bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cell cycle analysis in the cardiac and neuroepithelial tissues of day 10 rat embryos and the effects of phosphoramide mustard, the major teratogenic metabolite of cyclophosphamide
Authors: Mirkes Philip E. , Ricks Jerry L. , Pascoe‐Mason Julie M. 
Published: June 2005

AbstractUsing the autoradiographic technique of percent labeled mitoses (PLM), total cell cycle length (Tc) and lenght of the cell cycle phases G1, S, G2, and M have been estimated for the neuroepithelium and heart of day 10 rat embryos. The Tc for the neuroepithelium was estimated to be 9.45 hr, consisting of G1 of 1.24 hr, S of 6.15 hr, G2 of 1.34 hr, and M of 0.72 hr. The Tc for the heart was estimated to be 13.37 hr, consisting of G1 of 4.30 hr, S of 7.01 hr, G2 of 1.81 hr, and M of 0.25 hr. Comparison of cell cycle parameters in these two tissues indicates that the longer cell cycle in heart tissue is related primarily to an increase in G1. If embryos are exposed to the major teratogenic metabolite of cyclophosphamide, phosphoramide mustard, cell cycle analysis reveals that the S phase of the neuroepithelial cell cycle is lengthened and cells are either slowed or arrested in G2.
Evaluation of the bioeffects of prenatal ultrasound exposure in the cynomolgus macaque (Macaca fascicularis): II. Growth and behavior during the first year
Authors: Tarantal A. F. , Hendrickx A. G. 
Published: June 2005

AbstractThe extensive use of ultrasonography for the prenatal assessment of growth and development continues to present questions regarding biological effects. We are currently evaluating a nonhuman primate model (Macaca fascicularis) exposed to ultrasound from gestational day (GD) 21 to 152 ± 2. Exposures were performed with a commercial real‐time sector scanner (ATL, MK 600); animals were scanned five times weekly on GD 21–35 ± 2, three times weekly on GD 36–60 ± 2, and once weekly on GD 61–150 ± 2. The length of exposure was approximately the same as human exposure (GD 21–60 ± 2 = 10 min/exam and GD 61–150 ± 2 = 20 min/exam) although the frequency of the examinations was considerably greater. Initial reports indicated differences between control and treated animals including lower birth weight, higher simian Apgar scores, and changes in select hematologic parameters. Follow‐up evaluations of growth during the first year included measurements of body weight, hand and foot lengths, humerus and femur lengths, biparietal and occipitofrontal diameters, head circumference, arm circumference, chest circumference, skinfold thickness, and crown‐rump length. Results indicated a significant reduction in body weight in treated animals during the first three months, with nonsignificant differences during the following nine months. Hematologic analysis including complete blood counts (CBC) and clinical biochemistry at 6, 9, and 12 months of age were not significantly different. A series of behavioral evaluations including a neurobehavioral test battery (NBT) and tests assessing motor and cognitive skills were included. The NBT revealed increased muscle tone in treated animals at one, two, and four days. In an observation cage (week 1–14) more quiet activities were displayed by treated animals. Group differences in performance of motor and cognitive tasks were observed and may be attributable to agitation and difficulties in adjusting to test environments. There were no group differences observed in discrimination learning. When considering the possible implications to the human population, it is important to consider the amount of exposure these animals received, and the fact that most of the effects observed appeared to be transitory. Although human epidemiological studies have not revealed any significant bioeffects, the “prudent use” of diagnostic ultrasound should still be kept in mind. This is especially significant with the current rise in the use of endovaginal scanning and pulsed Doppler.
Teratogenicity of zinc deficiency in the rat: Study of the fetal skeleton
Authors: Da Cunha Ferreira R. M. C. , Marquiegui I. Monreal , Elizaga I. Villa 
Published: June 2005

