bluuebunny/crossref_metadata_2025_split huggingface dataset:
Role of oxygen free radicals in cocaine‐induced vascular disruption in mice
Authors: Zimmerman Ernest F. , Potturi Raju B. , Resnick Elisabeth , Fisher J. Edward 
Published: June 2005

AbstractTo test the hypothesis that cocaine‐induced embryonic vascular disruption is mediated by oxygen free radicals, the antioxidants 2‐oxothiazolodine‐4‐carboxylate (OTC) and α‐phenyl‐N‐t‐butylnitrone (PBN) were employed. When cocaine (78 mg/kg) was administered on day 8 of gestation to ICR mice and embryos evaluated on day 10 (in vivo), 62.3% of cocainetreated embryos showed increased vasodilation compared to 4.9% for controls, and 33.1% of the cocaine‐exposed embryos showed marked hemorrhage compared to 3.3% for controls. In addition, cocaine increased the incidence of neural defects, in the form of open neural tube, hypoplastic prosencephalon, and microcephaly. Administration of OTC (0.25 and 0.5 mmol/kg) or PBN (300 mg/kg) prior to cocaine significantly reduced cocaine‐induced vasodilation and hemorrhage, while not preventing neural defects. When cocaine (78 mg/kg) was administered in vivo on day 8 of gestation and embryos were dissected 15 min later and subsequently cultured for 48 hr in the absence of cocaine (in vivo‐in vitro), marked vascular disruption was observed: normal yolk circulation/heartbeat was decreased to 26.6%, while edema/blisters and vasodilation/hemorrhorage were increased to 45.6% and 59.6%, respectively. Administration of PBN (300 mg/kg) prior to cocaine completely prevented cocaine‐induced vascular disruption. When cocaine was administered in vivo and PBN (300 μg/ml) was incubated with cultured embryos in vitro, the antioxidant only partially prevented cocaine‐induced cardiovascular defects in this model. Neural defects produced by cocaine were not significantly affected by PBN, administered either in vivo or in vitro. Cocaine (78 mg/kg) administered in vivo stimulated lipid peroxidation maximally after 3 hr in both day 8 and day 9 embryos. When cocaine was incubated in vitro during embryo culture at 33 μg/ml), a concentration that produces nonspecific inhibition of growth and development, embryonic lipid peroxidation on day 9 was not affected. Finally, when PBN (300 mg/kg) was administered prior to cocaine (78 mg/kg) on day 8 of gestation, stimulation of lipid peroxidation by cocaine was prevented. These results suggest that cocaine‐induced vascular disruption in early development is mediated by maternal production of oxygen free radicals. © 1994 Wiley‐Liss, Inc.
Anticonvulsant teratogenesis: I. A study design for newborn infants
Authors: Holmes Lewis B. , Harvey Elizabeth A. , Brown Kelly Sue , Hayes Ailish M. , Khoshbin Shahram 
Published: June 2005

AbstractThe basis for the apparent teratogenicity of maternal epilepsy is controversial. Is the critical factor the anticonvulsant drugs taken by the pregnant woman, or the genes which cause the mother's epilepsy? We describe a study design developed to assess these competing theories in a cohort study of newborn infants. We show the feasibility of ascertaining exposed and unexposed infants at several birthing hospitals in one urban area. Between 1986 and 1988, we identified 180 drug‐exposed and 218 epilepsy‐history infants among 49,403 infants. The rate of exposure to seizure medication was 0.36% and of maternal history of epilepsy was 0.44%. A significant number of infants could not be evaluated because they were missed, ineligible, or either the doctor, nurse or parent refused to participate. Overall, there was a significant increase in major malformations, microcephaly or growth retardation among the drug‐exposed infants in comparison to both the epilepsy‐history and the unexposed infants. The types of epilepsy and the apparent etiology were the same among women who took anticonvulsants and women with a history of epilepsy but no anticonvulsants during pregnancy. This study must be extended to include a sufficient number of infants exposed to each commonly used drug as mono‐therapy to allow for a comparison of the effect of each drug on pregnancy outcomes; to provide a comparison of infants whose mothers had a strong family history of epilepsy with infants whose mothers had trauma‐induced epilepsy; and to assess the possible impact of the severity of the mothers' disease on the infants. © 1994 Wiley‐Liss, Inc.
Reversed circulation in acardiac fetuses is associated with anatomic inversions in the aortic wall
Authors: Park Hyoung W. , Kapur Raj P. , Shepard Thomas H. 
Published: June 2005

