm mitotic index. Insulin caused a reduction in neurectoderm cell proliferation, delay in pattern of turning and delay in neural tube closure to the greatest extent in exencephalic embryos. It was postulated that extensive delays in turning could provide a mechanical basis for the failure of the neural tube to close.
Developmental pattern of cAMP, adenyl cyclase, and cAMP phosphodiesterase in the palate, lung, and liver of the fetal mouse: Alterations resulting from exposure to methylmercury at levels inhibiting palate closure
Authors: Olson Fred C. , Massaro Edward J. 
Published: June 2005

AbstractExposure to methylmercury (MeHg: 10 mg Hg/kg maternal body weight) on 126 (dayshours) of gestation significantly delays palate closure in the Swiss Webster CFW mouse. The cAMP content and activity of adenyl cyclase and phosphodiesterase (PDE) were measured in the tissues of control and MeHg‐induced cleft palates between 136 and 176 of gestation. Lung and liver were investigated similarly to determine if MeHg affected the adenyl cyclase system of the palate in a unique manner.In control palatal tissue, cAMP levels increased sharply from 1322 (undetect‐able) to 146 (maximum). PDE activity increased similarly up to 142, but decreased 50% between 142 and 146. Since it has been reported that cAMP induces the synthesis of PDE, the difference in cAMP/PDE from 1322 to 142 and from 142 to 146 suggests the localization of relatively high levels of cAMP in at least two separate compartments. Between 146 and 1410, the adenyl cyclase activity of control palates decreased significantly. This rapid decrease suggests relatively high adenyl cyclase activity in the medial edge epithelial cells which undergo autolysis prior to shelf fusion (centered at 1415).Maternal MeHg administration at 126 delayed the median time of palatal shelf rotation (1413) by 5 hours, and significantly altered the developmental pattern of the adenyl cyclase system. Thus, the increase in cAMP between 142 and 146 was abolished and the decrease in adenyl cyclase activity between 146 and 1410 was delayed by almost 20 hours. These changes may be manifestions of a MeHg‐induced delay in medial edge epithelial cell differentiation.In a previous study, we observed that the fetal liver exhibits the highest MeHg concentration of all tissues. Since MeHg only slightly altered the adenyl cyclase system of the fetal liver compared to the lung and palate (in which MeHg uptake is considerably less), it may be that the effects of MeHg on palatal tissue are not due to a direct effect of MeHg on components of the adenyl cyclase system.
Congenital malformations in a post‐mortem series
Authors: Evans P. R. , Polani Nina 
Published: June 2005

AbstractOf 8,390 children necropsies, 1,249 showed congenital malformations. Thirteen different malformations were recorded relatively often and are here designated as common. Of the necropsied children 914 had only one of these common malformations, and 140 more than one. A variety of less common anomalies was found in the remaining 195 necropsies. The 13 selected common malformations were analyzed statistically to establish whether there was significant clustering of them. Only five of the common malformations proved to be significantly associated. Both frequency and variability of complication differed considerably between groups of common malformations. There was an overall preponderance of males with the common anomalies but the different anomalies differed in respect to sex ratio.
Palate development in the mouse: A quantitative method that permits the estimation of time and rate of palate closure
Authors: Biddle F. G. 
Published: June 2005

AbstractA quantitative technique is used to express the morphogenetic stages of palate development in the mouse in terms of gestational age and the normal probability distribution. The qualitative palate rating scale for mouse embryos was modified and the numbers of embryos that had reached the different palate stages at specific gestational ages were fitted to a cumulative multinomial frequency distribution by normal probability regression on gestational age. The median time for each stage can be estimated and the standard deviation of this time (slope of the probability regression) provides a measure of the rate of development. A/J and A.B6 F1 embryos (A/J maternal environment) differed significantly in median time but not in rate of development during a restricted examination time.
Differential staining of cartilage and bone in whole mouse fetuses by alcian blue and alizarin red S
Authors: McLeod M. Jean 
Published: June 2005

AbstractThe procedure described by Inouye ('76) for the staining of full‐term mouse fetal skeletons has been adapted for use with mouse embryos and fetuses of days 14–18 of gestation. The main adaptations for younger specimens involve a longer time in acetone, in lieu of skinning, and omission of the aqueous KOH step. These adaptations require more time but result in consistently good staining of intact specimens.
Agnathia, situs inversus, and associated malformations
Authors: Pauli Richard M. , Graham John M. , Barr Mason 
Published: June 2005

