bluuebunny/crossref_metadata_2025_split huggingface dataset:
An in vivo/in vitro evaluation of the teratogenic action of excess vitamin A
Authors: Steele C. E. , Trasler D. G. , New D. A. T. 
Published: June 2005

AbstractPregnant rats of CFHB strain were injected 8 1/2 days postcoitum with a 1% suspension of retinoic acid (RA) in arachis oil to give 20 mg RA per kg body weight. Control rats were injected with arachis oil only. After 26 hours, one uterine horn was removed from each rat and the embryos cultured in serum from untreated rats. The embryos in the other horn were allowed to continue development in vivo. After a further 48 hours the cultures were terminated and the second uterine horn removed from each rat. This provided four groups of embryos for comparison: (1) embryos from RA‐treated rats, (2) cultured embryos from RA‐treated rats, (3) embryos from control rats, and (4) cultured embryos from control rats. The results showed that the effects of the teratogen on the cultured embryos were similar to those on the embryos allowed to continue development for the same period in the mother. In both groups RA reduced protein synthesis, inhibited somite and limb bud formation, and caused various neural tube defects, particularly microcephaly and abnormalities in the closure of the anterior and posterior neuropores.
Experimental induction of two inner cell masses in mouse embryos by vinblastine treatment in vitro
Authors: Naruse Ichiro , Kano Satoshi , Shoji Ryujiro 
Published: June 2005

AbstractInduction of artificial fission of the inner cell mass in an in vitro embryonal culture system was attempted. Mouse blastocysts were collected from uteri on day 3 of gestation and exposed to vinblastine sulfate after removal of zona pellucida. Embryos in the control group had a single inner cell mass on the trophectoderm and developed to the postblastocyst stage. On the other hand, the inner cell masses of the embryos in experimental groups subdivided into two or more. The present results, therefore, revealed that the vinblastine treatment at the blastocyst stage induced fission of the inner cell mass in mouse embryos. Further studies are planned in improved culture conditions to determine whether each inner cell mass subdivision develops into independent embryos.
A kinetic analysis of rat embryo response to cyclophosphamide exposure in vitro
Authors: Mirkes Philip E. , Greenaway J. C. , Shepard Thomas H. 
Published: June 2005

AbstractDay 10 rat embryos were exposed in vitro to a teratogenic dose of cyclophosphamide (25 μg/ml) in the presence of a metabolic system (activated CP) for varying lengths of time and then were recultured in drug‐free medium. Development was assessed after a total of 24–26 hours of culture. Exposure periods of 2.5 hours or less had no significant effects on growth, incidence of malformed embryos, mitotic index, or necrotic index when compared to control cultures from which cofactors for metabolic activation were omitted. Embryos exposed to activated CP for 5 hours and then recultured in drug‐free medium for 19–21 hours were indistinguishable from embryos exposed to activated CP continuously over a 24–26‐hour period. These embryos are characterized by retarded growth as well as abnormalities of the prosencephalon, mandibular arches, limbs, and tail. Histological examination of embryos exposed to activated CP for 5 hours and immediately fixed revealed a decrease in the mitotic index and an increase in the necrotic index of the neuroepithelium and the surrounding mesenchyme of the prosencephalon. Our findings indicate that a 5‐hour exposure to activated CP during day 10 of rat gestation is sufficient to produce the molecular lesions necessary to elicit the teratogenic effects of cyclophosphamide.
External malformations in chick embryos following concomitant administration of methylxanthines and β‐adrenomimetic agents: 1. Gross pathologic features
Authors: Bruyere Harold J. , Fallon John F. , Gilbert Enid F. 
Published: June 2005