AbstractBlood vessel anatomy is probably related to hemodynamic factors which change during development. This principle has been postulated as the basis for differences in the numbers of elastic lamellae in the tunica media of the proximal and distal human aorta. Recent studies of human fetuses at varying stages confirmed that the number of elastin lamellae in the aortic wall varied along its length (spatially) and with age (temporally). These findings suggest that hemodynamic influences during prenatal development induce structural changes in the aortic wall. Acardiac fetuses provide a model for studying the effects of hemodynamic changes on the structure of elastic arteries because blood flow through the aorta in such fetuses is reversed and greatly reduced. Also, analysis of the vascular structure of acardiac fetuses would further define the characteristic features of this congenital disorder. In the present study, we have examined the gross and histological anatomy of the aorta from seven acardiac fetuses. In each case, the microscopic architecture of the aorta was deranged and the normal proximaldistal differences in arterial caliber and number of elastin lamellae were reversed. In the proximal aorta, medial lamellar units were thin, fragmented, and irregular. In some segments, only traces of medial lamellar units existed. We believe that these anatomic abnormalities represent degenerative or dysplastic responses to reversed flow and pressure gradients in the aorta. These findings are consistent with the hypothesis that aortic wall structure is influenced by hemodynamic factors during development. © 1994 Wiley‐Liss, Inc.
Methanol‐induced neural tube defects in mice: Pathogenesis during neurulation
Authors: Bolon Brad , Welsch Frank , Morgan Kevin T. 
Published: June 2005

AbstractA spectrum of cephalic neural tube defects was observed in near‐term (gestation day [GD] 17) mouse fetuses following maternal inhalation of methanol at a high concentration (15,000 ppm) for 6 hr/day during neurulation (GD 7–9). Dysraphism, chiefly exencephaly, occurred in 15% of fetuses, usually in association with reduction or absence of multiple bones in the craniofacial skeleton and ocular anomalies (prematurely open eyelids, cataracts, retinal folds). Measurements of cerebrocortical width in grossly normal, methanol‐exposed fetuses revealed significant semiquantitative differences in the thicknesses of the frontal cortex and its constituent layers (neuroepithelium, intermediate cortex/subventricular plate, and cortical layer 1) as well as apparent increases in subventricular plate cellularity relative to controls. Subsequently, the early morphogenesis of these neural changes was investigated in neurulating mouse embryos to define tissue‐specific patterns of methanol‐induced damage that lead to cephalic axial dysraphism. Following daily 6‐hr maternal inhalations of 15,000 ppm methanol during GD 7–8, the cephalic neural fold margins were swollen, blunted, and poorly elevated on GD 8.5 and 9 relative to controls. Histopathology of exposed GD 8.5 embryos revealed microcephaly in association with reductions in the cell density and mitotic index of at least 47% in the cranial mesoderm. The mitotic index in the embryonic neuroepithelium was also reduced by 55%, and groups of neural crest cells were displaced to the neural folds dorsal to the foregut (relative to the more ventral location in the facial regions of control embryos). When examined on GD 9.5 and 10.5, maternal methanol exposure (15,000 ppm for 6 hr/day) during GD 7–9 resulted in stunting, delayed rotation, and microcephaly in over 90% of the affected embryos. Persistent patency of the anterior neuropore and prosencephalic hypoplasia were seen in >40% and up to 90% of embryos, respectively. Shallow optic vesicles, stunted branchial arches, scoliosis, and hydropericardium were also observed. Many 10.5‐day‐old embryos were edematous. Occult dysraphism, recognized grossly by abnormally narrow cephalic conformation and histopathologically by the absence of mesoderm in the mesencephalon, was present in at least 21% of methanol‐exposed embryos on GD 9.5 and 10.5. Nile blue vital dye staining of methanol‐exposed embryos revealed no difference in dye accumulation between control and treated embryos on GD 8.5, 9.0, or 9.5. There were no apparent dysmorphogenic effects in control embryos at any stage of development. These data suggest 1) that exposure to a high concentration of methanol injures multiple stem cell populations in the neurulating mouse embryo and 2) that significant neural pathology may remain in older conceptuses even in the absence of gross lesions. © 1994 Wiley‐Liss, Inc.
Role of apoptosis in mediating phosphoramide mustard‐induced rat embryo malformations in vitro
Authors: Chen Beiyun , Cyr Daniel G. , Hales Barbara F. 
Published: June 2005

