bluuebunny/crossref_metadata_2025_split huggingface dataset:
Teratogenicity of three substituted 4‐biphenyls in the rat as a result of the chemical breakdown and possible metabolism of a thromboxane A2‐receptor blocker
Authors: Sutherland M. F. , Parkinson M. M. , Hallett P. 
Published: June 2005

AbstractAH23848 is a potent thromboxane A2‐receptor blocker inhibiting platelet aggregation in vitro and in vivo. Oral administration to pregnant rats during days 7–16 of pregnancy, at doeses of 0, 10, 45, or 200 mg/kg twice daily, resulted in dose‐related maternal, embryonic, and fetal toxicity. The most notable observation was herniation of the diaphragm occurring in 1.5 and 100.0% of fetuses at the 45 and 200 mg/kg doses, respectively, when examined at term. A further study at 150 mg/kg twice daily during days 7–16, 7–11, or 12–16 of pregnancy revealed incidences of diaphragmatic hernia up to 42%. Herniation varied from small areas of eventration of membranous diaphragm to fetuses with apparent total absence of the diaphragm. The positions of the hernias in the diaphragm, following dosing over varying periods of organogenesis, reflected the chronology of diaphragm formation in the rat. The teratology of AH23848 was unrelated to its thromboxane A2‐receptor blocker properties but was related to a chemical breakdown product, 4‐biphenylmethanol. Some substituted biphenyl compounds appear to be specific teratogens in the rat, with their effects targeted at the developing diaphragm. A possible mechanism of herniation is the interference with muscularisation of the membranous diaphragm, resulting in weakness and perforation.
Cortisone cure of the eyelid closure defect in lidgap‐stein fetal mice: A dose‐response and time‐response study as a test of the hypomorph hypothesis for the lidgap alleles
Authors: Harris M. J. 
Published: June 2005

AbstractThe lidgap‐Stein mutation is one of a series of alleles that cause the birth defect open eyes in mice. Previously it was known that cortisone administered during pregnancy prevents the defect in some lidgap‐Stein fetuses. In this study, the hypothesis that lidgap‐Stein is a hypomorph of effect intermediate between that of its alleles lidgap‐Miller (least abnormal) and lidgap‐Gates (most abnormal) was tested in a dose‐response, time‐response, and scanning electron microscopic study. Cortisone produced a response at doses of 20–80 mg/kg, with maximum cure of 30% in right eyes, 24% in left eyes, and 13% bilaterally. There was significantly more response in right than in left eyes. The response was slight at doses of less than 20 mg/kg and dropped to zero at the highest dose of 120 mg/kg. Treatment on days 13 or 14 gave the maximum response, with little or no response to treatment on days 10, 11, 12, 15, or 16. Severity of defect, measured as the size of gap in open eyes on day 18, was not reduced as the frequency of open eyes was reduced; most unclosed eyes remained wide open. The much lower level of maximum bilateral response to cortisone in lidgap‐Stein (13%) than in lidgap‐Miller (94%) is entirely compatible with the hypomorph hypothesis.
Fetus amorphus or placental teratoma?
Authors: Stephens Trent D. , Spall Richard , Urfer Alexander G. , Martin Roger 
Published: June 2005

AbstractA differential diagnosis between fetus amorphus and placental teratoma based on the presence of an umbilical cord and/or skeletal organization in the fetus amorphus has been proposed (Fox and Butler‐Manual: Journal of Pathology 88:137–140, 1964). We report a description of one new case of fetus amorphus, along with the results of a critical reexamination of 96 cases from the literature. Our findings fail to support the proposed criteria for distinguishing fetus amorphus from placental teratomas. We find that the presence or absence of an umbilical cord does not relate at all to the developmental state of the specimen. The extent of skeletal development may be a more valid criterion; however, the internal organization in the fetus amorphus forms an anatomical continuum with that of the placental teratoma, making a differential diagnosis meaningless. Additional research is necessary to solve this dilemma.
A scanning electron microscope study of fetal eyelid closure accelerated by cortisone in SWV/Bc mice
Authors: Juriloff D. M. , Harris M. J. 
Published: June 2005