AbstractThe objectives of this report are to document external malformations observed in chick embryos following concomitant administration of methylxanthines (caffeine, theophylline) and β‐adrenomimetic agents (isoproterenol, epinephrine) and to suggest reasonable explanations for the anomalies. Administration of caffeine or theophylline alone (2.5–5.0 mg/egg) retarded growth in a dose‐dependent fashion. Doses of 5.0 mg caffeine and theophylline produced beak malformations in 4.9% and 57.1% of embryos, respectively. Limb malformations, seen in low frequency (3.6% in 56 embryos) after administration of 1 μg isoproterenol, were not seen in 224 methylxanthine‐treated embryos. Structural defects following coadministration of methylxanthines and β‐adrenomimetics were frequently observed in limbs (primarily lower limbs with predilection for left‐sided oligodactyly) and beak. Other findings included limb hematomas, hygromas in the nuchal region, and prominent generalized edema. The most dramatic effects observed in this study were those induced by concomitant administration of 2.5 mg caffeine and 1 μg isoproterenol. This combination produced at least one of the embryopathies listed above in 87.9% of treated embryos and frequently induced beak (24.2%) and lower limb defects (75.8%) in addition to nuchal hygromas (9.1%). Similar severe malformations were observed following administration of 3.8 mg theophylline with 1 μg epinephrine. Embryos that died within 12–48 hours following drug insult demonstrated marked cardiac dilation, apparently due to congestive heart failure. The results of this study suggest that methylxanthines and β‐adrenomimetic agents are synertistic in their action in the developing chick. Doses of β‐adrenomimetic agents that were used in this study were not synergistic with methylxanthines. Increased intracellular cyclic adenosine monophosphate (AMP) is offered as an explanation for digital anomalies due to inhibition of proximodistal development of limbs. Increased intracellular cyclic AMP may also explain limb hypoplasia and loss of intermediate limb structures as a result of inhibited mitosis and/or necrosis of embryonic tissue.
A critical review of the McCredie‐McBride hypothesis of neural crest influence on limb morphogenesis
Authors: Stephens Trent D. , Strecker Teresa R. 
Published: June 2005

AbstractA number of hypotheses have been presented to explain the mechanism of action of thalidomide. The most widely published and apparently widely accepted hypothesis is that of embryonic neuropathy advanced by McCredie and McBride. This paper reviews the points of the hypothesis and analyzes it in light of known limb embryology supported with recent experimental evidence which directly tests the hypothesis. The hypothesis may be considered as being composed of two separate parts. The first part proposes that thalidomide‐induced limb defects exhibit a segmental pattern. The second proposes that the segmental pattern of limb defects is a result of segmental peripheral neuropathy. We are in complete agreement with the first portion of the hypothesis, but find the second portion quite unlikely.
Craniofacial malformation in Xenopus laevis tadpoles caused by the exposure of early embryos to ethanol
Authors: Nakatsuji Norio 
Published: June 2005

AbstractThe principal features of fetal alcohol syndrome (FAS) include microcephaly, reduced body size, and characteristic facial malformation, most of which are associated with hypoplasticity of structures around the mouth. A recent study using pregnant mice suggested that the malformations in FAS are caused by the effects of ethanol on early embryos during gastrulation and neurulation. Exposure of Xenopus laevis early embryos to 1–2% ethanol until they developed to the late neurula stage produced craniofacial malformations in tadpoles which have many similarities with the described features of FAS. They include reduced length of brain, reduced body size, and hypoplasticity of the anterior end of the body around the mouth. Size reduction from the control group was about 20% in the mouth region, and 10% in other head regions. Ethanol inhibited migration of mesodermal cells toward the animal pole during gastrulation, thus inducing a smaller neural plate with reduced anterior—posterior length. These very early effects of ethanol in development seem to produce various craniofacial malformations in tadpoles, and possibly also in human infants with FAS. In contrast to mammalian embryos, one can conveniently study in detail the effects of ethanol on morphogenetic movements in various in vitro experiments by using a large number of amphibian embryos. Thus, amphibian embryos represent a valuable animal model for the study of mechanisms of the teratogenic effects of ethanol.
Impermeability of the rat placenta to insulin during organogenesis
Authors: Widness John A. , Goldman Allen S. , Susa John B. , Oh William , Schwartz Robert 
Published: June 2005

AbstractThe cause of the embryopathy associated with diabetes mellitus is uncertain. To examine whether exogenously administered insulin may be teratogenic, tracer amounts of radiolabelled insulin were infused for two hours during organogenesis (day 12 1/2 of gestation) into three groups of pregnant rats: control (n = 8), diabetic (n = 5), and hyperinsulinemic (n = 4). For maternal plasma, no differences were found among the three study groups in the perecentage of the protein‐precipitable (insulin‐containing) radioactivity. Tissue radioactivities were expressed relative to the two‐hour maternal plasma sample. Maternal kidney samples had the highest total and protein precipitable counts followed in descending order by the maternal plasma, maternal liver, placenta, and embryo. No differences in radioactivities were noted among the three study groups for specific tissues studied. Protein‐precipitable radioactivities in the embryo were more than 100‐fold less than the maternal plasma values. In 11 of the 17 litters, the acid‐insoluble fractions of the embryos were not distinguishable from background counts, and none of the remaining six were greater than twice background. These studies demonstrate that during the period of organogenesis, the rat embryo is protected from maternal insulin by the placenta, and hence, maternal insulin in an unlikely teratogen.
The effect of aminothiadiazole on glycogenesis and glycogenolysis in fetal and neonatal rat liver
Authors: Beaudoin Allan R. 
Published: June 2005

