bluuebunny/crossref_metadata_2025_split huggingface dataset:
Vitamin A congeners
Authors: Rosa Franz W. , Wilk Ann L. , Kelsey Frances O. 
Published: June 2005

AbstractDespite animal vitamin A congener teratogenicity in animal studies since 1954, striking human findings only arose in 1983 following isotretinoin (ITR) marketing for oral treatment of severe acne. By November 1985, 44 outcomes with central nervous system (CNS), cardioaortic (CV), microtia, facial palsy, micrognathia, cleft palate, and/or thymic aplasia defects, and 33 spontaneous abortions have been reported. The critical period for exposure appears to be two to five weeks postconception, although this is clinically inexact. ITR half life is less than a day, although a teratogenic metabolite, 4‐oxo‐isoretinoin, has a half life of several days. Seven defect outcomes and one stillbirth have been reported with another congener, etretinate (ETR), used for psoriasis. Three of these had meningomyeloceles. Half life of several months makes levels cumulative. Only one additional defect, which may have occurred by chance, is reported with use stopped before conception (4 months). Other discontinuations 1 to 6 months before conception had 11 normal outcomes and two spontaneous abortions. ITR and ETR dose ranged from 0.5 to 1.5 mg/kg. Normal outcomes are reported both with ITR and ETR, but some of these appear not to have been exposed during the critical period. Less striking defects, abortions, and normal outcomes are less well reported. Because vitamin A analogs are therapeutically important and unplanned outcome not always avoidable, further animal research is needed for better risk/benefits. Megadose vitamin A (retinol) use is widespread, but experience poorly observed. Eighteen suspicious birth defect outcomes have been reported from pregnancies with high dose exposure. Twelve had findings similar to those seen in animals and in human retinoid syndromes, e.g., CNS, CV, microtia, and clefts. Epidemiological controls are lacking to establish human teratogenicity, but based on animal studies and experience with ITR and ETR, avoding long term megadose Vitamin A use in fertile women is warranted.
Effects of methylmercury on the morphogenesis of the rat cerebellum
Authors: Howard John D. , Mottet N. Karle 
Published: June 2005

AbstractDeveloping rat cerebellums were examined following continuous methylmercury exposure via maternal drinking water at 12.5 ppm during gestation and the suckling period. The continuous exposure resulted in reductions of the total cerebellar cell population and higher mercury tissue burdens than previous acute‐dose studies. Cell necrosis was not evident, but rather alterations in the pattern of mitotic figures were observed. A decreased number of cells in the methylmercury exposed cerebellums was associated with an increased number of mitotic figures in the early stages of mitosis and a decrease in the number in the middle and late stages. These in vivo exposure observations are consistent with in vitro cell cycle studies in which the cells were found to have accumulated in G2 and early M phases. Impaired cell proliferation is suggested to be a major mechanism of developmental neurotoxicity following continuous low‐does exposure to methylmercury.
Teratogenesis of calcium valproate in rabbits
Authors: Petrere Judith A. , Anderson John A. , Sakowski Raymond , Fitzgerald James E. , De La Iglesia Felix A. 
Published: June 2005

AbstractThe calcium salt of valproic acid (Valontin) has been proposed for use in the treatment of absence, myoclonic, and tonic clonic seizures of the primarily generalized type. The present study was conducted to determine the teratogenic potential of calcium valproate in rabbits. Groups of 20 Dutch‐belted rabbits were given oral doses of 50, 150, or 350 mg/kg on days 6–18 of gestation. A referece group was given 350 mg/kg sodium valproate and control groups were untreated or given vehicle alone. Animals were observed daily and body weights were recorded on gestation days 0, 6, 13, 18, and 30. Litter and fetal parameters were evaluated following uterotomies on day 30. No drug‐related clinical signs or deaths occurred. Postimplantation loss and the incidence of malformed vertebrae and ribs, rudimentary or absent pollices, and extra vertebrae and ribs were increased at 350 mg/kg with both calcium and sodium salts of valproic acid. At the 150‐mg/kg dose level, calcium valproate markedly increased the incidence of supernumerary ribs. No teratogenic or embryotoxic effects were seen with calcium valproate at 50 mg/kg. These data indicate that the sodium and calcium salts of valproic acid exhibit teratogenic potential in rabbits.
Abnormalities of the ear associated with exencephaly in mouse fetuses induced by maternal exposure to cadmium
Authors: Padmanabhan R. 
Published: June 2005