AbstractEyelid closure occurs earlier in SWV/Bc and CBA/J mouse fetuses whose mothers were treated with cortisone on day 14 of gestation than it does in fetuses from untreated mothers. Similar treatment prevents the open‐eyes defect of lidgap—Miller mutant mice, but examination by scanning electron microscope (SEM) has shown differences in the periderm of the closing eyelids of the cortisone‐treated mutant compared with those of untreated genetically normal fetuses. (Untreated mutant eyelids remain wide open and very abnormal.) The present study has examined at the SEM level the accelerated eyelid closure of cortisone‐treated normal strain, SWV/Bc, fetuses to investigate whether the differences from normal in the eyelids of treated lidgap—Miller fetuses are part of the mechanism of the cortisone “cure.”At the SEM level, cortisone‐accelerated eyelid closure of SWV/Bc fetuses is indistinguishable from that in untreated fetuses. This suggests that the early eyelid closure induced by cortisone in normal strain fetuses represents acceleration of the normal coordinated sequence of events that leads to closure, rather than an abnormality that fortuitously leads to closure. The data also indicate that the cellular abnormalities seen previously in treated lidgap—Miller mutant fetuses are a combination of 1) abnormalities due to the mutation that are not completely reversed by cortisone and 2) normal developmental stages that have become concurrent with the cortisone‐induced late closure in lidgap—Miller mutant fetuses.
Anatomical features associated with preaxial duplication (pd): A recessive mutation in the rat
Authors: Kaneda Masahiro , Teramoto Shoji , Shirasu Yasuhiko 
Published: June 2005

AbstractPreaxial polydactyly of the fore‐and hindlimbs was found in Wistar‐derived rats in 1978. Genetic analysis indicated that the polydactyly was due to the effects of an autosomal recessive gene (gene symbol; pd) Polydactylous and one to three preaxial extra digits (six to eight digits) in the hindlimbs. Skeletal examination revealed the presence of the extra carpal, metacarpal, and phalangeal bones that seemed to be complete or incmplete duplication of the navicular, greater multangular, first metacarpal, and phalanges of digit I in the forelimbs. In the hindlimbs, extra tarsal, metatarsal, and phalangeal bones were also observed preaxially. These extra elements seemed to be mirror‐image duplications of the talus navicular, second cuneiform, third cuneiform, cuboid, and metatersals and phakanges of digits II‐V with the absence of the first cuneoform, tibnials, first metatarsal, and phalanges of digit I. In addition, morphological changes were observed in the humerus, radius, and ulna in hte forlimbs and femur, tibia, and fibula in the hindlimbs. Especially in the radius andtibia, thickening and bifurcation were found, indicating incomplete duplication of these bones. Based on these findings, the limb anomaly was classfied as preaxial carpometacarpal/tarsometatarsal‐type polydactyly with incomplete duplication of the radius and tibia. The mutan rats had other associated anomalies such as accessory spleens and cryptorchism. The males are sterile, whereas the females breed normally.
Behavioral teratogenic effect of methylmercury and d‐amphetamine: Meta‐analysis and power analysis of data from the collaborative behavioral teratology study of national center for toxicological research
Authors: Tachibana Toshiaki 
Published: June 2005

AbstractThe data of the Collaborative Behavioral Teratology Study (CBTS) were analyzed. Population‐effect sizes were estimated, in terms of confidence intervals, by meta‐analysis. A treatment effect of methylmercury was clearly observed and a dose‐response effect was also observed. On the other hand, no clear treatment effect was observed in the d‐amphetamine study. The effect of auditory startle habituation was very large, although it was limited to the high‐dose group in the methylmercury study. The effects observed for physical landmarks were, as a whole, somewhat larger than those for behavioral measures. There is no clear evidence for sex‐related differences except for activity measures. A curious treatment effect that was not referred to in the CBTS report was observed: eye‐opening day and incisor‐eruption day were hastened by the treatment of methylmercury. Power analysis results showed that obtaining a statistically significant effect for these compounds is very difficult, suggesting that even though published papers reported the significant effect of these compounds there might have been many unpublished experiments that obtained nonsignificant effects. If one uses these compounds as positive controls, a very large sample size will be needed. No highly sensitive test that is reproducible across compounds or dose‐levels was observed among tests employed in the CBTS.
Prenatal α‐difluoromethylornithine treatment: Effects on postnatal renal growth and function in the rat
Authors: Gray Jacqueline A. , Rehnberg Blair F. , Rogers Ellen H. , Lau Christopher , Slotkin Theodore A. , Kavlock Robert J. 
Published: June 2005

