bluuebunny/crossref_metadata_2025_split huggingface dataset:
Oxidative metabolism of aflatoxin B1 by lipoxygenase purified from human term placenta and intrauterine conceptal tissues
Authors: Datta Kaushik , Kulkarni Arun P. 
Published: June 2005

AbstractAflatoxin B1(AFB1) is a teratogen in rodents and may be a human transplacental carcinogen. Although the presence of DNA adducts of AFB1 in the human placentas has been noted, the enzymes(s) responsible for the bioactivation was not identified. In this investigation, the linoleic acid (LA)‐dependent cooxidation of AFB1 catalyzed
by lipoxygenase (LO) purified by Con A affinity chromatography from the term placentas of nonsmokers was studied. HPLC chromatograms detected the presence of 5‐ and 15‐HETE as the major metabolites and 12‐HETE as a minor metabolite upon incubation of arachidonic acid (AA) with affinity purified human term placental LO. These results suggest that a mixture of LO isozymes is present in the affinity‐purified enzyme preparations of term placentas. The optimal assay conditions to observe maximum rate of epoxidation included in cubation of 250 μM AFB1 with 80 μg LO and 3.5 mM LA at pH 7.2 AFB1‐8, 9‐tris‐diol produced in the reaction was estimated spectrofluorimetrically. AVmax of 432 ± 26 pmol of AFB1‐8, 9‐tris diol produced/min/mg protein and a Km of 77 μM for AFB1 were observed. The AFB1‐8,9‐tris‐diol formation was dependent on the incubation time, concentration of enzyme protein, AFB1, and LA. LO catalyzed epoxidation of AFB1 was inhibited by NDGA, BHT, BHA. ETI, and gossypol. The evidence presented here clearly demonstrates that placental LO is capable of epoxidation of AFB1. Similar results were observed with LO preparations of human intrauterine conceptal tissue at 8–10 weeks of gestation. © Wiley‐Liss, Inc.
International study of sex ratio and twinning of neural tube defects
Authors: Källén Bengt , Cocchi Guido , Knudsen Lisbeth B. , Castilla Eduardo E. , Robert Elisabeth , Daltveit Anne Kjersti , Lancaster Paul L. , Mastroiacovo Pierpaolo 
Published: June 2005

AbstractThe goal of this study based, on information collected from eight congenital malformation registry programs around the world, was to analyze sex and twinning of affected infants and fetuses, according to type of neural tube defect (NTD) and other variables The type of defect and its location, whether it occurred in isolated form or was associated with other malformations, population from which data were retrieved, vital status of the infant, and gestational age of the fetus/infant were considered.The material included 3,416 infants and 168 selectively aborted fetuses with anencephaly, 4,830 infants and 76 fetuses with spina bifida, and 1,022 infants and 19 fetuses with encephalocele. Less than 20% of infants with anencephaly or spina bifida and more than one‐third of infants with encephalocele had associated malformations.A female excess was found among all infants with NTD but a male excess in fetuses delivered spontaneously before week 20, indicating selective male late fetal deaths. Sex ratio varied by type of NTD, vital status at birth, presence of associated malformations, and year of birth, with an increasing sex ratio for anencephaly during the 1960s and 1970s. Twinning was positively associated with NTD but the extent of this association varied with NTD type and program, while the distribution by sex type of pair of twin appeared to be similar to that of all births. Twins concordant for anencephaly or encephalocele were mainly found when the defect occurred as part of a syndrome, and only in like‐sexed pairs. Twins concordant for spina bifida had the isolated from of the defect and 5 of 6 pairs were like‐sexed. Thoracic spina bifida has a sex ratio more like anencephaly than lumbosacral spina bifida has, but twinning rate is more similar in anencephaly and lumbosacral than in thoracic spina bifida. © 1994 Wiley‐Liss, Inc.
Elevated midtrimester serum methylmalonic acid levels as a risk factor for neural tube defects
Authors: Adams M. J. , Khoury Muin J. , Scanlon Kelley S. , Stevenson Roger E. , Knight George J. , Haddow James E. , Sylvester Gregg C. , Cheek James E. , Henry Judy P. , Stabler Sally P. , Allen Robert H. 
Published: June 2005