AbstractPhosphoramide mustard, an active metabolite of the anticancer drug cyclo‐phosphamide, causes malformations in rat embryos undergoing organogenesis in vitro. The purpose of the present study was to investigate the hypothesis that apoptosis plays an important role in mediating the teratogenicity of phosphoramide mustard. Apoptosis is a process of active or programmed cell death which is characterized by internucleosomal DNA fragmentation and de novo RNA and protein synthesis. Sulphated glycoprotein‐2 (SGP‐2) or clusterin is induced in some models of apoptosis and is one of the proteins likely to be involved in the maintenance of cell integrity. In the present study, day 10 rat embryos were cultured for 6, 12, 24, and 45 hr, with or without the addition of 10 μM phosphoramide mustard. After culture for 24 or 45 hr with exposure to 10μM phosphoramide mustard, the embryos were both growth‐retarded and malformed. Exposure to phosphoramide mustard for 6 or 12 hr did not significantly alter the relative amounts of either the mRNA or protein for SGP‐2; this treatment also had no effect on DNA fragmentation in embryos or their yolk sacs. After 24 hr in culture, the relative amounts of SGP‐2 protein, but not mRNA, were increased 2‐fold in the yolk sacs of the phosphoramide mustard‐exposed embryos, but not in the embryos themselves. At this time, DNA fragmentation was detected in phosphoramide mustard‐exposed embryos, but not in their yolk sacs or in control embryos. After 45 hr in culture, SGP‐2 protein and mRNA levels were increased 2–4‐fold above the controls in the phosphoramide mustard‐exposed embryos and their yolk sacs. Immunohistochemical analysis revealed that in control embryos cultured for 45 hr, the SGP‐2 reaction product was localized in the heart, hindgut, and yolk sac. In contrast, in phosphoramide mustard‐treated embryos cultured for 45 hr, SGP‐2 immunostaining was found throughout the embryo, with a strong immunoreaction in the mesenchyme and ectoplacental cone. DNA fragmentation in the embryos exposed to phosphoramide mustard for 45 hr was more extensive than that found after 24 hr, but fragmentation was still not detected in the yolk sac. Thus exposure in vitro to a teratogenic concentration of phosphoramide mustard resulted in DNA fragmentation and an increased expression of SGP‐2 in the embryo. These data suggest that apoptosis is involved in mediating the teratogenicity of phosphormide mustard. © 1994 Wiley‐Liss, Inc.
A population‐based study of gastroschisis: Demographic, pregnancy, and lifestyle risk factors
Authors: Torfs Claudine P. , Velie Ellen M. , Oechsli Frank W. , Bateson Thomas F. , Curry Cynthia J. R. 
Published: June 2005

AbstractGastroschisis, an abdominal wall defect, most often occurs in infants of young mothers. To identify risk factors for gastroschisis, we conducted a case‐control study in the population surveyed by the California Birth Defects Monitoring Program (CBDMP). From structured questionnaire data, we compared sociodemographic, reproductive, and lifestyle factors for 110 mothers of infant with gastroschisis with those for 220 agematched mother of normal infants. Univariate matched‐pair analysis showed significant association of gastroschisis with mother's education, yearly family income, marital status, a history of mother's mother smoking, mothers fathers absence from home during the mother's youth, more than one elective abortion, a short interval between menarche and first pregnancy, siblings from different fathers, and use of either a recreational drug (either cocaine, amphetamine, marijuana, or lsd), alcohol, or tobacco during the trimester preceding pregnancy. For cocaine, amphetamine, and marijuana, use of more than one drug showed a stronger association than single drug use. The association was stronger if both parents used drugs. Although many variables were correlated, odds ratios (OR) were significant (95% confidence intervals) in multivariate conditional logistic analysis for; yearly family income <$10,000[OR = 4.34(1.54, 12.22)]or $10,000‐$49,999 [OR = 3.93(1.43, 10.80)]; mother's smoking status not known [OR = 3.99(1.66, 9.56)]; mother's fathers absence from home during her youth [OR = 3.11(1.14,8.46)]; and drug use by mother [OR = 2.21,(1.21, 4.03)], father [OR = [1.66(1.02, 2.69)], or both [OR = 3.05(1.48, 6.28)]. The best predictive model explained 32% of the deviance. Young, socially disadvantaged women with a history of substance use were at highest risk for a child with a gastroschisis. © 1994 Wiley‐Liss, Inc.
Development of the cerebellar defect in ataxic SELH/Bc mice
Authors: Harris M. J. , Juriloff D. M. , Gunn T. M. , Miller J. E. 
Published: June 2005

