bluuebunny/crossref_metadata_2025_split huggingface dataset:
Time‐lapse photographic study of neural tube closure defects caused by xylocaine in the chick
Authors: Lee H. , Bush K. T. , Nagele R. G. 
Published: June 2005

AbstractSequential changes in the morphology of early chick embryos were, for the first time, photographically recorded. Embryos were explanted at stage 8 (four‐somite) or 9– (six‐somite) of development using New's technique and grown in nutrient medium (thin albumen) with or without a teratologic dose (200 μg/ml) of xylocaine. They were photographed using a Nikon Diaphot inverted microscope equipped with both phase‐contrast optics and photomicro‐graphic accessories maintained in an incubator. It was found, among other things, that a characteristic neural tube closure defect often seen in the midbrain and anterior portion of the hindbrain of xylocaine (200 μg/ml)‐treated chick embryos was a consequence of failure of the neural tube to withstand the tension generated by the rapidly expanding cephalic region, which occurred, regardless of the stage at explantation, when corresponding control embryos had advanced to stage 10+ (11‐somite) of development.
Genetics of susceptibility to 6‐aminonicotinamide‐induced cleft palate in the mouse: Studies in congenic and recombinant inbred strains
Authors: Karolyi Jill , Erickson Robert P. , Liu Sharon 
Published: June 2005

AbstractIn a search for genetic differences in susceptibility to cleft palate, congenic and recombinant inbred strains of mice were treated with 6‐aminonicotinamide or control injections. Of six loci tested, only the chromosome segment marked by N‐acetyl transferase was found to affect susceptibility to 6‐aminonicotinamide‐induced cleft palate. This chromosome segment is known to affect glucocorticoid‐induced cleft palate and phenytoin‐induced cleft lip with or without cleft palate in these strains of mice.
Histological comparison of the effects of the splotch gene and retinoic acid on the closure of the mouse neural tube
Authors: Kapron‐Brás Carolyn M. , Trasler Daphne G. 
Published: June 2005

AbstractThe splotch gene (Sp) and all‐trans retinoic acid (RA) interact to cause spina bifida in mouse embryos. To investigate the mechanisms of action of the two, the spinal regions of Sp homozygotes, RA‐treated wild‐type, and control wild‐type embryos were examined histologically by light microscopy on day 9 of gestation. The mean numbers of cells per section in the neural tube, mesoderm, and notochord were determined, along with the percentages of mitotic and pyknotic nuclei and the numbers of migrating neural crest cells. As well, the effect of Sp and RA on the extracellular matrix was studied histochemically with Alcian blue staining for glycosaminoglycans. The main defect in Sp homozygotes was a marked reduction in the number of migrating neural crest cells and the amount of extracellular matrix around the neural tube. Retinoic acid, on the other hand, caused a number of disruptions in the embryo, including abnormalities in the position of the notochord and the shape of the neural tube. Sp and RA delay neural tube closure and thus cause neural tube defects, through different mechanisms. However, the combined effects of the gene and teratogen on the embryo lead to a greater inhibition of neural tube closure than when either is present separately.
Retinoic‐acid‐induced limb malformations resulting from apical ectodermal ridge cell death
Authors: Sulik Kathleen K. , Dehart Deborah B. 
Published: June 2005

AbstractPregnant C57B1/6J mice were treated with single oral doses of 400 mg/kg 13‐cis retinoic acid (RA, isotretinoin, Accutane) in sesame oil at 9 days, 12 hours postfertilization. Among the live 16‐day fetuses from ten treated mothers, 46% (26/56) had limb malformations including small fifth digits, preaxial and/or postaxial oligodactyly, and preaxial or postaxial polydactyly. Fetuses with preaxial digit deficiencies also had absent or malformed radii. Scanning electron microscopic and light microscopic analyses of the sequence of developmental alterations leading to these malformations demonstrated abnormalities in the apical ectodermal ridge (AER). Excessive cell death in the AER of 27–30 somite enbryos (12 hours after treatment) appears to play a major role in the pathogenesis of the limb malformations observed. Previous investigations of retinoid‐induced limb malformations have concentrated on later exposure times. Evidence from this study in addition to that from previous teratologic and clinical investigations has led to the hypothesis that 13‐cis RA results in excessive cell death in regions of programmed cell death and subsequent malformations of affected regions.
Developmental toxicity evaluation of Bendectin in CD rats
Authors: Tyl Rochelle W. , Price Catherine J. , Marr Melissa C. , Kimmel Carole A. 
Published: June 2005