AbstractThe role of folic acid in the primary prevention of neural tube defects (NTDs) is well established. However, questions related to the protective mechanism remain unanswered. To help answer these questions, we designed a case‐control study to assess the role of folate‐and cobalamin‐related metabolites in the pathogenesis of NTDs. Concentrations of folate, cabalamin, and 14 other related metabolites were measured by gas chromatography/mass spectrometry in midtrimester serum specimens from 32 women with an NTD‐affected pregnancy and from 132 control women, and in serum specimens from 46 nonpregnant women who had a history of NTD‐affected pregnancy and from 43 nonpregnant control women. Log‐transformed means of metabolites were compared between case and control women for both the midtrimester and nonpregnant groups. In the pregnant group, serum methylmalonic acid (MMA) concentrations were higher among case women than among control women (130 vs 105 nM). There was a strong dose‐response relationship between midtrimester serum MMA level and the risk for an NTD‐affected pregnancy, with the relative risk increasing 13‐fold for women with MMA levels>90th percentile. In the nonpregnant group, there was no difference in serum MMA levels between case and control women (140 vs 140 nM). Thus, the serum MMA levels of women in the midtrimester of pregnancies unaffected by NTDs were significantly lower than the levels of nonpregnant women, whereas the levels of women whose pregnancies were affected by NTDs were similar to those of nonpregnant women. The finding of elevated MMA serum concentrations among women in the midtrimester of NTD‐affected pregnancies suggests that cobalamin may be involved in the etiology of NTDs. The possible role of cobalamin in relation to the protective effect of folic acid needs further evaluation. © 1995 Wiley‐Liss, Inc. This article is a US Government work and, as such, is in the public domain in the United States of America
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Effects of prenatal alcohol exposure on the postnatal morphology of the rat oculomotor nucleus
Authors: Burrows R. C. , Shetty A. K. , Phillips D. E. 
Published: June 2005

AbstractMorphological development of the rat oculomotor nucleus was investigated on postnatal day 15 following a prenatal ethanol exposure. Analysis of toluidine blue stained plastic sections showed that the prenatal alcohol exposure caused a decrease in the density of neurons and an increase in the density of astrocytes in the center of the nucleus. There was an alcohol–induced reduction in the overall size of the cross‐sectional region of the oculomotor nucleus, but no effect on the number of neurons per unit area of that total oculomotor region, indicating a delay or alteration of the migration of neurons to their normal clustered position in the center of the nucleus. The areas of the neuronal cell nucleus and nucleolus were not affected by the alcohol exposure. Analysis of Golgi‐Cox‐impregnated multipolar neurons showed that the alcohol exposure caused a reduction in area of the cell soma; a reduction in the number of dendritic branches; and a reduction in the complexity of the dendritic arbor relative to distance from the soma, based on concentric ring analysis. The results of this study demonstrate that gestational alcohol exposure can retard the maturation of the oculomotor nucleus.© 1995 Wiley‐Liss, Inc.
Teratogen update: Ergot and ergotamine
Authors: Raymond Gerald V. 
Published: June 2005

AbstractErgotamine is a purified ergot alkaloid that has been suspected of being teratogenicAnimal data have shown effects mainly at doses toxic to the mother. Clinical reports in humans have been anecdotal, but in many the malformations are consistent with vascular injury. However, epidemiologic studies have not shown any clear increase in malformations among exposed infants. This may reflect the limited exposure and toxicity when used episodically. Ergot toxicity which can result in severe vasospasm does not spare the fetus or mother and ergotamine should not be considered without risk. Ergotamine should be avoided in pregnancy, and the counselling of the woman with an exposed fetus should focus on possible toxic exposure. © 1995 WiIey‐Liss, Inc.
Teratogenicity of low doses of all‐trans retinoic acid in presomite mouse embryos
Authors: Sulik Kathleen K. , Dehart Deborah B. , Rogers John M. , Chernoff Neil 
Published: June 2005

