bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparison of the behavioral teratogenic potential of phenytoin, mephenytoin, ethotoin, and hydantoin in rats
Authors: Minck Daniel R. , Acuff‐Smith Karen D. , Vorhees Charles V. 
Published: June 2005

AbstractPregnant Sprague‐Dawley CD rats were orally administered either phenytoin (PHT, 200 mg/kg), mephenytoin (MPH, 100 mg/kg), ethotoin (ETH, 600 mg/kg), hydantoin (HYD, 1,200 mg/kg) or vehicle (propylene glycol) on days 7–18 of gestation. Mean (±S.E.) maternal serum concentrations of PHT, MPH, and ETH 1 hour after dosing on gestational day 18 were 16.0 ± 3.3, 10.7 ± 3.0, and 65.2 ± 10.45, respectively, and free fractions were 16%, 18%, and 11%, respectively. The free fraction for PHT is similar, but was lower for both MPH and ETH than that seen in humans. Preweaning mortality for PHT, MPH, ETH, HYD, and controls was 25%, 6.3%, 12.5%, 2.0%, and 0.8%, respectively. The MPH and ETH‐exposed animals weighed approximately 6.6% less than controls throughout the study; the other groups did not differ significantly. PHT offspring showed increased early locomotor activity. Only PHT‐exposed animals (27%) exhibited abnormal circling behavior after weaning. PHT‐circlers accounted for higher levels of activity in an open‐field test and for longer straight channel swimming times. PHT‐circlers and noncirclers differed from one another and controls on performance of a complex (Cincinnati) maze and on the development of the air‐righting reflex. Offspring prenatally exposed to MPH showed an early delay in air‐righting. ETH and HYD offspring were not consistently different from controls in behavior. The data suggest the following ordinal relationship among the drugs for behavioral teratogenesis: PHT> >MPH>ETH≃HYD≃CON. The effects of PHT are consistent with previous findings. Data on the other drugs suggest that other hydantoins do not possess the behavioral teratogenic efficacy of PHT and that PHT may be unique in its effects on CNS development.
Fetal dexamethasone exposure impairs cellular development in neonatal rat heart and kidney: Effects on DNA and protein in whole tissues
Authors: Slotkin T. A. , Seidler F. J. , Kavlock R. J. , Bartolome J. V. 
Published: June 2005

AbstractFetal glucocorticoid exposure causes postnatal growth retardation. To examine the mechanisms underlying effects on specific organ systems, we administered 0.2 or 0.8 mg/kg of dexamethasone to pregnant rats on gestational days 17, 18, and 19 and assessed three biochemical markers of cell development in heart and kidney of the offspring: DNA content per organ as an index of total cell numbers, DNA per g tissue as an index of cell packing density, and protein/DNA ratio as an index of relative cell size. In both tissues, DNA content became markedly subnormal during the first postnatal week, the ontogenetic period of rapid cell division. Partial recovery occurred by the end of the first postnatal month. In the heart, cell packing density was subnormal initially and the cells were significantly enlarged. In contrast, packing density was slightly elevated in the kidney; protein/DNA was increased by the low dose of dexamethasone, but markedly decreased by the high dose. These results suggest that tissue growth impairment caused by prenatal dexamethasone treatment reflects primary deficits in cell proliferation that extend to a variety of different cell types; however, consequent effects on cell packing density and cell size are dose‐specific, possibly reflecting actions of glucocorticoids selective for certain cell types or phases of cell development.
Transplacental distribution of weak acids in mice: Accumulation in compartments of high pH
Authors: Srivastava M. , Collins M. D. , Scott W. J. , Wittfoht W. , Nau H. 
Published: June 2005

AbstractThe transplacental distribution of three weak acids was measured in mice on gestational day 11. The ratio of drug concentration in maternal, embryonic, and extraembryonic compartments compared to maternal plasma followed a consistent hierarchy such that amniotic fluid ⩾ exocoelomic fluid > embryo > embryo plasma > maternal skeletal muscle. This distribution pattern correlates well with pH in these compartments and suggests that pH gradients between compartments are an influential factor in determining weak acid drug disposition during pregnancy.
Morphogenetic and molecular correlates of teratogenesis in the amphibian embryo
Authors: Brennan Sean M. 
Published: June 2005