AbstractBendectin, composed of doxylamine succinate and pyridoxine HCl (1:1), is an antinauseant previously prescribed for nausea and vomiting during pregnancy. The present study examined the maternal and developmental effects of Bendectin (0, 200, 500, or 800 mg/kg/day, po) administered to timed‐pregnant CD rats (36–41/group) during organogenesis (gestational days [gd] 6–15). At death (gd 20), all live fetuses were examined for external, visceral, and skeletal abnormalities. At 500 and 800 mg/kg/day, maternal toxicity included reduced food consumption during treatment and for the gestation period, increased water consumption in the posttreatment period, reduced weight gain during treatment, and sedation; water consumption was reduced during treatment and for the gestation period, and maternal mortality (17.1%) was observed only at the high dose. Developmental toxicity included reduced prenatal viability (800 mg/kg/day) and reduced fetal body weight/litter (500 and 800 mg/kg/day). In addition, reduced ossification of metacarpals (800 mg/kg/day), phalanges of the forelimbs (500 and 800 mg/kg/day), and of caudal vertebral centra (all doses) was observed. No increase in percent malformed live fetuses/litter was observed. The proportion of litters with one or more malformed fetuses was higher than vehicle controls only at 800 mg/kg/day, with short 13th rib (to which the test species is predisposed) as the predominant observation. By contrast, a positive control agent (nitrofen, 50 mg/kg/day, po, 14 dams) produced 85% malformed fetuses/litter with the predominant malformation being diaphragmatic hernia. In conclusion, the incidence of litters with one or more malformed fetuses was increased only at a dose of Bendectin which produced maternal mortality (17.1%) and other indices of maternal and developmental toxicity (see Discussion).
Physical anomalies and developmental delays in nonhuman primate infants exposed to weekly doses of ethanol during gestation
Authors: Clarren Sterling K. , Astley Susan J. , Bowden Douglas M. 
Published: June 2005

AbstractEthanol was orally administered once per week to 54 gravid pigtailed macaques (Macaca nemestrina) in doses of 0.0, 0.3, 0.6, 1.2, 1.8, 2.5 or 4.1 gm/kg from the 1st week in gestation or in doses of 2.5, 3.3, or 4.1 gm/kg from the 5th week. Mean maternal mean peak plasma ethanol concentrations (MPPEC) ranged from 24 ± 6 mg/dl at the 0.3 gm/kg dose to 549 ± 71 mg/dl at the 4.1 gm/kg dose. Thirty‐three viable infants were followed from birth to 6 months of age and assessed for growth, health, congenital anomalies and developmental rate. Facial anomalies, growth deficiency, or central nervous system dysfunction were found in 57% of the alcohol‐exposed animals. No animal showed all the features of the human fetal alcohol syndrome. Ten of the twelve animals (83%) with mean MPPEC above 140 mg/dl had evidence of a teratogenic impact. The animals with full gestational exposure to ethanol and mean MPPEC between 140 and 249 mg/dl had much more severe and consistent cognitive abnormalities than the animals with delayed gestational exposures, even though the latter were exposed to mean MPPEC between 260 and 540 mg/dl. Conclusions from this study included: 1) ethanol‐related behavioral teratogenesis occurred without accompanying physical anomalies, 2) measurable teratogenic effects from weekly exposures occurred only at intoxicating doses of ethanol, and 3) early gestational exposure to ethanol appeared to be more damaging to cognitive function than later and considerably greater alcohol exposure.
Developmental variation of the diaphragm and liver in fischer 344 rats
Authors: Lu C. C. , Mull R. L. , Lochry E. A. , Christian M. S. 
Published: June 2005

AbstractThe nature and frequency of a developmental variation of the diaphragm and liver in Fischer 344 rats are described. Totals of 20, 98 and 55 (25 for caesarean‐sectioning and 30 for natural delivery) mated female rats were used for Experiments 1, 2, and 3, respectively. Each rat was intubated (gavage) with either an aqueous suspension of 0.2% METHOCEL®, 0.25% methyl cellulose, or distilled water as a single daily dose from days 6 through 15 (inclusive) of gestation. On the 20th day of gestation, a caesarean‐section was performed, and the uterine contents of each rat were examined. A gross necropsy was performed on the pups of 30 mated female rats on day 21 postpartum. The visceral examinations conducted on these fetuses and pups included an evaluation of a developmental variation in the diaphragm and liver. The variation consisted of a thin fibrous central tendon of the diaphragm with an area of liver (0.5–3 mm diameter) that protruded within the thin central tendon of the diaphragm. The incidence (mean % of fetuses affected per litter) of the diaphragm/liver developmental variation was 9% and 11% for METHOCEL®‐ and water‐treated groups, respectively. A thin central tendon was present in the diaphragm of all fetuses of methyl cellulose‐treated dams; these fetuses did not have a raised area of the liver present within the diaphragm's central tendon. However, in a few weaned pups of the Fischer 344 rats in this study, liver protruded within the central tendon of the diaphragm. The incidence of the diaphragm/liver developmental variation differed with the vehicles used, and it has never been observed in the Sprague‐Dawley or Wistar rat fetuses examined by us.
Glutathione status and the incidence of neural tube defects elicited by direct acting teratogens in vitro
Authors: Harris Craig , Stark Kevin L. , Juchau Mont R. 
Published: June 2005