AbstractExencephaly was induced in mouse fetuses by maternal injection of cadmium chloride (CdCl2) on day 7 of gestation. The heads of exencephalic, nonexencephalic experimental, and control fetuses were embedded in paraffin and sections were stained with hematoxylin and eosin. Compared to those of controls, the ears of the exencephalic fetuses were smaller (microtia) and low set. The meatal plug representing the external auditory canal was thick, variously branched, and often directed inferiorly. Usually, there were just two ossicles. The stapedial artery, facial nerve, and stapedius muscle were hypoplastic; the tensor tympani was small or absent. There were 1.0 to 2.0 turns of the cochlea in contrast to 2.5 turns in the controls. The organ of Corti was underdifferentiated; the spiral ganglion had fewer cells. In the control, the long axes of the anterior and posterior semicircular ducts were at right angles to each other and in vertical planes, but in the exencephalics, they tended more laterally towards the horizontal plane. The differentiation of the cristae ampullares and maculae was also severely affected. In several specimens, the entire membranous labyrinth had been distended; these labyrinths also had unusual epithelial infoldings. In cadmium‐treated nonexencephalic fetuses, the external ears were normal and appropriate to the body size; five of them were examined histologically; in all, the five middle ear contents were hypoplastic; in three, the cochlea had a maximum of two turns and the organ of Corti, crista ampullaris, and macula were hypoplastic. By an analogy to abnormalities of mutants with neural tube defects, it is suggested that the exencephaly induced by cadmium might affect the differentiation of the ear. Partial involvement of the ear in nonexencephalic experimental embryos may be the result of direct action of cadmium during critical stages of development.
Teratogenic effect of D‐amphetamine sulphate: Histodifferentiation and electrocardiogram pattern of mouse embryonic heart
Authors: Fein Amos , Shviro Yardena , Manoach Mordechai , Nebel Laslo 
Published: June 2005

AbstractPregnant albino mice (ICR random‐bred strain) received daily injections of 50 or 100 mg/kg body weight of D‐amphetamine sulphate between days 9 and 11 of gestation. Parallel control animals were injected with saline solution. Treated mice were sacrificed on day 15 or 19 of gestation. The embryos were examined for gross malformations and direct embryonic ECG recordings were made; they were weighed, and their hearts were carefully dissected. Microscopic sections of the heart were stained with hematoxylin and eosin. It was found that high doses of D‐amphetamine raised the incidence of mortality in the treated pregnant mice up to 40%. The resorption rate in the survivors was high (up to 58%) following the high dose of the drug. Up to 15% of the embryos from the treated groups showed gross malformations, including skeletal and eye malformations and exencephaly. The electrocardiogram (ECG) recordings in most 19‐day‐old embryos from both treated groups showed a pattern with prolonged Q‐T interval (PQT), similar to that of control embryos in the intermediate developmental stages (days 14–16 of gestation). The ECG of control embryos (from day 17 on) resembled that of prenatal fetuses. Microscopically, the hearts of treated embryos showed a large number of undifferentiated cardiac myoblasts. It can be inferred that high doses of D‐amphetamine affect embryonic development generally and delay the histodifferentiation of the myocardium, resulting in incomplete maturation of the cardiac muscles, thus leading to the immature ECG pattern, with PQT intervals.
Effects of protein deficiency on the teratogenicity of cytochalasins in mice
Authors: Singh Jarnail , Hood Ronald D. 
Published: June 2005