AbstractThe effect of the teratogen 2‐amino‐1,3,4‐thiadiazole on glycogenesis and glycogenolysis was investigated in the fetal and neonatal rat liver. At day 15, 16, or 17 of gestation (sperm day = day 0) pregnant Sprague‐Dawley rats received a single IP injection of an aqueous solution of aminothiadiazole. Dosages used were teratogenic (100 mg/kg maternal body weight) and nonteratogenic (10 mg/kg). At day 16 some rats received nicotinamide (100 mg/rat) in addition to a teratogenic dose of aminothiadiazole. Livers were recovered for assay at fetal day 20 and postnatal day 1. Only at day 16 did a teratogenic dose induce a significant depression in the fetal activity of glycogen synthetase (to 49.6% of control activity) and glucose‐6‐phosphatase (to 72.2% of control activity), and in glycogen accumulation (to 72.6% of control accumulation). At day 15, a teratogenic dose significantly depressed glucose‐6‐phosphatase activity but not glycogen synthetase activity or glycogen accumulation. Nicotinamide, given immediately after aminothiadiazole, was effective in blocking the inhibition. Teratogenic treatment had no effect on the postnatal activity of glucose‐6‐phosphatase. Apparently some event associated with birth releases the enzyme from its prenatal inhibition. These results demonstrate a parallelism between the perturbing effect of aminothiadiazole on biochemical development and morphological development with respect to time of insult, dose response, and protection with its antitertogen. The mechanism of action whereby aminothiadiazole depresses the activity of glycogen synthetase and glucose‐6‐phosphatase remains to be determined.
Sites of lead localization in embryonic chick tissues following treatment
Authors: Kuettel Michael R. , Kaplan Stanley 
Published: June 2005

AbstractLead treatment by subgerminal injection causes rupture of embryonic chick dorsal aortae during early morphogenesis, followed by localized caudal hematoma formation. Shortly thereafter, damaged tissues are resorbed, leading to a condition known as rumplessness (caudal dysplasia syndrome in humans). We have studied this process by light microscopy and have found that the caudal dorsal aortae exhibit morphological alterations as early as 4 hr after injection. Further, we used energy dispersive X‐ray analysis (EDXA) to establish the precise localization and distribution of lead in the developing embryo, 4 hr after Pb(NO3)2 treatment. Embryos treated with NaNO3 were used as controls. The hierarchy of lead concentrations was endothelium of the caudal dorsal aortae > caudal endoderm > blood cells. The surrounding mesenchyme, neural tube, and notocord, as well as all control embryonic tissue, exhibited no detectable lead levels. These results suggest that lead has a high degree of specificity for entering and damaging the developing caudal dorsal aortae. A possible mechanism for this phenomenon is that lead gains access to the vascular net surrounding the caudal region of the embryo at the time of injection. Parts of this vascular net including the lead are then incorporated into the developing caudal dorsal aortae as they grow distally, thus further concentrating the lead.
Importance of the route of administration for genetic differences in benzo[a]pyrene‐induced in utero toxicity and teratogenicity
Authors: Legraverend Catherine , Guenthner Thomas M. , Nebert Daniel W. 
Published: June 2005