AbstractIn attempting to develop a system to study molecular mechanisms of teratogenesis, examination of the effects of a teratogen (dimethyl sulfoxide) on both molecular and morphological aspects of embryonic development in the amphibian Xenopus laevis has been conducted. Characteristic morphological effects, which occur during the period from 7 to 16 hours after fertilization (i.e., gastrulation) are noted. Delays in gastrulation are accompanied by changes in the regulation of transcription of several genes known to be active during gastrulation in normal development. Later morphological effects are also observed, and these probably arise as a consequence of the changes occurring during gastrulation. Thus, molecular responses to a teratogen have been detected, and a correlation between molecular and morphological responses to a teratogen is observed. These findings represent the first demonstration of the effects of a teratogen on the transcription of specific genes, and invite speculation that one or more molecular events mediate teratogenesis. They further suggest that the amphibian system may be useful for studying early molecular responses to teratogens.
Glucocorticoid teratogenesis in the developing nephron
Authors: Crocker J. F. S. , Ogborn M. R. 
Published: June 2005

AbstractAlthough the induction of polycystic kidney disease by neonatal glucocorticoid treatment has been extensively documented, there are no data on induction of polycystic kidney disease with fetal exposure to glucocorticoids. We injected groups of pregnant Swiss Webster albino mice subcutaneously with 250 mg/kg of hydrocortisone acetate on individual days from days 1 to 19 of gestation. A control group received an equal volume of saline. Histologic analysis of 1,522 kidneys from the offspring of these animals revealed no evidence of polycystic kidneys in the control group or in offspring of animals injected before day 11 of pregnancy. A bimodal distribution of cystic kidney disease was noted in the remaining animals, with highest prevalence after injection on day 12 (50.8%) and day 17 (34.3%). We conclude that 250 mg/kg of glucocorticoids may induce polycystic kidney disease in utero, but possibly only during critical periods of metanephric development.
Lack of attenuation of valproic acid‐induced effects by folinic acid in rat embryos in vitro
Authors: Hansen Deborah K. , Grafton Thomas F. 
Published: June 2005

AbstractThe anticonvulsant drug valproic acid (VPA) is suspected to be a developmental toxicant in humans, inducing primarily neural tube defects. The mechanism for this effect is unknown, but it has been suggested that the drug may act via a deficiency of the vitamin follic acid. We examined this possibility by concurrent treatment of rat embryos in a whole embryo culture system with VPA and folinic acid (FA), a folic acid derivative. Groups of CD rat embryos were treated with various concentrations of VPA, various concentrations of FA, or a combination of a teratogenic dose of VPA plus various levels of FA. At the end of the 44 hour culture period, each embryo was evaluated for viability (presence of a heartbeat), yolk sac circulation, presence of any malformations, morhological score, crown–rump and head lengths, as well as DNA and protein contents. The anticonvulsant did not decrease viability but did decrease yolk sac circulation and all growth and developmental endpoints in a dose‐responsive manner. There was also a dose‐related increase in the incidence of open neural tubes. The addition of FA alone had no significant effect on growth and development. When various concentratins of FA were added simultaneously with a teratogenic dose of VPA, there was no decrease in the incidence of open neural tubes. Growth and developmental endpoints were altered in a somewhat random fashion but were never increased to the control level. The lack of attenuation of FA was not due to instability of the compound in the culture system, nor was there a difference in the amount of FA, present in the exocoelomic fluid of VPA‐treated and control embryos. Overall, these results suggest that VPA‐induced open neural tubes in rat embryos cultured in vitro are not due to a deficiency of folinic acid.
Medical sonography: Reproductive effects and risks
Authors: Brent Robert L. , Jensh Ronald P. , Beckman David A. 
Published: June 2005