AbstractValproic acid (VPA), cytochalasin D (CD) and 7–hydroxy–2–acetylaminofluorene (7–OH–AAF) each caused abnormal closure of the anterior neuropore in rat embryos cultured in vitro in the absence of an exogenous bioactivation system. Morphological comparisons showed that although all three compounds prevented normal neural tube closure, each did so in a distinctive manner. Modulation of GSH in cultured rat conceptuses was evaluated to determine whether common responses occurred relative to the ability of different chemicals to elicit neural tube defects. Malformation incidence in embryos (10–14 somites) varied widely following exposure to CD (44%), 7–OH–AAF (29%) or VPA (17%). The incidence of CD‐elicited malformations was increased by 50% following GSH depletion by L‐buthionine‐S, R‐sulfoximine (BSO) and was decreased by nearly 60% when the cysteine pro‐drug 2–oxothiazolidine–4–carboxylate (OTC) was added to the culture medium. GSH modulation also exerted significant effects on the incidence of abnormal neurulation caused by VPA or 7–OH–AAF. A relatively low incidence of open neural tubes produced by VPA or 7–OH–AAF alone was shown to be a function of the state of maturation in the embryos. Conceptuses cultured in the presence of VPA or 7–OH–AAF from an earlier gestational age (6–10 somites) showed 2–3 fold increases in the number of embryos with open neural tubes. Differential alterations in protein and DNA content were observed among embryos and yolk sacs after various treatments indicating possible differences in the site of embryotoxicity. These results demonstrate the role of GSH status on the capacity of three chemically diverse compounds to elicit abnormal neurulation in cultured rat embryos and suggest some possible mechanisms by which normal neurulation may be compromised.
Vertical development of the secondary palate in hamster embryos following exposure to 6‐mercaptopurine
Authors: Burdett David N. , Waterfield J. Douglas , Shah Ravindra M. 
Published: June 2005

AbstractCellular aspects of vertical development of the secondary palate were examined in control and 6‐mercaptopurine (6MP)‐treated hamster embryos. Cross‐sectional area of the palatal shelf was measured and the numbers of both epithelial and mesenchymal cells counted. Also, in 6MP‐treated palates the damaged mesenchymal cells, characterized by the presence of dense bodies, were counted. DNA synthesis in both control and treated fetuses was measured by 3H‐thymidine incorporation. The results indicated that both the shelf area and cell numbers increased with age in control and 6MP‐treated palates. However, in controls the mesenchymal cell density and DNA synthesis showed two peaks that were absent following 6MP treatment. Unlike controls, in treated embryos the damage to mesenchymal cells became increasingly pronounced between days 10:00 and 10:12 but subsided by day 11:00 of gestation. It is suggested that a major force in the development of the initial primordia and early vertical development of the palatal shelf may be provided by a spurt of DNA synthesis in the mesenchymal cells resulting in their increased number. After 6MP treatment, depression of DNA synthesis and consequent reduction in the mesenchymal cell number and density followed by cell damage lead to retardation in the vertical development of the palatal shelves.
A method to increase the survival rate of early chick embryos in experiments involving surgical intervention
Authors: Bagnall K. M. 
Published: June 2005

AbstractA method is presented by which the survival rate of early chick embryos following surgical procedure can be greatly improved. It was discovered that the embryos were dying at the stage of the operating procedure at which ink was being introduced under the embryo. Ink was used to visualize the embryonic features more easily. The use of a contrast medium in which the ink has been previously mixed with yolk in the ratio of 1:30 solved the problem.
Strain differences in the teratogenicity induced by sodium valproate in cultured mouse embryos
Authors: Naruse Ichiro , Collins Michael D. , Scott William J. 
Published: June 2005