AbstractDFMO (α‐difluoromethylornithine) is a specific irreversible inhibitor of ornithine decarboxylase (ODC), a key enzyme in the biosynthesis of polyamines, which in turn control macromolecule synthesis during cell proliferation. The current study was designed to investigate the effects of inhibition of ODC during discrete prenatal periods on renal growth and function. We administered 5 doses of 500 mg/kg DFMO or saline s.c. to timed pregnant Sprague‐Dawley rats at 12 hr intervals beginning on gestation days (GD) 11, 14, or 17. Half the dams were killed on GD 20 for fetal morphological analyses and half were allowed to go to term. Renal function was assessed on postnatal days (PD) 3, 6, 10, and 14 by tests of basal renal clearance and urinary concentrating ability, and on PD 42–44 we measured serum chemistries. All three gestational treatment regimens resulted in postnatal deficits in general growth. Only in the GD 11–13 treatment group was there evidence of embryotoxicity and neonatal renal pathophysiology. Fetal weights and urogenital morphology were altered following GD 14–16 treatment and there were persistent deficits of renal growth. GD 17–19 treatment was associated only with transient postnatal deficits of renal growth. Thus, inhibition of ODC during critical prenatal periods induced distinct developmental effects. However, there were no associations between impaired renal growth and function. These data indicate that general tissue growth is not always a predictor of physiological development and support the necessity of multifaceted approaches to the understanding of adverse developmental effects.
Neuroblastoma after prenatal exposure to phenytoin: Cause and effect?
Authors: Koren Gideon , Demitrakoudis Demitri , Weksberg Rosanna , Rieder Michael , Shear Neil H. , Sonely Marylin , Shandling Barry , Spielberg Stephen P. 
Published: June 2005

AbstractWe evaluated the causality of the association between intrauterine exposure to phenytoin and postnatal neuroblastoma using an in vitro lymphocyte toxicity assay for phenytoin‐induced reactions in an unusual sibship. In addition, we investigated intrauterine phenytoin exposure in a case series of infants and children with neuroblastoma diagnosed over 17 years at our center. The response of lymphocytes from our index case with neuroblastoma exposed in utero to phenytoin was within the normal range, whereas the mother and a sibling with fetal hydantoin syndrome (FHS) exhibited an intermediate toxicity. None of the 188 case of childhood neuroblastoma diagnosed between 1969 and 1988 had been exposed in utero to phenytoin, indicating that, statistically, the drug cannot be associated with neuroblastoma in more than two cases with this malignancy in our cohort, or in 1.5% of all cases of neuroblastoma. Although our data do not suggest an association between phenytoin in pregnancy and postnatal neuroblastoma, it is still possible that there is an increased risk for neuroblastoma in children with FHS.
Retinoic‐acid‐induced limb‐reduction defects: Perturbation of zones of programmed cell death as a pathogenetic mechanism
Authors: Alles Ajit J. , Sulik Kathleen K. 
Published: June 2005

AbstractPregnant C57B1/6J mice were treated with 100 mg/kg body weight of all‐trans retinoic acid in sesame oil on day 11.0 of gestation. Among the live fetuses harvested on day 18 of gestation, 100% had mesomelic defects of the limbs as determined by gross examination and skeletal staining. Control fetuses treated with sesame oil had no observable limb malformations. Some treated and control embryos were harvested 12 hr after treatment and examined for patterns of cell death by using the supravital stain Nile blue sulphate and methylene‐blue‐ and acid‐fuchsin‐stained histological sections. Retinoic‐acid‐induced cell death in the core of the limb was always associated with the zones of programmed cell death as seen in control embryos of comparable stages. This, in concet with previous studies demonstrating excessive cell death in regions of programmed cell death that correlated with subsequent malformations, leads us to conclude that the pathogenesis of mesomelic malformations has a primary association with the phenomenon of programmed cell death.
Brain abnormalities induced by murine cytomegalovirus injected into the cerebal ventricles of mouse embryos exo utero
Authors: Naruse Ichiro , Tsutsui Yoshihiro 
Published: June 2005