AbstractWhile it is clear that the levels and types of medical sonography that have been used in the past have no measurable risks, it would be inaccurate to label the modality of ultrasound as totally safe regardless of exposure. Most agents have reproductive risks and even teratogenic risks if the exposure is raised sufficiently. Thus the prudent use of sonography means that clinicians and designers of equipment have to maintain exposures far below the risks that have been demonstrated in animal studies and from the knowledge obtained about the physical changes that can be produced in humans as the absorbed dose is elevated. The reproductive risks were evaluated using five criteria: 1) human epidemiology, 2) secular trend data, 3) animal experiments, 4) dose response relationships, and 5) biologic plausibility. The analysis reveals that the human epidemiology does not indicate that diagnostic ultrasound presents a measurable risk to the developing embryo or fetus. Animal studies also indicate that diagnostic levels of ultrasound are safe and do not elevate the fetal temperature into the region where deleterious embryonic and fetal effects will occur. Because higher exposures of ultrasound can elevate the temperature of the embryo, the use of diagnostic procedures and the design of sonographic equipment should take into consideration the hyperthermic potential of higher exposures of ultrasound and the hypothetical additional risk of performing sonography on pregnant patients who are febrile. It would appear that if the embryonic temperature never exceeds 39°C, then there is no measurable risk. We suggest that sonography (the field) and sonogram (the procedure) are the most appropriate and least anxiety provoking terms.
Development of the lung in mice with bromodeoxyuridine‐induced cleft palate
Authors: Bannigan John G. , Cottell David C. 
Published: June 2005

AbstractClinical and laboratory observations show that denial of free communication between the amniotic fluid and lung fluid results in pulmonary hypoplasia. Thus, cleft palate resulting from tongue obstruction to palatal shelf elevation might be associated with disturbed lung development. This association exists in the Pena‐Shokeir phenotype. The goal of these experiments was to see what effect bromodeoxyuridine (BUdR)‐induced cleft palate had on lung development. LACA mice were injected with 500 mg/kg BUdR on E11 or E11 and E12 of gestation, a treatment known to produce a 25% and 50% incidence of cleft palate, respectively. BUdR had a direct retarding effect on lung growth but, when cleft palate occurred as well, the lungs were more severely affected. Morphometry showed that lungs from fetuses with cleft palate had only one‐half the saccular volume of controls or of treated fetuses with normal palates. Although hypoplastic, lungs associated with cleft palate had type I and type II pneumocytes, and the latter were shown by electron microscopy to be capable of producing surfactant. Hence, cellular differentiation had not been affected by the treatment.Fetuses with cleft palate had less amniotic fluid than controls but significantly more than those with normal palates after treatment. Thus, the pattern of abnormalities in this animal model bears some resemblance to that of the human Pena‐Shokeir phenotype.
Bias in congenital malformations information from the birth certificate
Authors: Hexter Alfred C. , Harris John A. 
Published: June 2005

AbstractAn analysis of 1983 data from California birth certificates, and from the California Birth Defects Monitoring Program case registry, showed that there is a bias in reporting of congenital malformations on the birth certificate. Hospitals with many births erroneously report lower malformation rates than do hospitals with few births. The bias is partly due to the source of information; larger hospitals are more likely to get their information about malformations from the obstetrician than from the pediatrician. Since malformation data recorded on the birth certificate is both incomplete and biased, at present it is advisable to use these data for epidemiologic analyses with great caution.
Ultrastructure and function of the rat yolk sac: Damage caused by teratogenic anti‐VYS serum and recovery
Authors: Beckman David A. , Ornoy Asher , Jensen Marcela , Arnon Judi , Brent Robert L. 
Published: June 2005