AbstractC57BL/6N (Ahb/Ahb) mice have a high‐affinity Ah receptor in tissues, whereas AKR/J and DBA/2N (Ahd/Ahd) mice have a poor‐affinity Ah receptor. The cytochrome P1‐450 induction response (enhanced benzo[a]pyrene metabolism) occurs much more readily in Ahb/Ahb and Ahb/Ahd than in Ahd/Ahd mice, at any given dose of the inducer benzo[a]pyrene.Embryos from the AKR/J × (C57BL/6N)(AKR/J)F1 and the reciprocal backcross were studied during benzo[a]pyrene feeding of the pregnant females. Oral benzo[a]pyrene (120 mg/kg/day) given to pregnant Ahd/Ahd mice between gestational day 2 and 10 produces more intrauterine toxicity and malformations in Ahd/Ahd than Ahb/Ahd embryos. This striking allelic difference is not seen in pregnant Ahb/Ahd mice receiving oral benzo[a]pyrene. Pharmacokinetics studies with [3H]benzo[a]pyrene in the diet and high‐performance liquid chromatographic analysis of benzo[a]pyrene metabolism in vitro by the maternal intestine, liver, and ovary and the embryos of control and oral benzo[a]pyrene‐treated pregnant females are consistent with “first‐pass elimination” kinetics and differences in benzo[a]pyrene metabolism by the embryos and/or placentas versus maternal tissues. In the pregnant Ahd/Ahd mouse receiving oral benzo[a]pyrene, little induction of benzo[a]pyrene metabolism occurs in her intestine and liver; this leads to much larger amounts ofbenzo[a]pyrene reaching her embryos, and genetic differences in toxicity and teratogenesis are manifest. In the pregnant Ahb/Ahd mouse receiving oral benzo[a]pyrene, benzo[a]pyrene metabolism is greatly enhanced in her intestine and liver; this leads to less benzo[a]pyrene reaching her embryos, much less intrauterine toxicity and malformations, and no genetic differences are manifest. More toxic metabolites (especially benzo[a]pyrene 1,6‐ and 3,6‐quinones) are shown to occur in Ahd/Ahd embryos than in Ahb/Ahd embryos. In additional studies, no prenatal or neonatal “imprinting” effect in C57BL/6N mice by 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin or Aroclor 1254 on benzo[a]pyrene metabolism later in life was detectable.These genetic differences in intrauterine toxicity and teratogenicity induced by oral benzo[a]pyrene are just opposite those induced by intraperitoneal benzo[a]pyrene (Shum et al., '79; Hoshino et al., '81). The data in the present report emphasize the importance of the route of administration when the teratogen induces its own metabolism.
The effects of prenatal ethanol in cynomolgus monkeys
Authors: Scott William J. , Fradkin Rochelle 
Published: June 2005

AbstractEthanol was administered to pregnant cynomolgus monkeys (Macaca fascicularis) from day 20 to 150 of gestation. The ethanol was delivered by intragastric intubation twice a day at 8 AM and 5 PM. Dosage was begun at a relatively low level, 2 g/kg/day and increased gradually to attain a final dosage of 4 or 5 g/kg/day. The offspring were allowed to be delivered naturally and remained with their mother until 23 days of age when they were sacrificed. Maternal blood ethanol and acetaldehyde levels were monitored at weekly intervals throughout pregnancy. Pregnancy wastage in the form of abortions and stillbirths was increased by ethanol treatment especially at the high dose. Birthweight was significantly lowered in offspring of mothers receiving 5 g/kg/day of ethanol. However, no structural malformations or facial changes suggestive of those seen in the human fetal alcohol syndrome were found in any of the offspring. We conclude that the conditions of our study did not produce a satisfactory model of human fetal alcohol syndrome.
Growth parameters in normal fetuses
Authors: McBride Mary L. , Baillie Joan , Poland Betty J. 
Published: June 2005

AbstractA total of 14 linear measurements, seven ratios of linear measurements, and the weights of eight organs were taken from 100 normal fetuses. The fetuses had been therapeutically aborted between 11 and 19 weeks of gestational age by prostaglandin induction or hysterotomy. Measurements were obtained from at least five fetuses for each week of development age. A correlation matrix was calculated in order to identify those variables that showed a significant relationship with each other and with total body measurements. Significant correlations were obtained between crown–rump length and the following: head circumference, femur length, and humerus length. These three measurements were also significantly correlated with body weight. First‐order regression equations were produced for these significantly correlated variables. This information can be used to estimate fetal growth even when the fetus is incomplete.
The effects of ethanol exposure during the brain growth spurt in rats
Authors: Burns Elizabeth M. , Kruckeberg Thomas W. , Stibler Helena , Cerven Erik , Borg Stefan 
Published: June 2005