AbstractMurine cytomegalovirus (MCMV) was injected into the cerebral ventricle of mouse embryos on day 13 of gestation after exposing the embryos out of the uterus in the abdominal cavity of the mother. The embryos were allowed to develop to day 18 of gestation, then taken out from the abdominal cavity. Macroscopically, there were four expanded and three distorted brains out of 19 surviving embryos, whereas no brain abnormality was noticed in 13 embryos injected with culture medium instead of MCMV in the same way. Histopathological examination showed hydrocephalic lesions with strong dilatation of the ventricles and atrophy of the cerebral cortex, and inflammatory lesions with granulomatous proliferation of the ventricular walls with disappearance of the cortical zonation. Immunohistochemically, MCMV‐induced nuclear antigen‐positive cells were frequently observed in the wall of the ventricles and occasionally scattered in the cerebral cortex, white matter, and the nucleus basalis. Some fetuses injected with MCMV in the same way were recovered from the abdominal cavities on day 18 of gestation and transferred to foster nurse mothers. They showed massive cerebral necrosis after feeding for 9 days after birth. Brain abnormalities of mouse embryos after intraventricular injection with MCMV may provide an experimental model of brain damage induced by congenital cytomegalovirus infection.
Moebius syndrome: Animal model—human correlations and evidence for a brainstem vascular etiology
Authors: Lipson A. H. , Webster W. S. , Brown‐Woodman P. D. C. , Osborn R. A. 
Published: June 2005

AbstractThe Moebius syndrome consists of congenital seventh nerve palsy associated with other cranial nerve palsies, most often of the sixth, and/or musculoskeletal abnormalities. A retrospective study of the events of pregnancy in 15 cases was undertaken, after a rat animal model showed that abdominal trauma, uterine vessel clamping and handling and hyperthermia caused bilateral brainstem lesions in fetal rats. Eight of the 15 cases surveyed included a possible associated event during pregnancy; hyperthermia, previous uterine surgery, electric shock, failed abortion, prolonged rupture of the membranes, or alcohol abuse. These events can be correlated with animal studies that involve acute uteroplacental vascular insufficiency produced by a variety of methods. The cause of most cases of Moebius syndrome is probably a transient ischemic/hypoxic insult to the fetus.
Susceptible period of nitrous oxide teratogenicity in sprague‐dawley rats
Authors: Fujinaga Masahiko , Baden Jeffrey M. , Mazze Richard I. 
Published: June 2005

AbstractThe susceptible period of nitrous oxide (N2O) teratogenicity was studied in 170 Sprague‐Dawley rats. Seven groups of 20 timed‐pregnant rats were exposed to 60% N2O for 24 hours on each of days 6–12 of gestation; a control group of 30 timed‐pregnant rats was exposed to air on day 9. On day 20 of gestation, dams were killed and reproductive indices were determined; their fetuses were subsequently examined for external, skeletal, and visceral abnormalities. There were no differences among the groups in the number of implantations and live fetuses, mean fetal weight, and sex ratio. The incidence of fetal wastage was higher than control in N2O‐treated groups exposed on days 8 and 11 of gestation. Skeletal malformations of the ribs and vertebrae were increased following exposure on day 9 of gestation. However, the specific minor anomaly, cervical rib, was increased only following exposure on day 8 of gestation. The incidences of right‐sided aortic arch and left‐sided umbilical artery, abnormalities indicative of altered laterality, were increased following exposure on day 8 of gestation. Nitrous oxide administration during organogenesis causes several reproductive defects by mechanisms which remain to be determined.
Teratogenic effects of phenytoin on chick embryos
Authors: Singh Mandavi , Shah G. L. 
Published: June 2005

AbstractThe antiepileptic drug phenytoin was injected into the yolk sac of White Leghorn chick embryos. A dose‐response study was followed by a detailed teratological study using a single dose of 3 mg. The surviving embryos were sacrificed on the 19th day of incubation. The embryos showed a generalized decrease in body weight together with a wide range of malformations. The malformations could be roughly divided into limb, craniofacial, abdominal, and ocular defects, as well as deficiencies in growth. Skeletal defects included hypoplasia of digital phalanges and nails and shortened wings.
Difference in teratogenic potency of ethylenethiourea in rats and mice: Relative contribution of embryonic and maternal factors
Authors: Daston G. P. , Yonker J. E. , Powers J. F. , Heitmeyer S. A. 
Published: June 2005