AbstractTwo infants with a striking pattern of associated malformations including agnathia, situs inversus, renal agenesis and ectopia, and multiple vertebral and rib abnormalities are described. It appears that these two infants represent a previously unrecognized malformation association that involves far more than developmental arrest of the mandibular arch. It is conceivable that a single defect at a very early stage in development could account for the multiple manifestations seen.
The teratogenicity of cytochalasin D and its inhibition by drug metabolism
Authors: Fantel A. G. , Greenaway J. C. , Shepard T. H. , Juchau M. R. , Selleck S. B. 
Published: June 2005

AbstractPregnant rats received intraperitoneal injections of cytochalasin D (CD) on gestational days 7–11. Doses of 400 μg/kg were only minimally and nonsig‐nificantly teratogenic, leading to 2 exencephalic fetuses among the 111 fetuses delivered. By contrast, embryos exposed to CD in vitro on day 10 showed significant frequencies of neural tube abnormalities when exposed to CD concentrations at or above 3.1ng/ml. These embryos also exhibited significantly decreased protein, somite counts, and crown‐rump lengths.In order to understand this apparent discrepancy between the teratogenicity of CD in vivo and in vitro we performed experiments to determine whether drug metabolism could inhibit the teratogenicity in vitro. Male rats were pretreated with a mixture of polychlorinated biphenyls as cytochrome P‐450 inducers, and their livers were used to prepare a microsome‐rich fraction (S‐9). This S‐9 fraction, plus a source of reducing equivalents (NADPH), significantly inhibited the teratogenicity of CD. The teratogenicity was restored by the omission of NADPH, and was partially restored with the addition of carbon monoxide.These results led us to conclude that the teratogenic effect of CD can be inhibited by drug metabolism in vitro; additionally, it is likely that some or all of this drug metabolism may depend on cytochrome P‐450. We further speculate that CD may be inactivated in vivo by these same systems, explaining the discrepancy between the teratogenicity of CD in vivo and in vitro.
Effect of ethinyl estradiol on development of mouse fetuses
Authors: Yasuda Yoshiko , Kihara Takahide , Nishimura Hideo 
Published: June 2005

AbstractPregnant ICR/JCL mice were given orally 0.02, 0.2, or 2.0 mg/ kg body weight/day of ethinyl estradiol in olive oil or vehicle alone on day 11 through day 17 of pregnancy. Pregnant mice of another group received a single oral dose of ethinyl estradiol on day 8 or day 11 of pregnancy. A lethal effect on fetuses of both groups with single and continuous exposure to ethinyl estradiol was observed in a dose‐response relationship. Growth suppression of fetuses was only found at term in a dose‐response relationship following continuous exposure to ethinyl estradiol. Hypertrophic nipples were seen in 42% of surviving female fetuses prenatally exposed to 2.0 mg/kg of ethinyl estradiol singly on day 11 of gestation. There was not an increase in other congenital malformations in any of the treated groups. These findings indicate that administered ethinyl estradiol can affect the developing mouse embryo but the embryotoxic doses in the mouse are substantially greater than the usual therapeutic or contraceptive doses in the human.
Limb development in mouse embryos. III. Cellular events underlying the determination of altered skeletal patterns following treatment with 5′fluoro‐2–deoxyuridine
Authors: Knudsen T. B. , Kochhar D. M. 
Published: June 2005

AbstractA potent inhibitor of thymidylate synthetase, 5–Fluorodeoyxyuridine (FUdR), produced dose‐ and stage‐dependent skeletal defects in embryos of mice injected during early development (10th‐13th day). The dose of 25 mg/kg was teratogenic producing few resorptions and little reduction in fetal weight. Hindlimbs were much more sensitive to the drug than were the forelimbs and showed dose‐dependent long bone reductions. Specific long bone reductions occurred after treatment on the 11th or 11.5 day and were accompanied by preaxial polydactyly; treatment on the 12th or 12.5 day produced high incidence of ectrodactyly but no long bone reductions. Limbs were insensitive on the 13th day of development and beyond. Limb buds in organ culture demonstrated a direct action of FUdR on undifferentiated mesenchymal cells, incurring what has been previously termed “thymineless” cell death. Dose‐dependent reduction of viable cell number led to a reduction in chondrogenic expression in vitro–more so in the hindlimb than the forelimb. Similar occurrence of cell death was also noted after in utero exposure, and here, it was followed by a process of recovery. The recovery phase was characterized by the formation of a distal synchronized cell population derived from undamaged subridge cells leaving damaged cells at the proximal extent of the subridge zone. Limb segments maintained their temporal sequence of differentiation, and their regulatory capability was related to the time allotted for repopulation of the subridge zone. We propose that a faster growth during early development of the elements of the hindlimb versus analogous ones of the forelimb allows the former less time for regulation–and hence, higher sensitivity to antiproliferative agents such as FUdR.
The effect of diazepam on meiosis in the CF‐1 mouse
Authors: Stenchever Morton A. , Smith W. Dianne 
Published: June 2005