AbstractThis study was designed to examine the developmental dose response for all‐trans retinoic acid (TRA) administered at presomite stages in mouse embryos. Previous studies using hamsters [Shenefelt (1972) Teratology5: 103‐118] have shown that developmental stages corresponding to those present early on gestational day (GD) 7 in mice are most sensitive to retinoid‐induced teratogenesis. Our preliminary studies showed that at this treatment time, gavage dosages of 7. 5 mg/kg maternal body weight administered to C57B1/6N mice, an inbred strain, resulted in severe craniofacial malformations representing the holoprosencephaly, aprosencephaly spectrum. Additionally, in an outbred mouse strain, CD‐1, exencephaly was induced by dosages of 2. 5 mg/kg TRA and above. Readily detectable abnormalities of the eyes, including anophthalmia and severe microphthalmia and iridial colobomata, were induced by even lower doses of TRA in the C57B1/6N strain. Incidences of micro/anophthalmia were 6. 7%, 8. 1%, 12. 9% and 32. 4% at 0, 0. 313, 0. 625, and 1. 25 mg/kg, respectively. The dosages required to induce significant incidences of exencephaly (2. 5 mg/kg) and severe ocular abnormalities (125 mg/kg) on GD 7 in mice are approximately 50‐100‐fold less than those that are commonly used to examine the teratogenicity of this compound at later developmental stages in this species. The trend toward an increase in the incidence of severe ocular malformations at the lowest dose examined and the fact that subtle ocular malformations were not taken into account for this study suggest that even lower dosages may be effective. Practical implications of this study include (1) the obvious need to conduct threshold dose determination studies at the most sensitive developmental stage in a sensitive strain/species, and (2) the need for careful surveillance of human populations for brain and ocular malformations (not necessarily those falling within the realm of retinoic acid embryopathy) following retinoid exposure during early stages of pregnancy. © 1995 Wiley‐Liss, Inc.
Teratogen update: Carcinogenesis and teratogenesis associated with exposure to diethylstilbestrol (DES) in utero
Authors: Mittendorf Robert 
Published: June 2005

AbstractExposure of the human of the fetus to physician‐prescribed diethylstilbestrol and other synthetic estrogens (collectively referred to as “DES”) led to an important iatrogenic epidemic In the United States alone, at least four million fetuses and their mother had a substantial exposed these estrogens now known to be mild carcinogens and potent teratogens. Mothers exposed to DES may have a somewhat higher risk of breast cancer than women who were not exposed. The sequelae of in utero exposure of daughters include clear cell adenocarcinoma of the vagina and cervix, various gross anomalies of the genital tract that are associated with adverse outcomes of pregnancy, vaginal adenosis and other vaginal epithelial changes, and other possible health effects that have not yet been fully evaluated. Among sons exposed in utero to DES, no increase in the incidence of any cancer has been reported, but several anomalies of the genital tract have been described, and it is possible that some social behaviors are modified Although the grandchildren of the DES‐exposed daughters and sons have not been shown to have any abnormalities, some of them have been the products of short gestations. Future research, being funded by the National Cancer Institute, will permit monitoring of the DES‐exposed population to dertermine whether any other abnormalities will become apparent in them. © 1995 Wiley‐Liss, Inc.
Genetically determined absence of an initiation site of cranial neural tube closure is causally related to exencephaly in SELH/Bc mouse embryos
Authors: Gunn T. M. , Juriloff D. M. , Harris M. J. 
Published: June 2005

AbstractThe SELH/Bc mouse strain (SELH) has a high frequency of the lethal neural tube closure defect, exencephaly, in newborns and embryos. Previous work has shown that all SELH mouse embryos have an abnormal mechanism of rostral neural tube closure. They lack initiation of contact and fusion of the cranial neural tube at the prosencephalon/mesencephalon boundary (Closure 2), and undergo closure by extension of a more rostral site of fusion. This process fails in 10‐20% of embryos, where the mesencephalic folds remain unelevated, resulting in exencephaly. Previous work has also shown that the cause of liability to exencephaly in SELH mice is multigenic, involving a small number of loci.The purpose of the present study was to test the hypothesis that the genes causing the lack of Closure 2 also cause the liability to exencephaly in SELH, by observation of their joint transmission from genetically segregating animals. A concurrent mapping study provided the necessary genetic material, a segregating F2 generation from a cross of SELH with the normal LM/Bc strain. The genetic liability to exencephaly transmitted by individual F2 sires had been measured by the frequencies of exencephalic day 14 embryos they produced in testcrosses with SELH females. A selected subset of 13 of these test‐crossed F2 sires was bred with a second set of SELH females, and the embryos were examined earlier, during the period of neural tube closure, on days 8 and 9 of gestation, to determine the presence of Closure 2. Six F2 sires were among the highest exencephaly producers (6‐11%), six were among the lowest (0%), and one was intermediate (5%). Among embryos at the appropriate stage for scoring, the presence of Closure 2 was observed to be inversely correlated with the later risk of exencephaly, being present in 93% (71/76) from the low‐risk sires and 35% (36/103) from the high‐risk sires. In each case, the remaining embryos had a closure mechanism like that of SELH embryos. Among the individual intermediate‐ and high‐risk sires, there was also a clear correlation between the frequency of exencephaly in older embryos and the frequency of lack of Closure 2 in early embryos (rs=0.88; P<0.05). this study demonstrates that high liability to exencephaly and absence of Closure 2 are genetically transmitted together. That is, the cause of the lack of Closure 2 in SELH mice is shown to be also the probable cause of the high liability to exencephaly. © 1995 Wiley‐Liss, Inc.
Developmental toxicity of mangafodipir trisodium and manganese chloride in Sprague‐Dawley rats
Authors: Treinen Kimberley A. , Gray Tim J. B. , Blazak William F. 
Published: June 2005