AbstractThe developmental toxicity of cytochalasins B (CB) and D (CD) was evaluated in protein‐deprived mice. Pregnant CD‐1 mice were assigned to control (26%), 16%, 8%, or 4% dietary protein groups on gestation day 1 and dosed by gavage with 0 or 1.5 mg/kg CB or CD on gestation day 8 (plug = day 1). They were killed and subjected to teratological examination on day 18. CD, but not CB, increased prenatal mortality but failed to interact significantly with dietary protein level. Fetal weights were decreased in the 4% and 8% dietary protein groups, but cytochalasin treatment did not exacerbate this effect. Cytochalasin treatment was associated with gross fetal malformations, primarily neural tube defects. Although CB and CD did not significantly increase the percentage of grossly malformed fetuses per litter, the data was suggestive of such an effect, and the incidence of affected litters was increased by cytochalasin treatment in all but the 4% protein group. Skeletal defects, such as jaw malformations, rib or sternebrae variations, and unossified skull bones appeared to be increased by both cytochalasin treatment and dietary protein deficiency. The differences from control values were nonsignificant, however, except for some cases of cytochalasin effects on skull ossification. These results show a general lack of effect of protein deprivation on the developmental toxicity of cytochalasins.
Deleterious effects of adrenocorticotrophic hormone administration during late pregnancy upon offspring somatic, neurological, and sexual development in mice
Authors: Harvey P. W. , Chevins P. F. D. 
Published: June 2005

AbstractThe influence of administration of adrenocorticotrophic hormone (ACTH) during days 12–17 of pregnancy upon somatic, neurological, and neuromuscular development of offspring in mice was studied. The effects upon the onset of puberty in female offspring was also examined. Litters from mice given the higher of two doses of ACTH (1 IU/day or 8 IU/day) showed lower body weights at birth and weaning than controls. This treatment also increased pre‐ and postnatal mortality rates, although not significantly. Litters from mice treated with either dose of ACTH showed retarded development of the forelimb and hindlimb grasp reflexes, the body righting reflex, the auditory startle response, and eye opening. Although ear opening was delayed in litters from ACTH‐treated mice, results did not achieve statistical significance. Study of female offspring housed in small groups revealed that one indicator of puberty, vaginal opening, was delayed in female offspring of ACTH‐treated mice. Experiments were conducted to identify factors mediating this syndrome: ACTH did not depress maternal food intake or alter the length of pregnancy, therefore fetal undernutrition or premature birth can be excluded as mediating factors. All litters were fostered to untreated mice to control for postnatal factors influencing development. As ACTH cannot cross the placenta, the syndrome is likely to result from in utero exposure to abnormally high concentrations of glucocorticosteroids of maternal origin. It is concluded that such alterations to the fetal environment can exert a deleterious influence upon somatic, neurological, and sexual development, and that hormones of the maternal pituitary‐adrenocortical axis may naturally act to regulate general development of the fetus.
In vitro teratogenicity of ethylenethiourea in the rat
Authors: Daston George P. , Ebron Marian T. , Carver Brenda , Stefanadis James G. 
Published: June 2005

AbstractWe have demonstrated that ethylenethiourea (ETU) is a potent teratogen to the rat embryo developing in vitro. Sprague Dawley rat embryos were explanted on gestation day 10 and cultured for 48 hours in the presence of 40–200 μg/ml ETU. This resulted in a dose‐related inhibition of growth and differentiation as assessed by crown‐rump length, protein and DNA content, and somite number and in an increase in the frequency of abnormalities. A variety of anomalies was produced, including fluid accumulation in the brain (hydrocephalus), decreased mandibular size, decreased telencephalon size, abnormal dorsiflexion, as well as subectodermal blisters on the tail and limb buds and maxilla. Frank malformations have been observed at these same sites–hydrocephalus, brachygnathia, kyphosis, limb and tail defects, cleft palate–in the term fetus in vivo. The presence of abnormal fluid accumulation in the embryos–distended neural tube and subectodermal blisters–suggested that the osmotic environment of the embryo had been altered by ETU exposure. Osmolality of the exocoelomic fluid (ECF) surrounding the embryo was measured after 48 hours of exposure to a concentration of ETU that caused nearly a 100% incidence of subectodermal blisters. ECF osmolality was found to be significantly lower than that of control embryos. Lowered osmolality would cause water to move out of the ECF, presumably causing the observed fluid accumulation in the embryo. It is speculated that altered osmotic balance and localized edema in the embryo are contributory steps in the formation of defects after ETU exposure.
Cardiac and noncardiac malformations: Observations in a population‐based study
Authors: Ferencz Charlotte , Rubin Judith D. , McCarter Robert J. , Boughman Joann A. , Wilson P. David , Brenner Joel I. , Neill Catherine A. , Perry Lowell W. , Hepner Seymour I. , Downing John W. 
Published: June 2005