AbstractZinc deficiency (ZD) is teratogenic in rats, and fetal skeletal defects are prominent. This study identifies fetal skeletal malformations that affect calcified and non‐calcified bone tissue as a result of gestational zinc deficiency in rats, and it assesses the effect of maternal ZD in fetal bone calcification. Pregnant Sprague‐Dawley rats (180–250 g) were fed 1) a control diet (76.4 μg Zn/g diet) ad libitum (group C), 2) a zinc‐deficient diet (0 μg/g) ad libitum (group ZD), or 3) the control diet pari‐fed to the ZD rats (group PF). On day 21 of gestation, laparotomies were performed. Fetuses were weighed, examined for external malformations, and stained in toto with a double‐staining technique for the study of skeletal malformations. Maternal and fetal tissues were used for Zn, Mg, Ca, and P determinations. Gross external malformations were present in 97% of the ZD fetuses. No external malformations were found in fetuses from groups C and PF. Ninety‐one percent of cleared ZD fetuses had multiple skeletal malformations, whereas only 3% of the fetuses of group PF had skeletal defects; no skeletal malformations were found in fetuses from group C. Some of the skeletal malformations described in the ZD fetuses, mainly affecting non‐calcified bone, were not mentioned in previous reports, thus stressing the importance of using double‐staining techniques. Examination of stained fetuses and counting of ossification centers revealed important calcification defects in ZD fetuses. These effects were confirmed by lower Ca and P concentrations in fetal bone with alteration of the Ca:P ratio.
Effects of dinocap on otolith development: Evaluation of mouse and hamster fetuses at term
Authors: Rogers John M. , Burkhead Lesley M. , Barbee Brenda D. 
Published: June 2005

AbstractThe morphology of otoliths in CD‐1 mouse and Syrian hamster fetuses exposed to the fungicide dinocap were evaluated at the end of gestation. Pregnant mice were dosed by gavage with 0, 10, 15, 30, or 60 mg/kg/day dinocap in corn oil on days 7–16 of gestation. Pregnant hamsters were dosed by the same route with 0, 50, 100, or 200 mg/kg/day on days 7–14 of gestation. At the end of gestation (day 18 in mice, day 15 in hamsters) dams were killed and all fetuses were removed and fixed overnight in 70% ethanol. Fetal heads were then removed, left in 70% ethanol for at least 3 days, and then dehydrated in a graded ethanol series and cleared with methyl salicylate. Otoliths were examined by darkfield microscopy, and each otolith was scored for morphological completeness on a scale of 0 to 3. Otolith development was complete by day 18 of gestation in control mouse fetuses. Otolith development was complete in many, but not all, of the hamster fetuses by day 15 of gestation. In the mouse, dinocap exposure inhibited fetal otolith formation in a dose‐related manner, with a significant effect on total otolith score occurring at 10 mg/kg/day and above. Dinocap affected otolith formation in the hamster only at 100 mg/kg/day (200 mg/kg/day was embryolethal), concommitant with severe maternotoxicity and fetotoxicity. The results of this study indicate that the CD‐1 mouse is more sensitive than the Syrian golden hamster to the effects of dinocap on otolith development, and that otolith morphology can be easily examined in the mouse and hamster fetuses at term, although not by techniques currently used for fetal examination in standard teratology bioassays (e.g., Segment II studies).
Protective effect of ouabain on adriamycin‐induced cardiovascular anomalies in chick embryos
Authors: Takagi Yasuo , Bruyere Harold J. , Nishikawa Toshio 
Published: June 2005

AbstractAdriamycin (2.5–10.0μg) was administered to 41/2 and 5 day embryonic chicks (Hamburger‐Hamilton developmental stages 24–26) to investigate the effect of the drug on cardiovascular morphogenesis. The drug produced dose‐related increases in both mortality rate and malformation frequency with a maximum incidence of 82% cardiovascular anomalies following a dose of 10.0 μg/egg (P < .001 relative to saline controls). Frequencies of embryos with ventricular septal defect (P < .005), dextroposition of the aorta (P < .005), or aortic arch anomalies (P < .05) were significantly higher than among controls. In a second study, embryos were pretreated with ouabain (12.2 μg), verapamil (0.5 μg), coenzyme Q10 (100 μg, 200μg), or vitamin E (1.0 mg, 5.0 mg)—agents previously shown to protect against adriamycin‐induced cardiotoxicity. Pretreatment of embryos with ouabain significantly reduced the incidence of cardiovascular malformations induced by adriamycin from 55 to 21% (P < .05). A major protective effect was observed relative to the induction of ventricular septal defect, the frequency of which was reduced from 45 to 14% (P < .05). However, administrations of verapamil, coenzyme Q10, or vitamin E did not have an appreciable effect on adriamycin‐induced frequencies of cardiovascular malformations. Negative inotropism is suggested as a mechanism for adriamycin‐induced cardiac anomalies but warrants further study.
Differential neuronal loss following early postnatal alcohol exposure
Authors: Pierce Dwight R. , Goodlett Charles R. , West James R. 
Published: June 2005