AbstractOocytes from virgin CF‐1 female mice were treated in vitro with Krebs‐Ringer media containing 1.0, 10.0, 30.0, 50.0, 100.0, and 200.0 μg/ml of diazepam. In addition, oocytes were exposed to no drug and to 4% propylene glycol and Krebs‐Ringer media. The latter was chosen because diazepam is frequently injected in a propylene glycol vehicle. After 17 hours of incubation at 37°C in a 5% C02 atmosphere, all oocytes were scored for the presence of germinal vesicles, Metaphase I, Metaphase II, or degenerative and abnormal forms. Cells from the pure control, propylene glycol, 1.0, and 10.0 μg/ml concentration preparations demonstrated progress to Metaphase II in from 86–89% of cells. Only a small percentage of oocytes was noted to be degenerative or abnormal in any of these groups. From 0.6–2% of oocytes were arrested in Metaphase I. At 30.0 μg/ml concentration 18.7% of cells were arrested at Metaphase I but only 1.5% were noted to be degenerated. At 50.0 μg/ml, 26.6% of cells were arrested at Metaphase I and 13.3% were degenerated. At 100.0 μg, 7.7% of cells were found in Metaphase I, 9.2% in Metaphase II, and 67.7% degenerated. At 200.0 μg/ml 3.1% of cells were found at Metaphase I, none at Metaphase II, and 88% in the degenerative form. Since blood levels of diazepam rarely rise above 6 μg/ml even in patients treated with as much as 200 mg per day, and are generally observed in the 1 μg/ ml range for patients on typical treatment regimen, it is not likely that human tissues will achieve concentrations seen to have toxic effects in these studies. Future in vivo studies, however, seem indicated.
Teratogenic effects of mescaline, epinephrine, and norepinephrine in the hamster
Authors: Hirsch Kenneth S. , Fritz H. Ira 
Published: June 2005

AbstractMescaline was administered orally at doses of 16 and 32 mg/kg on the seventh through tenth days of gestation to pregnant cream‐strain hamsters. This treatment resulted in a dose‐dependent effect on reproductive success and skeletal ossification. The effect of mescaline on reproductive success included an increased number of resorptions resulting in a decreased litter size. The 32 mg/kg dose of mescaline caused 48.8% resorptions, while 16 mg/kg and control animals had 12.0% and 6.4% resorptions, respectively. Litter size was decreased from 12.0 pups in controls to 10.3 (16 mg/kg) and 6.5 (32 mg/kg) pups per litter in treated groups. No gross abnormalities were observed at necropsy; there was, however, a dose‐dependent increased delay in the ossification of the skull, sternum, and metatarsals. Both epinephrine and norepinephrine caused a decrease in reproductive success when administered at 500 μg/kg. Epinephrine appeared to cause a trend towards preimplantation wastage as indicated by an increased corpora lutea to implantation site ratio (from 1.3–1.9). Norepinephrine, however, caused an increased number of resorptions (29.1% in controls). Both norepinephrine and epinephrine produced similar delays in ossification.
Correlation between the molecular structure of N‐alkylureas and N‐alkylthioureas and their teratogenic properties
Authors: Teramoto S. , Kaneda M. , Aoyama H. , Shirasu Y. 
Published: June 2005