AbstractThe purpose of this study was to determine whether micromorphological changes occur at a low level of ethanol exposure previously shown by us to induce alterations in synaptosomal biochemistry. The results suggest that 4 g ethanol per kg body weight daily throughout the brain growth spurt causes no significant structural changes in the cerebellum, lobule IX, at the light and electron microscopic levels. Although ethanol‐ and isocaloric sucrose‐treated groups did not differ from each other in cumulative percent body weight gain throughout the treatment period, both groups differed significantly in this parameter from isocaloric milk‐treated and “handled” control groups. On the day following completion of the treatment period, brain weight in the ethanol‐treated group was significantly less than that of all other groups. Further, the results indicate that isocaloric sucrose “pair feeding” is contraindicated in postnatal studies and that nutritional status is better controlled by daily gavage of neonates than by other methods currently used in ethanol studies in postnatal animals.
A short‐term screening test for teratogens using differentiating neuroblastoma cells in vitro
Authors: Mummery C. L. , van den Brink C. E. , van der Saag P. T. , de Laat S. W. 
Published: June 2005

AbstractThirty‐nine teratogenic and 18 nonteratogenic compounds were tested using an assay based on the ability of agents to interfere with normal growth and differentiation of murine neuroblastoma cells (clone N1E‐115) in culture. Induction of differentiation in cells under growth‐promoting conditions and inhibition of differentiating cells over a period of 7 days was dose‐dependent, with the lowest effective dose not being highly toxic. Eighty‐six percent of the compounds were correctly identified by the assay. The proportions of both false negatives (10%) and false positives (22%) were of the same order or better than in current, comparable tests. The possibilities offered by the system in rapid screening for teratogenic potential of environmental agents are discussed.
The neuroteratogenicity of procarbazine in the rat: Behavioral, morphological, and neurochemical aspects
Authors: Johnson J. M. , Thompson D. J. , Burek J. D. , Haggerty G. C. , Dyke I. L. , Lower C. E. , Solomon J. L. 
Published: June 2005

AbstractPregnant female sprague‐Dawley rats were treated from day 12 through day 15 of gestation with procarbazine, an antineoplastic drug, and their offspring were subjected to tests of locomotor development and behavior. Treatment levels ranged from 0.5 mg/kg/day, a dose that produced no abnormalities, to 10 mg/kg/day, a dose that caused a marked micrencephaly in the absence of other teratological changes. Despite marked morphological brain changes, preweaning locomotor development, as assessed by open‐field swimming activity and vertical grid climbing, was normal in all offspring. Postweaning passive avoidance learning and retention were also normal. Groups that had been treated prenatally with teratogenic doses (5.0 and 10.0 mg/kg/day) displayed less rearing behavior in the open field, while ambulation in the periphery of the open field arena was unaffected. Groups treated with subteratogenic doses (0.5 and 1.0 mg/kg/day) did not differ from control. In addition to the behavioral studies, sodium‐dependent high‐affinity choline uptake and choline acetyltransferase activity (CAT) were measured (per mg protein) in the cortex and hippocampus of animals that had been exposed prenatally to either teratogenic or subteratogenic doses of procarbazine. In spite of a substantial reduction in size of both brain structures in the group receiving a teratogenic dose, choline uptake and CAT did not differ from control.
Teratology of intravaginally administered contraceptive Jelly containing octoxynol‐9 in rats
Authors: Saad Dorothy J. C. , Kirsch Robert M. , Kaplan Leonard L. , Rodwell Dean E. 
Published: June 2005

AbstractOctoxynol‐9, a nonionic surfactant used as a spermicidal agent in ORTHO‐GYNOL (registered trademark) Contraceptive Jelly (Ortho Pharmaceutical Corporation, Raritan, NJ), was administered intravaginally to pregnant Sprague Dawley COBS CD rats at dosages of 0.5 mg/kg/day and 5 mg/kg/day (two‐thirds and six times the clinical dosage) on days 6–15 of gestation in order to assess its teratogenic potential. Untreated, sham, and vehicle control groups were also incorporated into the study protocol. No meaningful differences were observed between the treated and control groups in maternal toxicity, maternal reproductive parameters, fetal toxicity, and the incidence of external, visceral, and skeletal malformations or developmental variations. It is concluded that octoxynol‐9 is not embryotoxic or teratogenic when administered intravaginally to rats during organogenesis.