AbstractNeonatal rats were exposed to 6.6 g/kg of alcohol each day between postnatal days 4 and 10 while artificial‐rearing procedures were used, in a manner which produced high peak and low trough blood alcohol concentrations each day. Gastrostomy controls were reared artificially with maltose/dextrin isocalorically substituted for alcohol in the milk formula, and suckle controls were reared normally by dams. The pups were sacrificed on day 10 and tissue sections (2 μm thick) were obtained in the sagittal plane through the cerebellum and in the horizontal plane through the hippocampal formation. Overall area measures were obtained for the hippocampus proper, area dentata, and cerebellum, along with areas of the cell layers of these regions. In the hippocampal formation, cell counts were made of the pyramidal cells of the hippocampus proper, the multiple cell types of the hilus, and the granule cells of the area dentata. In the cerebellum, cell counts of Purkinje cells, granule cells of the granular layer, granule cells of the external granular layer, and mitotic cells of the external granular layer were obtained from lobules I, V, VII, VIII, and IX. Alcohol selectively reduced areas and neuronal numbers in the cerebellum but had no significant effects on neuronal numbers in the hippocampal formation. Purkinje cells exhibited the greatest percent reductions, and cerebellar granule cells were significantly reduced in the granular layer but not in the external granular layer. All lobules showed these effects, but lobule I was significantly more affected than the other four lobules that were analyzed. The results demonstrate the differential vulnerability of selected neuronal populations to the developmental toxicity of alcohol exposure during the brain growth spurt.
Enhancement of murine phenytoin teratogenicity by the gamma‐glutamylcysteine synthetase inhibitor L‐buthionine‐(S, R)‐sulfoximine and by the glutathione depletor diethyl maleate
Authors: Wong Mayme , Helston Lori M. J. , Wells Peter G. 
Published: June 2005

AbstractThe teratogenicity of phenytoin may result from its enzymatic bioactivation to a reactive intermediate, which, if not detoxified, can interact with embryonic tissues and alter development. Glutathione (GSH) is an important cofactor/substrate for many physiological processes and for the detoxification of xenobiotic reactive intermediates. This study examined the effects of the GSH depletor diethyl maleate (DEM) and the GSH synthesis inhibitor L‐buthionine‐(S,R)‐sulfoximine (BSO) on phenytoin embryopathy. Phenytoin, 55 mg/kg, was administered intraperitoneally (ip) to pregnant CD‐1 mice at 0900 hr on gestational days 12 and 13. Pretreatment with DEM, 150 or 300 mg/kg ip, enhanced the incidence of phenytoin‐induced cleft palates by 3.3‐fold and 2.3‐fold, respectively (P < 0.05), without affecting the incidence of resorptions, postpartum death, or mean fetal weight. BSO, 1,800 mg/kg ip, given 0.5 hr prior to phenytoin, resulted in a 2.4‐fold increase in postpartum lethality and a 5‐fold increase in fetal weight loss (P < 0.05), without altering the incidence of resorptions or cleft palates. In two subsequent studies, BSO, 680–1,018 mg/kg/day, was given in the drinking water on gestational days 9 to 13 in the first study and on days 10 to 14 in the second study. Phenytoin, 55 mg/kg ip, was given on days 11 and 12 and on days 11 to 13 in the respective studies. In the first drinking water study, BSO enhanced the incidence of phenytion‐induced fetal resorptions 3.8‐fold and cleft palates 3.3‐fold (P < 0.05) but did not affect postpartum death. In the second study, BSO enhanced the incidence of resorptions, cleft palates, and postpartum death by 2‐fold, 2.6‐fold, and 1.7‐fold, respectively (P < 0.05). In both of the latter two studies, phenytoin‐induced fetal weight loss was altered by BSO treatment (P < 0.05). BSO alone had no embryopathic effects. These results suggest that GSH may be involved in the detoxification of a reactive intermediate of phenytion and/or in fetal cytoprotection.
Growth of the secondary palate in the hamster following hydrocortisone treatment: Shelf area, cell number, and DNA synthesis
Authors: Shah Ravindra M. , Chen Yung Ping , Burdett David N. 
Published: June 2005