AbstractMangafodipir trisodium (MnDPDP) is a manganese chelate being developed as a contrast agent for magnetic resonance imaging of the hepatobiliary system. The intended clinical dose is 5 μmol/kg. The potential for MnDPDP to induce embryotoxicity and/or teratogenicity in Sprague‐Dawley rats was investigated. Twenty five inseminated rats/group were intravenously administered 0, 2, 5, or 20 μmol/kg MnDPDP form days 6‐17 of gestation. Maternal toxicity was not observed at any dose of MnDPDP. There were no treatment‐related effects on the numbers of fetuse, fetal viability, numbers of resorptions, implantations and corpora lutea, or the percent of pre‐ and post‐implantation losses. However, at 20 μmol/kg, fetal body weights were significantly decreased (3.3 g vs. 3.9 g for control) and increased skeletal malformations were observed (141/270 vs. 0/285 in control). The malformations were of a specific type, which included. angulated or irregularly shaped clavicle, femur, fibula, humerus, ilium, radius, scapula, tibia, and/or ulna. To better define the developmental stage that is most susceptible to the effects of MnDPDP, a segmented developmental study was conducted. Twelve inseminated rats were administered 0, 20, 40, or 80 μmol/kg MnDPDP on days 6‐8, 9‐11, 12‐14, or 15‐17 of gestation. Skeletal malformations, identical to those seen in the previous study, were increased in adose‐dependent manner with the highest incidence occurring in fetuses from females dosed from days 15‐17 of gestation. A third study, in which 15 rats/group were dosed intravenously with 0, 5, 20, or 40 μmol/kg MnCl2 on days 6‐17 of gestation, produced indentical skeletal malformations to those seen with MnDPDP, indicating that manganese is the active moiety responsible for these specific malformations. © 1995 Wiley‐Liss, Inc.
Pantothenic acid decreases valproic acid‐induced neural tube defects in mice (I)
Authors: Sato Masako , Shirota Mariko , Nagao Tetsuji 
Published: June 2005

AbstractThe effect of the administration of pantothenic acid (PTA) on valproic acid (VPA)‐induced teratogenesis was examined in ICR mice. VPA (300, 400, and 500 mg/kg, s.c.) or PTA (3 × 10,3 × 100, and 3 × 300 mg/kg, i.p.) was injected on day 8.5 of gestation (plug day = day 0.5). Exencephaly was induced dose dependently by single injections of VPA. three administrations of PTA alone at any dose levels showed neither embryocidal nor teratogenic effects. In combined treatment experiements, PTA (3 × 300 mg/kg) was injected 1 hr before, immediately before, and 1 hr after VPA administration. PTA significantly reduced VPA‐induced exencephaly, while none of the other external malformations such as open eyelid or skeletal malformations such as fused, absent, or bifurcated ribs and fused thoracic vertebrae and fused sternebrae were reduced. The results suggest that PTA reduces the incidence of neural tube defect induced by VPA in mice. © 1995 Wiley‐Liss, Inc.
Zinc deficiency causes apoptosis but not cell cycle alterations in organogenesis‐stage rat embryos: Effect of varying duration of deficiency
Authors: Rogers John M. , Taubeneck Marie Weldon , Daston George P. , Sulik Kathleen K. , Zucker Robert M. , Elstein Kenneth H. , Jankowski Margaret A. , Keen Carl L. 
Published: June 2005

