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Teratogenic Effects (teratogenic + effects)

Distribution by Scientific Domains

Life Sciences	50%
Medical Sciences	41%
2 Other Domains	9%

Selected Abstracts

Teratogenic Effects of Antiepileptic Drugs: Use of an International Database on Malformations and Drug Exposure (MADRE)

EPILEPSIA, Issue 11 2000
Carla Arpino
Summary: Purpose: The study goal was to assess teratogenic effects of antiepileptic drugs (AEDs) through the use of a surveillance system (MADRE) of infants with malformations. Methods: Information on all malformed infants (1990,1996) with maternal first-trimester drug exposure was collected by the International Clearinghouse for Birth Defects and Monitoring Systems (ICBDMS). Cases were defined as infants presenting with a specific malformation, and controls were defined as infants presenting with any other birth defect. Exposure was defined by the use of AEDs during the first trimester of pregnancy. The association of AEDs with malformations was then estimated by calculating the odds ratios with 95% confidence intervals and testing their homogeneity among registries. Results: Among 8005 cases of malformations, 299 infants were exposed in utero to AEDs. Of those exposed to monotherapy, 65 were exposed to phenobarbital, 10 to methylphenobarbital, 80 to valproic acid, 46 to carbamazepine, 24 to phenytoin, and 16 to other AEDs. Associations were found for spina bifida with valproic acid. Infants exposed to phenobarbital and to methylphenobarbital showed an increased risk of oral clefts. Cardiac malformations were found to be associated with phenobarbital, methylphenobarbital, valproic acid, and carbamazepine. Hypospadias was associated with valproic acid. Porencephaly and other specified anomalies of brain, anomalies of face, coarctation of aorta, and limb reduction defects were found to be associated with valproic acid. Conclusions: Using the MADRE system, we confirmed known teratogenic effects of AEDs. We also found increased risks for malformations that had never been reported associated with AEDs or for which the association was suggested by case reports. [source]

Investigation of Direct Toxic and Teratogenic Effects of Anticoagulants on Rat Embryonic Development Using In Vitro Culture Method and Genotoxicity Assay

ANATOMIA, HISTOLOGIA, EMBRYOLOGIA, Issue 2 2006
I. I. Uysal
Summary Heparin and low molecular weight heparins (LMWHs) are used to reduce the incidence of venous thromboembolism in pregnancy. Although, these agents have been shown to be safe when used during pregnancy, the studies about direct toxic and teratogenic effects of these drugs on embryonic development are limited. In this study, the effects of heparin and LMWHs on rat embryonic development were investigated by using in vitro embryo culture and micronucleus (MN) assay methods. Rat embryos were cultured in vitro in the presence of different concentrations of heparin (5,40 IU/ml), dalteparin (2.5,20 IU/ml), enoxaparin (25,100 ,g/ml) and nadroparin (1,4 IU/ml). Effects of anticoagulants on embryonic developmental parameters were compared and embryos were evaluated for the presence of any malformations. After culturing the embryos, classic MN assay was performed. Anticoagulants significantly decreased all growth and developmental parameters dose-dependently. Dalteparin and enoxaparin were found to cause more developmental toxicity than heparin and nadroparin. Along with haematoma in general, heparin and nadroparin caused maxillary deformity, situs inversus and oedema most frequently, while neural tube defects were observed with dalteparin and enoxaparin. All agents also significantly induced MN formation in rat embryonic blood cells. These results indicate the possible genotoxic effects of anticoagulant agents on the developing rat embryo when applied directly. [source]

Attenuating effects of natural organic matter on microcystin toxicity in zebra fish (Danio rerio) embryos,benefits and costs of microcystin detoxication