AbstractThe contribution made by mesenchymal cells during the later stages of palatal development was examined in control and hydrocorti‐sone‐treated hamster embryos. Cross‐sectional area of the palatal shelf was measured, and the numbers of both epithelial and mesenchymal cell were counted. DNA synthesis was measured by 3H‐thymidine incorporation and was usd as an index of growth by cell proliferation. The observations in controls indicated that, unlike development during the initial 24 hr, the later period of vertical palate development, followed by reorientation of shelves and their closure, was characterized by a steady level of mesenchymal cell number and palatal shelf area. An absence of corresponding growth in the epithelial cell number suggests that the cells may accommodate the growth either by increasing their size and/or by stretching along the basal lamina. Hydrocortisone treatment did not alter the growth pattern of cell numbers or shelf area. However, it prevented the fusion between the opposing shelves, perhaps by affecting the cytodifferentiation of the palatal tissues. Although a continuous increase in the number of mesenchymal cells during the latter half of vertical shelf development, i.e., between days 11:00 and 12:00 of gestation, is not required for reorientation and fusion of the shelves, it is not clear from the data from the present study whether a critical number of cells and/or cell density is essential for reorientation and fusion of the palate. It was suggested that, for normal palatal development, information on cell cycle and positioning of mesenchymal cells within the shelf during the vertical development may be crucial for further understanding of subsequent events of palatogenesis.
Developmental exposure of mice to pulsed ultrasound
Authors: Kimmel Carole A. , Stratmeyer Mel E. , Galloway W. Don , Brown Natalie T. , Laborde James B. , Bates Hudson K. 
Published: June 2005

AbstractExposure of pregnant mice on gestation day (gd) 8 to 1 MHz continuous‐wave ultrasound (0, 0.05, 0.50, or 1.00 W/cm2) was reported previously to result in a slight (nonsignificant) increase in malformations. The present study was conducted in a similar fashion using pulsed ultrasound but was designed to maximize the likelihood of finding effects of gd 8 ultrasound exposure on prenatal development. Pregnant ICR mice (approximately 60 animals/group) were exposed on gd 8 to pulsed ultrasound with a center frequency of 1 MHz at levels of 0 (sham control), 0.05, 0.50, or 1.00 W/cm2 (spatial average, temporal average intensities; ISATA) with a spatial peak, pulse average intensity (ISPPA) of 90 W/cm2 and pulse duration of 6.5 μsec. Anesthetized animals were placed in a degassed water bath (30°C) and exposed for two 10 min intervals during which the beam was centered 1 cm on either side of the abdominal midline. On gd 17, dams were killed; the uterus and its contents were weighed and examined; and live fetuses were weighed and examined for external, visceral, and skeletal malformations. Although one female in the 0.50 W/cm2 group and seven animals in the 1.00 W/cm2 group died following exposure, no other significant change from controls was seen in any maternal or fetal parameter evaluated. Thus the results of this study indicate that there was no detectable effect on prenatal development of mice following exposure to ultrasound on gd 8 (a time of maximal sensitivity), even at exposure intensities that were lethal to some maternal animals.
Prenatal dexamethasone administration disrupts the pattern of cellular development in rat lung
Authors: Navarro Hernan A. , Kudlacz Elizabeth M. , Eylers John P. , Slotkin Theodore A. 
Published: June 2005

AbstractTo examine whether prenatal exposure to glucocorticoids could adversely affect subsequent cellular development of the lung, we administered 0.2 mg/kg of dexamethasone to pregnant rats on gestational days 17, 18, and 19. Lungs of the offspring were then examined for patterns of cell acquisition (DNA) and growth (protein). DNA concentration (a marker of cell packing density) and DNA content (a measure of total cell numbers) were reduced during gestation, and the shortfalls in concentration persisted past weaning. Disruption of development was also apparent in the protein/DNA ratio, which was consistently elevated, a finding consistent with cellular hypertrophy. In addition, lung, ODC became coupled to β‐adreñergic receptors prematurely in the dexamethasone group, suggesting that neural control of tissue differentiation is altered. These data indicate that prenatal glucocorticoids may compromise lung development through effects on cell replication and differentiation, which derive, in part, from alterations in the reception of trophic neural signals.
Teratogenicity of 3,3‐dimethyl‐1‐phenyltriazene in the rat: Histopathologic and ultrastructural alterations
Authors: Frank Anthony A. , Kazacos Evelyn A. , Hullinger Ronald L. , Thompson Daniel J. 
Published: June 2005