AbstractA regional case‐control study of congenital cardiovascular malformations (CCVMs) searches for all live‐born infants in the community in whom the cardiac diagnosis has been confirmed by echocardiography, cardiac catheterization, surgery, or autopsy. Their families are studied in comparison to those of a representative sample of resident live‐born infants. Detailed descriptions of noncardiac abnormalities are obtained from physician reports and maternal interviews expanded by medical record and death certificate data.Among 1,494 cases and 1,572 controls, chromosomal abnormalities, syndromes, heritable disorders, and suspect syndromes occurred with an overwhelming excess in cases (chromosomes, P < 10−4; syndromes/heritable disorders, P < .005). Abnormalities affecting chromosomes 13, 18, and 21 constituted 93% of the cytogenetic defects. Syndromes and heritable disorders were of 39 types. Nonsyndromic abnormalities were three times more frequent in cases than in controls (P < .005). Case excesses occurred for central nervous system malformations, eye disorders, major abdominal wall defects, and abnormalities of the alimentary and urinary tracts. Severe anomalies frequent among cases were those which also occur in certain recognized syndromes, and it is suggested that paired combinations of cardiac and other midline anomalies may represent “formes frustes” of syndromes with similar though variable phenotypic expressions. Cleft lip and palate, inguinal hernia, and lower limb anomalies occurred with equal frequency, suggesting their association with CCVMs by chance alone.
A new method to express embryotoxic data obtained in vitro on whole murine embryos
Authors: Picard J. J. , Van Maele‐Fabry G. 
Published: June 2005

AbstractThis report proposes to express the effect of drugs in the whole embryo culture system by a new method using an intrinsic reference. Percentages of malformed embryos or other defects in development, expressed as percentages of controls, are plotted against concentrations of the drug expressed as percentages of the concentration inducing 50% embryolethality (ELC50). It is suggested that the slope generated by this method is directly related to the intensity of the in vitro teratogenic potential of the agent and allows an estimation of the specific interference with developmental processes. The method has been applied to data obtained from the literature and pertaining to 22 drugs. The slope generated by these drugs varied widely. The effect of these drugs could be meaningfully compared in spite of the wide range of ELC50 displayed by the drugs. In addition, results obtained for two drugs in different laboratories using different methods and species were in fair agreement when they were compared by using the proposed method. Finally, it is suggested that the method provides an improved means to inquire if there is any relevance of in vitro data to teratological results obtained in vivo.
Fate of adriamycin‐induced dilated renal pelvis in the fetal rat: Functional and morphological effects in the offspring
Authors: Kavlock Robert J. , Rehnberg Blair F. , Rogers Ellen H. 
Published: June 2005

AbstractPreviously we reported that gestational exposure to Adriamycin, an anthracycline antibiotic used in the treatment of neoplasms, reduced renal function in the neonatal rat, and we suggested that alterations in the development of the renal papilla might be responsible for the dysfunction. In this study we exposed groups of Sprague‐Dawley rats to 0, 1.0, 1.25, or 1.5 mg/kg of Adriamycin on gestation days 10–12, a period previously shown to be effective in altering postnatal renal function with this compound. Offspring were evaluated at several developmental periods in order to (1) precisely define the morphological status of the urogenital system in Adriamycin‐treated offspring; (2) replicate the finding of a decreased renal concentrating ability in the neonates; (3) determine the transience/permanence of any morphological effect; and (4) correlate any permanent alterations in urogenital morphology with our indicator of neonatal functional competence. Maternal Adriamycin treatment induced alterations in the development of the renal papilla that persisted well into the postnatal life of the offspring. The first appearance of the morphological alteration occurred in the absence of other general indicators of developmental toxicity such as growth retardation. The determination of the ultimate fate and functional consequences of the structural alterations required postnatal evaluations of the renal system. Finally, a relatively simple test of renal function in the neonate proved to be predictive of the permanence of the morphological effect, and the absolute test result showed a strong correlation with the incidence of the morphological effect in the overall population.
Neuronal degeneration caused by ethylenethiourea in neuronal monocell layers in vitro and in fetal rat brain in vivo
Authors: Khera K. S. 
Published: June 2005