AbstractIn SELH/Bc mice, 5–10% of young adult are ataxic, due to a midline cleft in the cerebellum. An additional 10–20% of SELH/Bc embryos have exencephaly and die at birth. All SELH/Bc embryos omit a normal step in cranial neural tube closure, initiation of fusion at Closure 2. In the 80–90% that complete cranial neural tube closure, the last region of the closure, on late D9, is the region of prospective cerebellum, and its closure is late. We postulated that the cleft cerebellum in ataxic SELH/Bc mice derives from this delay in neural tube closure and predicted that we would see evidence of a cerebellar midline cleft in all earlier stages after cranial neural tube closure in normally complete.In the present study we show that cerebellum in cleft in a 7–9% proportion of SELH/Bc D16 fetuses (2/28) and D11 embryos (15/167), and that the defect is detectable on D10. In these abnormal D16 fetuses, D11and D10 embryos, there is gap in midline continuity of cerebellar neuroepithelium, a finding consistent with our hypothesis that the neuroepithelium in this region fails to complete fusion in those embryos. We also show that cerebella of adult SELH/Bc ataxic mice have no obvious deficiency of lobules, or disorganization of tissue as in the Wnt−1 mutants. © 1994 Wiley‐Liss, Inc.
Anticonvulsant teratogenesis: 2. Statistical methods for multiple birth outcomes
Authors: Legler Julie M. , Ryan Louise M. , Harvey Elizabeth A. , Holmes Lewis B. 
Published: June 2005

AbstractThe purpose of this paper is to demonstrate the application of generalized estimating equations to assess an exposure effect using multiple birth outcomes. This multivariate approach provides the flexibility of regression modeling and improved power, as compared to series of univariate analyses or collapsing the multiple endpoints to a single indicator of affectedness. Motivating the discussion will be a large cohort study designed to assess the effects of anticonvulsant medications on a variety of birth outcomes, including major malformations, and growth and weight parameters, as well as a broad spectrum of minor physical anomalies. Because the study is still in progress, the aim here is not to present a definitive analysis, but to present and describe the application of these recently developed statistical methods to analyze studies with multiple outcomes. For simplicity, we will focus on the control and drug‐exposed groups only from that study (ignoring the seizure history group), and we will concentrate on an analysis of minor physical anomalies. © 1994 Wiley‐Liss, Inc.
Pathogenetic changes in the lung bud of mutant rats with heritable pulmonary lobation anomalies
Authors: Aoyama Hiroaki , Fujii Sakiko , Hojo Hitoshi , Teramoto Shoji 
Published: June 2005

AbstractThe present study aimed at investigating pathogenesis of pulmonary lobation anomalies in fpl/fpl mutant rats. Day 12–15 embryos were first examined for pulmonary lobation. Lung serial sections were then made and examined for bronchial branching and distribution of extracellular matrices (ECMs). The lung buds of both fpl/fpl embryos and their phenotypically normal fpl/+ littermates were formed as bilateral protrusion of the foregut on gestation day 12. In fpl/+ embryos, three processes appeared on the right lung bud on day 13, and fissures were completely formed by day 14. In fpl/fpl embryos, the right lung bud had no clear process on gestation day 13, and fissures were not formed on day 14 and thereafter, with the exception of incomplete separation between the cranial and middle lobes. Histological observation revealed that the right main bronchial bud of fpl/+ embryos ramified all lobar bronchial buds by gestation day 13. ECMs, a borderline between endodermal bronchial buds and surrounding mesenchyme, disappeared at the distal end of each lobar bronchial bud. By contrast, in fpl/fpl embryos, the right main bronchial bud did not ramify the middle and intermediate lobar bronchial buds at its lateral and ventral portions, but swelled on gestation day 13. It was covered with ECMs at the lateral side but not at the ventral region, from which the middle and intermediate lobar bronchial buds arose on gestation day 14. These observations suggest that altered distribution of ECMs causes branching abnormalities of the lobar bronchial buds and subsequent lobation anomalies in fpl/fpl embryos. © 1994 Wiley‐Liss, Inc.
12‐O‐tetradecanoyl‐phorbol‐13‐acetate‐induced rat embryo malformations in vitro are associated with an increased relative abundance of embryonic E‐cadherin mRNA
Authors: Chen Beiyun , Hales Barbara F. 
Published: June 2005