Abstract3,3‐Dimethyl‐1‐phenyltriazene (DMPT) is a methylating agent which is teratogenic, carcinogenic, and mutagenic. A single intraperitoneal injection of 30 mg DMPT/kg given to pregnat rats on day 12 of gestation produces malformations with minimal maternal toxicity. Malformations include skeletal deformities such as micrognatism, cleft palate, and digital malformations, as well as central nervous system hypoplasia. The purpose of the present study was to characterize the light and electron microscopic alterations produced by DMPT. Electron microscopy (EM) revealed that at 4 hr postinjection of DMPT, rare cells of the neural tube contained few membrane‐bound aggregations of organelles and condensed chromatin; this change was consistent with apoptosis, a type of cell death characterized by morphologic and biochemical alterations distinct from necrosis. At 8 hr postinjection, apoptosis was more prominent in the neural tube and also observed in the mandibular process. At 16 hr postinjection, numerosu apoptotic cells were interspersed with unaffected cells that contained phagocytized apoptotic bodies. Light microscopic examination of DMPT‐exposed conceptuses showed apoptosis in the neural tube at 24 hr postinjection. Forty‐eight hours postinjection, apoptosis, in decreasing order of severity, was observed in the neural tube, craniofacial processes, limb buds, and somites and liver. Apoptosis was absent in all tissues by 72 hr postinjection. Nervous tissues failed to achieve proper histologic organization, but all other tissues appeared microscopically normal from 72 hr postinjection until the end of gestation. There appeared to be some degree of tissue specificity to the effects of DMPT.
Altered placental morphology associated with murine trisomy 16 and murine trisomy 19
Authors: Bersu Edward T. , Mossman Harland W. , Kornguth Steven E. 
Published: June 2005

AbstractThe morphology of placentas from trisomy 16 and trisomy 19 mouse conceptuses aged 12 to 18 gestational days was studied at the light microscopic level. Comparisons were made with placentas from normal littermate animals. Trisomy 16 placentas showed marked changes from normal: 1) the junctional zone showed little indication of normal morphologic differentiation throughout gestation; 2) clusters of germinal trophoblast cells persisted in the labyrinth throughout gestation, whereas these cells disappeared by gestational day 16 in the normal littermate placentas; 3) the labyrinth was reduced in size in the trisomic placentas, and the differentiation of the interhemal membranes was delayed. The size of the labyrinths from trisomy 19 placentas appeared to be decreased, but otherwise the placentas appeared to have normal morphology. These observations and others from the literature show that placental development is affected by the presence of a trisomic genome, and that different trisomies influence the development of the placenta differently. Fortrisomy 16, we propose that the striking changes of the junctional zone may be associated with the trisomy 16‐related gene dosage effect for alpha‐ and beta‐interferon cell surface receptors. Because of the homology for this and other genes on mouse chromosome 16 with genes on human chromosome 21, findings related to the altered development of the trisomy 16 mouse may be relevant to understanding some of the phenotypic variations associated with human trisomy 21, the Down syndrome.
Human achondroplasia: Defective mitochondiral oxidative energy metabolism may produce the pathophysiology
Authors: Mackler Bruce , Shepard Thomas H. 
Published: June 2005

AbstractA summary is presented of previous studies by other investigators of human achondroplasia and dyschondroplastic animal models. In addition, studies previously reported from our laboratories are discussed, and they demonstrate that defective oxidative energy metabolism is present in mitochondrial preparations from achondroplastic human subjects and rabbits (ac/ac) with chondrodystrophy. The results of the studies support the hypothesis discussed fully in the manuscript that a partial defect in mitochondrial oxidative metabolism in achondroplastic subjects is expressed specifically in the growth plates of the long bones because this tissue has the lowest oxygen tension of any bodily organ undergoing active proliferation, thus leading to the achondroplastic phenotype in humans and the ac/ac rabbit. In the ac/ac rabbit phosphorylation at the cytochrome c oxidase region (site III) of the terminal respiratory system was shown to be absent in mitochondrial preparations from the livers of newborn ac/ac rabbits. Normal‐appearing littermates did not exhibit the defect. Studies of mitochondrial preparations from human skin fibroblasts (grown in tissue culture) from normal human subjects and subjects with homozygous achondroplasia demonstrated that concentrations of cytochrome a3 were decreased approximately 80% in preparations from homozygous achondroplastic cells. Levels of cytochrome a3 in heterozygous achondroplastic cells were intermediate between the levels in normal cells and homozygous achondroplastic cells demonstrating the effects of gene dosage. Determination of total heme a (as the pyridine hemochromogen) in the normal and achondroplastic preparations from human subjects showed that the observed decrease in concentration of cytochrome a3 in the achondroplastic preparations was due to an absence of cytochrome a3 and not to a change in its absorbancy (extinction coefficient).