AbstractStrain differences in the teratogenicity of valproic acid (VPA) have been reported in mice. Finnell and Chernoff (Proc. Grnwd. Genet. Ctr. 5:162–163, 1985) showed that 300 mg/kg of VPA twice a day on days 6–8 of gestation induced exencephaly in 82% of SWV embryos but in 0% of C57BL/6J embryos. In the present experiment, we have collected similar results and investigated this strain difference using whole embryo culture in an attempt to determine whether maternal or embryonic factors are responsible for the difference. Mouse embryos were explanted on day 8.5 (plug day 0), and embryos at the 6–8‐somite stage were cultured for 48 hours in rat serum containing various doses of sodium valproate (NaVP). All the embryos died within 24 hours with 4.5‐mM and higher doses of NaVP in C57BL/6NCr1BR (C57) and with 3.0‐mM and higher doses in SWV. Unfused brain folds were recognized in embryos treated with 3.0‐mM and higher doses in C57, and with 1.0‐mM and higher doses in SWV. Irregular somite formation was observed in many embryos treated with 1.6‐mM and higher doses in C57 and with 1.0‐mM and higher doses in SWV. These results indicate that SWV embryos have 1.5–3 times the sensitivity of C57 embryos to the embryolethal and teratogenic effects of NaVP. Furthermore, the results suggest that the basis of the strain difference resides within the embryo rather than the mother.
Alterations in developing rat uterine cell populations after neonatal exposure to estrogens and antiestrogens
Authors: Branham William S. , Zehr David R. , Chen James J. , Sheehan Daniel M. 
Published: June 2005

AbstractExposure of rats to either estrogens or antiestrogens during early postnatal development reduces subsequent uterine growth as measured by uterine weight. However, individual uterine cell types respond differently to these agents and uterine weight alone cannot discern subtle or even large alterations in individual cell populations. Using a computerized planimetric technique, we estimated the prepubertal growth of the uterine luminal epithelium, endometrial stroma, glands, and circular and longitudinal muscle after exposure of neonatal rats (postnatal days 1–5) to the estrogens 17β‐estradiol (E2), diethylstilbestrol (DES), or ethynylestradiol (EE), and the antiestrogens tamoxifen or clomiphene citrate. On postnatal day 26, the cross‐sectional areas of the luminal epithelium, endometrial stroma, and circular muscle were reduced after estrogen exposure, compared to untreated controls, while longitudinal muscle cross‐sectional area was not affected. Since cell densities (cell number/unit area) were increased, these estrogen‐induced area reductions demonstrate a decrease in cell size. Total cell numbers, estimated as the product of cell type areas and their respective cell densities, were also reduced by neonatal estrogen exposure. The synthetic estrogens DES and EE were more potent than E2 with respect to reduction of uterine growth. Neonatal antiestrogen exposure caused large area reductions only in the uterine glands and luminal epithelium. Little change in cell density occurred in any cell population exposed to antiestrogen. These data demonstrate that the decreased uterine growth resulting from estrogen exposure during early postnatal development is a consequence of combined hypotrophy and hypoplasia in all cell types except longitudinal muscle while antiestrogen‐induced morphological alterations were limited to hypoplasia having epithelial cell specificity.
On “rates” of birth defects
Authors: Schulman Jane , Shaw Gary , Selvin Steve 
Published: June 2005

AbstractThe proportion of children born with a particular defect is not a “birth defect rate” but, rather, a prevalence proportion. The implications of confusing a rate and a proportion are discussed in terms of the interpretation of birth defect data. It is recommended that “prevalence proportion” or “prevalence” be used to report the frequency of various defects rather than the often‐used “prevalence rate”.
Embryotoxicity studies of norfloxacin in cynomolgus monkeys: I. Teratology studies and norfloxacin plasma concentration in pregnant and nonpregnant monkeys
Authors: Cukierski M. A. , Prahalada S. , Zacchei A. G. , Peter C. P. , Rodgers J. D. , Hess D. L. , Cukierski M. J. , Tarantal A. F. , Nyland T. , Robertson R. T. , Hendrickx A. G. 
Published: June 2005