AbstractThe monocell layers, containing a mixture of neuronal and non‐neuronal (primarily glial) cells, were obtained by growing cells dissociated from trypsinized fetal brains of 19‐day pregnant rats under optimum conditions. Ethylenethiourea (ETU), at ≥ .5 mM concentrations, caused in monocell layers in vitro a necrosis of neuronal cells and a marked depression in the formation of neurites and fascicles without any noticeable change in the non‐neuronal cells. In the in vivo study, ETU orally administered as a single 30 or 45 mg/kg dose to rats on day 19 of pregnancy was found to induce necrosis of neuroblasts in the fetal CNS after 18 and 24 hours of dosing and a high incidence of hydrocephalus in postnatal pups at both doses. In an in vivo/in vitro experiment, rat fetal brains from 19‐day pregnant dams which had previously been dosed with 80 or 120 mg ETU/kg were trypsinized and then dissociated into a cell suspension in a nutrient medium. The total number of viable cells in the suspension was significantly reduced compared to the number in the control suspension. The test suspension with cell density adjusted to that in the control suspension grew into monocell layers manifesting a marked decreased population of neuronal cells with a concomitantly increased population of non‐neuronal cells. It was concluded that the target of ETU action was most likely the neuronal cells rather than the organization of nervous tissue per se.
Migration and proliferation of primordial germ cells in the rat
Authors: Kemper C. H. , Peters P. W. J. 
Published: June 2005

AbstractInformation about early primordial germ cell (PGC) formation and migration in rats is lacking. In utero developed and in vitro cultivated whole rat embryos were studied on days 10‐‐13 postcoitum (p.c.). The development of the PGCs was investigated in serial sections stained for alkaline phosphatase activity. On postcoital day 10, PGCs were found in the invaginating visceral yolk sac endoderm and at the base of the allantois. At day 11 p.c. PGCs were mostly found in the ventral and lateral gut wall or in the mesenchyme between the gut and the future genital ridges. At day 12 p.c. most of the PGCs (94%) could be localised in the mesenchyme or in the future genital ridges. On postcoital day 13 almost all PGCs had reached the now‐well‐developed genital ridges. Quantitative measurements showed an increase in the number of PGCs from 84 at day 10 p.c. up to 2,768 at day 13 p.c. Only slight differences were found between in vivo and in vitro embryos with respect to the number of PGCs and their developmental pattern. The in vitro culture of whole rat embryos enables the discrimination between the effects of indirect (maternal) and direct action of PGC‐toxic agents.
Ethanol treatment inhibits mesoderm cell spreading in the gastrulating chick embryo
Authors: Sanders E. J. , Cheung E. , Mahmud E. 
Published: June 2005

AbstractGastrulating chick embryos in culture were treated with ethanol solutions, following which the mesoderm cells migrating from the primitive streak were examined by scanning electron microscopy. Morphometric analysis of cell shape showed that mesoderm cells from treated embryos were significantly more rounded and therefore less well spread than controls, and showed fewer filopodial contacts with the overlying basement membrane. This result was only obtainable for cells leading the migration from the primitive streak, since the following cells in the mesodermal mass apparently did not show this difference. The ethanol concentration required to obtain a reliable effect was 5%, while lower concentrations produced highly variable results. The mesoderm cells were also examined for their in vitro responsiveness to ethanol by investigating their adhesiveness and cytoskeleton. No effect was observed on cell‐glass adhesion as judged by interference reflection microscopy using up to 1% ethanol. This concentration did, however, disrupt the actin cytoskeleton of cultured cells when stained with NBD‐phallacidin, but lower concentrations were ineffective. It is concluded that ethanol treatment of cultured embryos has a significant effect on the substratum relationships of some migrating mesoderm cells.