AbstractIt was hypothesized that heterologous anti‐rat visceral yolk sac serum (AVYS) exerts its teratogenic effect by reducing the endocytosis of serum proteins by the visceral yolk sac (VYS), thus reducing the supply of amino acids to the embryo and VYS. To evaluate this hypothesis, we studied the effect of teratogenic AVYS on the endocytic function of the VYS and the ultrastructure of the VYS and parietal yolk sac (PYS). Rat conceptuses were exposed to a teratogenic dose of AVYS on the 10th day of gestation in vivo or in vitro. Control and AVYS‐exposed specimens were collected 24–192 hr later and prepared for scanning and transmission electron microscopy (SEM and TEM, respectively) utilizing standard procedures. The Endocytic Index was calculated for the VYS utilizing standard procedures. Approximately 97% of the in vivo exposed and 94% of the in vitro exposed embryos were morphologically abnormal. Ultrastructural observations showed that exposure to AVYS in vivo or in vitro caused severe damage to the VYS endodermal epithelial cells with loss of cellular borders, reduction in the number and length of microvilli, and increased cellular inclusions; and some damage to PYS endodermal cells with increased blebbling and decreased cell number. Recovery was evident at 72 hr and complete by 96 hr. The Endocytic Index was significantly reduced in the VYS 24 and 48 hr after injecting AVYS into the pregnant rat but was not significantly different at 96 and 192 hr. Our results show that the AVYS antiserum damaged visceral endodermal epithelium experienced ultrastructural recovery with parallel functional recovery. These studies suggest that transient yolk sac placental ultrastructural damage and dysfunction was probably sufficient to cause irreversible damage to the developing embryo during early organogenesis. We conclude that the proximate effect of the AVYS was on the plasma membrane of the visceral endoderm and that decreased pinocytosis is a consequence of this effect.
Effects of in vivo exposure of pregnant hamsters to glucose. 1. Abnormalities in LVG strain fetuses following intermittent multiple treatments with two isomers
Authors: Gale Thomas F. 
Published: June 2005

AbstractThe increased frequency of congenital malformations including caudal regression syndrome, in infants of women with insulin‐dependent diabetes mellitus is well documented. Most of the related animal research has involved the in vitro embryo culturing methodology. This study involved the alternative in vivo approach in order to determine the effects of treatment of pregnant hamsters with the D‐ and L‐isomers of glucose at five times just before and during the period of embryonic organogenesis on maternal blood glucose levels and the rates and types of fetal abnormalities. One group of animals was injected with 5 doses (4 g/kg each) of D‐glucose, i.e., on gestation day (D) 6, 3 PM; D7, 8 AM and 3 PM; D8, 8 AM and 3 PM. Two other groups were treated the same way but with L‐glucose (4 g/kg per dose) and water (10 ml/kg per dose), respectively. The D‐glucose treatment produced alternating periods of hyperglycemia and normoglycemia in the pregnant hamsters, enlarged placentae and fetuses with small urinary bladders, microphthalmia and skeletal abnormalities of the sternum, caudal vertebrae, pelvic bones, and femora. The L‐glucose treatment did not produce changes in maternal blood D‐glucose levels but did produce fetuses with small urinary bladders, microphthalmia and abnormal ossification limited to the manubrium. Several interpretations of the D‐glucose‐induced fetal abnormalities involving the vertebrae, proximal hindlimb bones and urinary bladders are discussed, including the consideration that this cluster has interesting similarities to the spectrum of skeletal and soft tissue abnormalities of human diabetes‐related caudal regression syndrome.
Pathogenesis of ethanol‐induced hydronephrosis and hydroureter as demonstrated following in vivo exposure of mouse embryos
Authors: Gage Jennifer C. , Sulik Kathleen K. 
Published: June 2005

AbstractUrinary tract abnormalities have been noted to occur in 10–27% of individuals diagnosed as having Fetal Alcohol Syndrome. Among a wide range of functional and structural abnormalities, renal agenesis/hypoplasia, hydronephrosis, and ureteropelvic obstruction feature most prominently. This study was designed to examine the pathogenesis of ethanol‐induced urinary tract abnormalities in a mouse model. C57Bl/6J mice were acutely exposed to two doses of ethanol (2.9 g/kg IP) administered 4 hours apart beginning on gestational day (GD) 9, hour 4. This resulted in an incidence of 40.7% urinary tract anomalies among GD18 fetuses. With the exception of duplicate ureter, urinary tract abnormalities consisted exclusively of hydroureter/hydronephrosis. Examination of GD13–17 fetuses revealed that the first grossly detectable differences in the urinary tracts of control vs. affected specimens occurred on GD16 and initially only involved ureteral changes. Hydronephrosis was first detected on GD17. A contributing factor to the development of hydronephrosis appears to be the abnormal location of the ureterovesicle junction which commonly involves duplicate ureteral lumens with resultant functional obstruction to urine flow at the distal end of the ureter. Study of the early pathogenetic changes which appear to result in the urinary tract malformations observed involved utilization of scanning electron microscopy, vital dye (Nile blue sulphate) staining of whole embryos, and analysis of histological sections. These studies revealed that 12 hours following initial maternal ethanol exposure, embryos have excessive amounts of cell death localized in the region of the developing mesonephric duct just proximal to the cloaca. Also affected were premigratory neural crest cells located just proximal to the posterior neuropore. We conclude that excessive amounts of ethanol‐induced cell death in these selectively vulnerable populations could account for the subsequently observed urinary tract malformations.
Microinjection of cultured rat embryos: Studies with retinol, 13‐cis‐ and all‐trans‐retinoic acid
Authors: Lee Qwihee P. , Juchau Mont R. , Kraft Joan Creech 
Published: June 2005