AbstractNorfloxacin, a new orally active antibiotic, was investigated in cynomolgus monkeys for potential developmental toxicity. Fifty seven monkeys were administered a control vehicle or norfloxacin by nasogastric gavage during the major period of organogenesis on gestational days (GD) 21 through 50 at doses of 0, 50, 100, 150, or 200/300 mg/kg/day. There was no evidence of teratogenicity at any dose level. Maternotoxicity and a significant increase in embryolethality occurred following doses of 200/300 mg/kg/day. The maternotoxicity was not expected based on rangefinding studies in nonpregnant female monkeys, which showed no signs of toxicity in doses up to 500 mg/kg/day. Additional studies were conducted to determine if norfloxacin caused similar toxicity later in gestation. Forty‐six pregnant monkeys were dosed with a control vehicle or 200 mg/kg/day norfloxacin for one of three 10‐day periods on GD 36–45, 71–80, or 111–120. There were no maternotoxic, embryotoxic, or fetotoxic effecs observed. Plasma concentrations of norfloxacin in five cynomolgus monkeys following 50 and 200 mg/kg oral doses were not dose‐proportionate. However, at a given dose, administered in cross‐over fashion, plasma concentrations of norfloxacin were higher in nonpregnant females (± 20–40%) than during pregnancy when the same subject was compared. At the no‐observed‐effect dose for maternal and embryotoxicity (50 mg/kg), peak plasma concentrations of norfloxacin in pregnant cynomolgus monkeys are approximately threefold higher than those observed in human volunteers receiving norfloxacin at the maximum recommended therapeutic dose of 400 mg (5.7 mg/kg based on 70 kg body weight) twice per day.
Teratogenicity of 3,3‐dimethyl‐1‐phenyltriazene in the rat: Gross malformations including micrognathism
Authors: Frank Anthony A. , Thompson Daniel J. , Kazacos Evelyn A. 
Published: June 2005

Abstract3,3‐Dimethyl‐1‐phenyltriazene (DMPT), an alkylating agent, has been reported to be teratogenic in chickens, mice, and rats. One of the most commonly affected structures is the mandible; however, a complete description and incidence rates of all malformations produced have not been published. Rats were treated on day 12 of gestation (day 0 = sperm in vaginal smear) with a single intraperitoneal injection of 30 mg DMPT/kg. Fetuses were examined on each subsequent day of gestation for external and skeletal abnormalities. Standard soft tissue examinations were performed on day‐20 fetuses. A high percentage (≥80%) of treated litters contained numerous fetuses with micrognathism, cleft palates, syndactyly, adactyly, and misshapen digits and limbs. Lordosis, cerebellar and cerebral hypoplasia, decreased fetal size, and generalized delayed ossification were also observed. Dams exposed to DMPT had decreased food consumption and weight gains, although clinicopathologic and histopathologic evaluations failed to indicate other evidence of maternal toxicity. DMPT caused numerous permanent structural alterations that were not attributed to maternal toxicity.
Studies of mechanisms of niridazole‐elicited embryotoxicity: Evidence against a major role for covalent binding
Authors: Fantel A. G. , Juchau M. R. , Tracy J. W. , Burroughs C. J. , Person R. E. 
Published: June 2005

AbstractStudies reported here were designed to examine the hypothesis that covalent binding of reactive intermediates to macromolecules of the conceptus represents a major mechanism for the embryotoxicity of niridazole (NDZ). The roles of embryonic thiol content and oxygenation on: (1) malformation incidence; (2) reductive metabolism; and (3) covalent binding to embryonic macromolecules of metabolites resulting from reductive biotransformation of NDZ were studied. Results were compared with those from studies with the nondysmorphogenic analog of NDZ, 4′‐methylniridazole (MNDZ). Day 10 rat embryos were pretreated for 5 hours in vitro with either L‐buthionine‐S, R‐sulfoximine (BSO) or N‐acetylcysteine (NAC) to modulate their glutathione (GSH) content. BSO reduced GSH levels, but NAC was ineffective. Following pretreatment, embryos were cultured for an additional 15 hours in the presence of [14C]NDZ or [14C]NDZ with an initial oxygen concentration of 5%. At the end of the culture period (day 11, AM), those embryos with active heartbeat and vitelline circulation were examined for asymmetric malformations. Drug metabolites were subjected to multiple extractions from the culture medium and subjected to quantitative high‐performance liquid chromatography (HPLC) analysis. Homogenates of the embryos were extracted with trichloroacetic acid (TCA) to estimate the covalent binding of radiolabeled parent compound/metabolites. Autoradiographic analyses were performed on other embryos. BSO pretreatment, which reduces embryonic GSH tissue levels, dramatically increased both the conversion of NDZ to 1‐thiocarbamoyl‐2‐imidazolidinone (TCI) (generated via reductive metabolism of NDZ) and covalently bound label but failed to increase embryotoxicity. NAC, by contrast, did not significantly affect embryonic GSH levels, TCI generation, or covalent binding. Because both rates of metabolism of NDZ to TCI and covalent binding could vary independently of malformation incidence, we concluded that they do not represent critical mechanistic factors for the embryotoxicity of NDZ and related nitroheterocycles.