AbstractEleven urea compounds were administered individually as a single oral dose to rats either on day 12 or 14 and to mice on day 10 of pregnancy. 1‐Methylurea and 1‐ethylurea were not teratogenic in either of the animal species. Administration of 1‐methylthiourea and 1‐ethylthiourea, however, resulted in high incidences of malformations in the rat but not in the mouse fetuses. The types of malformation were similar to those produced by the known teratogen ethylenethiourea. Methylated ureas such as 1,3‐dimethylurea, 1,3‐dimethylthiourea, 1,1,3,3‐tetramethylurea, and 1,1,3,3‐tetramethylthiourea were fetotoxic and produced malformations in the tail, palate, or extremities of the surviving rat and/or mouse fetuses. These findings suggest that the teratogenic properties of N‐alkylureas can be categorized into two groups, i.e., mono‐alkylated thioureas and methylated ureas or thioureas.
Correlation between alterations in Meckel's cartilage and induction of cleft palate with β‐aminoproprionitrile in the rat
Authors: Diewert Virginia M. 
Published: June 2005

AbstractThe lathyrogen β‐aminoproprionitrile (BAPN) induces cleft palate in rats when administered at a critical time in secondary palate formation. BAPN is known to inhibit the crosslinking of newly synthesized collagen, but its primary site of action in producing cleft palate is unknown. In this study timemated Sprague‐Dawley rats were given a single oral dose of 600 mg/kg BAPN at five known gestational ages in the 48 hours before palatal shelf elevation, and the fetuses were studied on days 16, 17 and 18. Evaluation of craniofacial relations and palate development in BAPN‐treated heads revealed that delayed palatal shelf elevation and resulting cleft palate were related to retrognathia of the mandible. However, shortening of the mandible was due primarily to vertical and lateral bending of Meckel's cartilage. High and retruded tongue positions that were present with the deformities in Meckel's cartilage interfered with palatal shelf movement to the horizontal plane. The group treated with BAPN at 15 days 7 hours, approximately 24 hours before normal palatal shelf elevation, had the most severe defects in Meckel's cartilage, the longest delay in palatal shelf elevation and the highest incidence of cleft palate. Inhibition of crosslinking of collagen in Meckel's cartilage appeared to weaken the cartilage during the critical period in facial development when extention of the tongue and mandible beneath the primary palate is required to facilitate palatal shelf elevation.
Cortisone‐induced cleft palate in A/J mice: Failure of palatal shelf contact
Authors: Diewert Virginia M. , Pratt Robert M. 
Published: June 2005

AbstractAlthough cortisone treatment for induction of cleft palate in mice has been shown to delay the time of palatal shelf elevation, the effects of delayed elevation of shelf contact have not been critically evaluated in a cortisone‐sensitive mouse strain. The objective of this study was to evaluate palatal development in cortisone‐treated A/J mice in order to determine whether the shelves make contact upon elevation. Morphometric analysis of frozen sections revealed that cortisone‐treated shelves were smaller than control shelves with apparent reductions in both the content of extracellular matrix and the number of cells. At a light microscopic level, thinning of medial epithelium in cortisone‐treated palates appeared similar to that in untreated palates with spontaneous cleft lip and palate. Shelf elevation was delayed by approximately 12 hours and only half of the cortisone‐treated palates achieved complete horizontal positioning of the shelves in all regions of the palate. Immediately after elevation, all control palates had extensive vertical contact along the complete length of the palate. In contrast, approximately 20% of the cortisone‐treated fetuses had contact between the shelves in the middle palate region only, with the mean area of contact only 20% as large as in control fetuses. As a result, the net shelf contact in all the cortisone‐treated fetuses was only 4% of the potential contact shown in control fetuses. Therefore, failure of the palatal shelves to elevate and make extensive contact appeared to be the major factor contributing to cortisone‐induced cleft palate in A/J mice.
The effects of phenytoin on rat development: An animal model system for fetal hydantoin syndrome
Authors: Lorente Carol A. , Tassinari Melissa Sherman , Keith David A. 
Published: June 2005

AbstractAn animal model system has been established which reproduces some of the features of the Fetal Hydantoin Syndrome. This pattern of altered growth and development includes growth retardation, craniofacial anomalies, distal phalangeal hypoplasia, and mental deficiency. Rats exposed in utero to phenytoin on gestational days 9, 11, and 13 exhibited fetal onset growth retardation, abnormalities of the craniofacial region and axial skeleton. In addition, the exposed offspring had significantly lower fetal weights, a shortened snout and a high‐arched, irregular palate, and significant delays in skeletal maturation. These abnormalities resemble those reported for the Fetal Hydantoin Syndrome and provide a means to study the effect of phenytoin on the morphological and biochemical development of the fetus.