AbstractEpithelial‐cadherin (E‐cadherin) is a member of a family of Ca2+‐dependent cell adhesion molecules which are localized in zonulae adherens and play an important role during development. E‐cadherin is abundant in rat embryos and their yolk sacs during organogenesis. The phorbol ester, 12‐O‐tetradecanoyl‐phorbol‐13‐acetate (TPA), has been reported to disrupt the morphology and functional development of the rat embryonic visceral yolk sac. The present study investigated the possibility that the effect of TPA on yolk sac development may be due to the altered expression of E‐cadherin. Rat embryos, with their yolk sacs intact, were cultured on day 10 of gestation for 1 hr. At this time the vehicle, dimethyl sulfoxide (DMSO), or TPA (at different concentration) was added to the culture medium; the cultures were continued for up to 24 hr. Embryos and yolk sacs were collected separately at the end of each culture period. The relative abundances of E‐cadherin mRNA and protein were analyzed with Northern and Western blot analyses. Despite the TPA‐induced abnormalities in yolk sac development, the relative abundance of E‐cadherin mRNA or protein in the yolk sac was not altered by TPA exposure. However, in embryos exposed to dysmorphogenic concentration of TPA, the relative abundance of E‐cadherin mRNA was significantly increased after 24 hr in culture, compared to either controls or embryos exposed to non‐dysmorphogenic concentration of TPA. The magnitude of the increase in embryonic E‐cadherin mRNA appeared to correlate with the severity of the embryo malformations. Interestingly, despite this increase in embryonic E‐cadherin mRNA abundance, no increase in E‐cadherin protein concentrations was found in the embryo. The timing of the increased relative abundance of E‐cadherin mRNA in TPA‐exposed malformed would suggest an indirect relationship with the embryo malformations observed. Activation of protein kinase C is likely to be involved in both the embryotoxic effects of TPA and the induction of increased concentrations of E‐cadherin mRNA in the embryo since 4α‐phorbol‐12,13‐didecanoate (4α‐PDD), a phorbol ester analog which does not activate protein kinase C, had no effect. This study demonstrates that TPA‐induced embryo malformations are associated with an increased abundance of E‐cadherin mRNA in the embryo, but not in the yolk sac, and that these action of TPA depend on the activation of protein kinase C. © 1994 Wiley‐Liss, Inc.
Prevention of neural tube defects by and toxicity of L‐homocysteine in cultured postimplantation rat embryos
Authors: Vanaerts Leon A. G. J. M. , Blom Henk J. , Deabreu Ronney A. , Trijbels Frans J. M. , Eskes Tom K. A. B. , Peereboom‐Stegeman Jenny H. J. Copius , Noordhoek Jan 
Published: June 2005

AbstractMild hyperhomocysteinemia is frequently observed in mothers who gave birth to a child with a neural tube defect (NTD). In a previous study we showed L‐homocysteine was embryotoxic to gestational day 10 (GD 10) rat embryos in culture, however, no NTDs were observed. We therefore investigated the effect of L‐homocysteine on the development of neural plate stage (GD9. 5) rat embryos. Other objectives of this study were investigation into whether the embryotoxicity of L‐homocysteine could be attenuated by compounds related to its metabolism and clarification of the mechanism of L‐homocysteine embryotoxicity. In GD9. 5 rat embryos L‐homocysteine was not toxic at 1‐ and 2‐mM concentrations. Rather at these concentrations it promoted development of the rat embryos in serum that without supplementation caused NTDs in the embryos. L‐Methionine had the same preventive effect at even lower concentrations, but folinic acid (1mM) did not improve embryonic development. N5‐Methyltetrahydrofolate (5‐Ch3‐THF)(100 μ,M)L‐serine(6 mM), and L‐methionine(6 and 12 mM) attenuated the embryotoxicity of L‐homocysteine(6 mM) in GD10 rat embryos. Vitamin B12(10 μM) completely abolished the embryotoxicity of L‐homocysteine, which was shown to be mediated by catalysis of the spontaneous oxidation of L‐homocysteine, to the less toxic. L‐homocysteine. In GD 11 rat embryos, both L‐and D‐homocysteine were readily and taken up when added to the culture (3 mM)and increased embryonic S‐adenosylhomocysteine (SAH) levels 14‐and 3‐fold, respectively. This difference was shown to be caused by the stereospecific preference of SAH hydrolase. We propose the basis for L‐homocysteine embryotoxicity is an inhibition of transmethylation reactions by increased embryonic SAH levels. © 1994 Wiley‐Liss, Inc.