AbstractZinc deficiency is teratogenic in all species in which it has been examined. Zinc is an essential component of enzymes involved in DNA synthesis and cell proliferation, and may play an as yet undetermined role in apoptosis. To further our understanding of the role of zinc in normal development, we examined cell death and cell cycle parameters in embryos of pregnant rats fed a zinc‐deficient diet for 2 to 10 days (0.5 μg zinc/g diet; zinc‐adequate diet was 25 μg zinc/g). To elucidate sensitive periods of development and susceptible cell populations, dams were fed the zincdeficient diet from gestation day 1, 3, 7, or 9 and killed on day 11. Embryos were examined for morphology and developmental stage. From each litter, 2–3 embryos were stained with Nile blue sulfate (NBS) to visualize cell death, 3 embryos were frozen for flow cytometric cell cycle analysis and cell counts, and selected embryos were preserved for histological examination. Dams fed the zinc‐deficient diet for more than 3 days reduced their food intake through gestation day 8 but increased food intake on day 9. Maternal plasma zinc dropped to 10–25% of control levels in the zinc‐deficient groups. Zinc deficiency from gestation day 1 or 3 resulted in two categories of affected litters on day 11. One category had embryos which were morphologically normal but displayed extensive NBS staining in the visceral arches, neural tube, and somites. The second category had developmentally retarded or maldeveloped embryos which showed little NBS staining. Zinc deficiency from gestation day 7 produced cell death in the posterior dorsal midline in the area of premigratory neural crest cells, which was confirmed by histological examination. Zinc deficiency from gestation day 9 did not affect morphology or NBS staining. Percentages of cells in the G0/G1, S, and G2M phases of the cell cycle on gestation day 11, determined by flow cytometry, were similar to controls in all groups. This study shows tht as few as 4 days of maternal zinc deficiency can produce excess embryonal cell death, and that neural crest cells may be particularly sensitive. © 1995 Wiley‐Liss, Inc.
Studies of mitochondria in oxidative embryotoxicity
Authors: Fantel Alan G. , Person Richard E. , Tumbic Ruslan W. , Nguyen Tien‐Dat , Mackler Bruce 
Published: June 2005

AbstractWhile the limb bud and brain of the rat develop abnormally in response to transient uteroplacental hypoperfusion during late gestation, the heart appears to be protected. These malformations have been associated with the generation of reactive oxygen species (ROS). Studies were designed to examine superoxide generation by mitochondrial electron transport particles (ETP) from adult and conceptal tissues and to investigate characteristics that could be responsible for heightened concentrations of ROS in sensitive tissues. Parameters investigated included NADH oxidase and cytochrome c oxidase activities, cytochrome content, and superoxide dismutase activity.NADH oxidase activities were significantly lower in sensitive tissues that also developed the highest concentrations of superoxide. Because ETP from adult CNS also had low NADH oxidase activity but did not show increased concentrations of superoxide, inhibition of electron transport did not adequately account for increased ROS concentrations. The reduced NADH oxidase activity of sensitive tissues could not be caused by inhibition at the cytochrome c oxidase region since this latter activity equaled or exceeded the former in all instances. No significant differences were found in the cytochrome contents of different tissues. There was significantly less superoxide dismutase activity in homogenates prepared from either of the two sensitive conceptal tissues compared with those from insensitive conceptal or adult tissues.These studies confirm the presence of heightened concentrations of superoxide anion radical in ETP from teratogenically sensitive tissues and suggest that these concentrations may result primarily from decreased activity of superoxide dismutase(s) in those tissues. Superoxide anion radical could therefore be available to participate in the generation of the more toxic oxidant species such as the hydroxyl radical. © 1995 Wiley‐Liss, Inc.
Arnold‐Chiari‐like malformation associated with a valproate model of spina bifida in the rat
Authors: Briner Wayne , Lieske Ryan 
Published: June 2005

AbstractThe brains of rat fetuses exposed to saline and valproic acid (VA: 600 mg/kg or 1,200 mg/kg) at 10 days of gestation were examined for structural changes similar to that seen for the Arnold‐Chiari malformation (ACM) in humans. Only fetuses exposed to the 1,200‐mg/kg level VA demonstrated spina bifida (SB) type widening of the vertebral arch when compared to saline treated animals. When compared to controls, both 600‐and 1,200‐mg/kg VA animals demonstrated microencephaly. The brains of treated animals demonstrated alterations in their angular morphology such that the cerebellum was displaced toward the foramen magnum in a manner akin to human ACM. These findings indicate that valproate‐induced SB in the rat more closely approximates SB in humans than was previously appreciated and provides a model for experimental study of both SB and ACM. © 1995 Wiley‐Liss, Inc.