AbstractEthylenethiourea (ETU) is a potent teratogen in the rat but. not in the mouse or any other species tested. Embryotoxic and teratogenic effects are produced in mice only after exposure to 10‐40 times the teratogenic dose of ETU in rats. This study was undertaken to determine whether the difference in sensitivity between rats and mice is due to differences within the embryo, to maternal metabolic differences, or both. Comparably staged rat and mouse embryos (gestation day 10.5 and 8.5, respectively) with intact extra‐embryonic membranes were maintained under identical conditions in whole embryo culture and exposed to static concentrations of ETU for 48 hours. The teratogenic effects of ETU were qualitatively similar in both species, characterized by excessive fluid accumulations in embryonic structures., The most common abnormalities were distended neural tube, especially in the hindbrain, and clear blisters on the caudal region. At least two times as much ETU was required to produce a similar incidence of abnormalities in mice as in rats. Thus, there is some intrinsic difference in the quantitative response of rat and mouse embryos to ETU, but it is insufficient to account for the in vivo discrepancy. The role of maternal metabolism in modifying the teratogenicity of ETU was assessed by adding hepatic S‐9 fractions from Aroclor 1254‐induced rats and mice to whole embryo culture. Rat S‐9 had no effect on ETU teratogenicity. Mouse S‐9 virtually eliminated the formation of abnormalities typical of ETU in both rat and mouse embryos. Decreased exocoelomic fluid osmolality, a physiological effect produced by ETU, also was not observed in embryos exposed to ETU and mouse S‐9. ETU‐typical defects were observed in embryos exposed to ETU and mouse S‐9 which had been treated with carbon monoxide to inactivate its monooxygenase system, indicating that the mouse S‐9 was metabolizing ETU. A surprising result was that adding mouse S‐9 to embryo cultures containing ETU resulted in the formation of abnormalities (principally open neural tube) that were not observed in in vitro rat or mouse embryos exposed to ETU alone, or in mouse embryos in vivo. We believe that the most likely cause of these abnormalities is a putative ETU metabolite, which is rapidly excreted by the dam in vivo, but accumulates to teratogenic concentrations in vitro.
Heat shock affects cell cycling in the neural plate of cultured rat embryos: A flow cytometric study
Authors: Walsh D. A. , Morris Valerie B. 
Published: June 2005

AbstractThe effects of heat shock on cell cycling in the mammalian neuroectoderm were determined by applying heat shocks to cultured rat embryos at the neural plate stage, as part of a study on the teratogenic effects of heat shock on neural development. The heat shocks had been characterized previously (Walsh et al.: Teratology 36:181‐191, 1987) with respect to their effects on the gross morphological development of the rat embryos. The effects on cell cycling were observed in DNA histograms of neural plate cells recorded in a flow cytometer after staining with DAPI. The mild heat shock (42°C for 10 min) arrested cells at entry to S phase. The teratogenic heat shock (43°C for 7.5 min) arrested cells at entry to S phase also but for a longer time and inhibited cycling through S phase. After each arrest, a synchronized peak of cells later entered S phase and progressed through the cycle. The induced‐thermotolerance heat shock, which was the mild heat shock followed after an interval by the teratogenic heat shock, showed that pre‐treatment with the mild heat shock reduced the magnitude of the response to the teratogenic heat shock. The cell‐cycle inhibitor ICRF 159 showed the effects on cycling rates of the heat‐shock treatments. The arrest of cells at entry to S phase by heat‐ shock may function to prevent cells entering DNA synthesis under non‐optimal conditions. We report estimates of proportions of nonproliferative cells in the neural plate of the rat embryos.
Toxic effects of cyclophosphamide in differentiating chicken limb bud cell culture using rat liver 9,000 g supernatant or rat liver cells as an activation system: An in vitro short‐term test for proteratogens
Authors: Wiger Richard , Trygg Bente , Holme Jørn A. 
Published: June 2005

AbstractCells from 4‐day chicken embryo limb buds plated as micromass cultures differntiate and form cartilage nodules after a 5‐ to 6‐day growth period. The innate ability of these cells to biotransform compounds, such as cyclophosphamide (CP), into reactive metabolites is apparently inadequate. Protocols used rat liver S9 from Aroclor 1254 pretreated (PCB) rats or hepatocytes from control rats or polychlorinated biphenyls (PCB)‐pretreated rats and were added to micromass cultures with CP causing concentration‐related toxicity in the cell cultures. Coculturing chicken limb bud cells with PCB‐hepatocytes was the most efficient method, yielding an IC50 of 2 μg CP per ml. Toxic CP metabolites accumulated in the medium of PCB‐hepatocyte cultures and were quite stable. The toxicity of bioactivated CP was nearly identical for both proliferation and cartilage proteoglycan accumulation.