AbstractRetinol, all‐trans‐retinoic acid or 13‐cis‐retinoic acid were intraamniotically microinjected in rat embryos on day 10 of gestation and cultured until day 11.5. A comparison of the concentration–effect relationships of the retinoids showed that the dysmorphogenic effects were qualitatively similar for all three, but were elicited by a low concentration of all‐trans‐retinoic acid (250 ng/ml), a 6‐ to 7‐fold higher concentration of 13‐cis‐retinoic acid and an approximately 16‐fold higher concentration of retinol. After microinjection of 2,000 ng/ml of retinol, no dysmorphogenesis was observed but instead an increase in all growth parameters as compared to the controls.
Asymmetric development of mitochondrial activity in rat embryos as a determinant of the defect patterns induced by exposure to hypoxia, hyperoxia, and redox cyclers in vitro
Authors: Fantel A. G. , Person R. E. , Burroughs‐Gleim C. , Shepard T. H. , Juchau M. R. , Mackler B. 
Published: June 2005

AbstractPrevious study has shown that midorganogenesis‐stage rat embryos exposed to strong redox cyclers under moderate hypoxia in vitro develop severe necrotic defects on the right side. Similar effects can be produced by exposure to severe hypoxia alone. Studies presented here indicate that exposure to severe but survivable hyperoxia induces comparable necrotic degeneration on the left sides of all embryos. We hypothesize that the basis of these axially asymmetric defects is relatively precocious mitochondrial maturity on the left side of the embryo. In order to investigate this hypothesis, we compared mitochondrial oxygen utilization (NADH oxidase activities) on either side of rat embryos between days 11 and 14 of gestation. Activities were consistently higher on the left side during this period and significantly higher on day 11. We also found that the asymmetric embryotoxicity induced by niridazole, a strong redox cycler, could be attenuated by prior culture under hyperoxic conditions. We propose that mitochondrial immaturity on the right results in inadequate energy generation under hypoxic conditions, either directly or as a result of redox cycling. On the other hand, necrosis associated with hyperoxic conditions results from “leakage” of superoxide from functionally mature mitochondria on the left side.
Maternal and developmental toxicity of low doses of cytosine arabinoside in mice
Authors: Ortega Arturo , Puig Misericòrdia , Domingo José L. 
Published: June 2005

Abstract1‐β‐D‐Arabinofuranosylcytosine (Ara‐C), an effective drug for the treatment of leukemia and breast cancer, was evaluated for developmental toxicity in pregnant Swiss mice. Ara‐C was administered by intraperitoneal injection on gestational days 6–15 at doses of 0, 0.5, 2, and 8 mg/kg/day. Maternal observations included clinical signs, body weight change, food consumption, and gross evaluation of organs and uterine contents at necropsy (day 18). Live fetuses were examined for external, visceral, and skeletal alterations. Maternal toxicity was observed at 2 and 8 mg/kg/day, as evidenced by a significant decrease in body weight gain and food consumption during the treatment period. Significantly increased early and late resorptions and reduced number of live fetuses per litter as well as decreased fetal body weight were observed at 8 mg/kg/day. At 2 mg/kg/day, the incidence of cleft palate, renoureteral agenesis or hypoplasia, and poly‐ or oligodactyly was significantly increased, whereas fetal weight was reduced at 0.5 mg/kg/day. Thus, the developmental no‐observed‐adverse‐effect‐level (NOAEL) of Ara‐C in the pregnant mouse is lower than 0.5 mg/kg/day, while the NOAEL for maternal toxicity is 0.5 mg/kg/day. We believe that exposure to this agent ought to be avoided during organogenesis.