ENVIRONMENTAL TOXICOLOGY, Issue 1 2006
Jimena Cazenave
Abstract To contribute to the understanding of joined factors in the environment, impact of pure microcystins (-RR and -LF) on zebra fish (Danio rerio) embryos were investigated individually and in combination with a natural organic matter (NOM). The applied NOM was a reverse osmosis isolate from Lake Schwarzer See (i.e., Black Lake, BL-NOM). Teratogenic effects were evaluated through changes in embryonic development within 48 h of exposure. Detoxication activities were assessed by the activities of phase II biotransformation enzymes, soluble and microsomal glutathione S -transferase (s, mGST). Oxidative stress was assessed by determining both the production of hydrogen peroxide and by analyzing the activities of the antioxidative enzymes, guajacol peroxidase (POD), catalase (CAT), glutathione peroxidase (GPx), and the glutathione restoring enzyme glutathione reductase (GR). Energetic costs were evaluated by determining contents of fat, carbohydrates, and proteins in both exposed and control embryos. BL-NOM attenuated toxic effects of MC-LF and MC-RR verified by less pronounced teratological effects within 24 h, in particular, as well as less rise in the activity of s-GST, when compared with embryos exposed to either pure toxins or in combination with organic matter. BL-NOM also diminished oxidative effects caused by MC-LF; however, it failed to attenuate oxidative stress caused by MC-RR. Content of lipids was significantly reduced in exposed embryos following a trend similar to that obtained with teratological and enzymatic assays confirming the attenuating effect of BL-NOM. Physiological responses to microcystins and NOM required energetic costs, which were compensated to the expense of the energy resources of the yolk, which in turn might affect the normal development of embryos. © 2006 Wiley Periodicals, Inc. Environ Toxicol 21: 22,32, 2006. [source]

Tetramethylcyclopropyl analogue of the leading antiepileptic drug, valproic acid: Evaluation of the teratogenic effects of its amide derivatives in NMRI mice,

BIRTH DEFECTS RESEARCH, Issue 9 2008
Akinobu Okada
Abstract BACKGROUND: Although valproic acid (VPA) is used extensively for treating various kinds of epilepsy, it causes hepatotoxicity and teratogenicity. In an attempt to develop a more potent and safer second generation to VPA drug, the amide derivatives of the tetramethylcyclopropyl VPA analogue, 2,2,3,3-tetramethylcyclopropanecarboxamide (TMCD), N -methyl-TMCD (MTMCD), 4-(2,2,3,3-tetramethylcyclopropanecarboxamide)-benzenesulfonamide (TMCD-benzenesulfonamide), and 5-(TMCD)-1,3,4-thiadiazole-2-sulfonamide (TMCD-thiadiazolesulfonamide) were synthesized and shown to have more potent anticonvulsant activity than VPA. Teratogenic effects of these CNS-active compounds were evaluated in Naval Medical Research Institute (NMRI) mice susceptible to VPA-induced teratogenicity by comparing them to those of VPA. METHODS: Pregnant NMRI mice were given a single sc injection of either VPA or TMC-amide derivatives on gestation day 8.5, and then the live fetuses were examined to detect any external malformations on gestation day 18. After double-staining for bone and cartilage, their skeletons were examined. RESULTS: In contrast to VPA, which induced NTDs in a high number of fetuses at 2.4,4.8 mmol/kg, TMCD, TMCD-benzenesulfonamide, and TMCD-thiadiazolesulfonamide at 4.8 mmol/kg and MTMCD at 3.6 mmol/kg did not induce a significant number of NTDs. TMCD-thiadiazolesulfonamide exhibited a potential to induce limb defects in fetuses. Skeletal examination also revealed that fetuses exposed to all four of the tetramethylcyclopropanecarboxamide derivatives developed vertebral and rib abnormalities less frequently than those exposed to VPA. Our results established that TMCD, MTMCD, and TMCD-benzenesulfonamide are distinctly less teratogenic than VPA in NMRI mice. CONCLUSIONS: The CNS-active amides containing a tetramethylcyclopropanecarbonyl moiety demonstrated better anticonvulsant potency compared to VPA and a lack of teratogenicity, which makes these compounds good second-generation VPA antiepileptic drug candidates. Birth Defects Research (Part A), 2008. © 2008 Wiley-Liss, Inc. [source]

Teratogenic effects of bis-diamine on the developing myocardium

BIRTH DEFECTS RESEARCH, Issue 3 2004
Nobuhiko Okamoto
Abstract BACKGROUND Bis-diamine induces conotruncal anomalies and disproportional ventricular development in rat embryos when administered to the mother. To evaluate the mechanisms of disproportional ventricular development in the anomalous heart, we analyzed the morphology of the embryonic heart and investigated cardiomyocytic DNA synthesis and apoptosis. METHODS A single dose of 200 mg of bis-diamine was administered to pregnant rats Wistar on day 9.5 of pregnancy. The embryos were removed on each embryonic day from 10.5 to 18.5. Expression of cardiotrophin-1 and hepatocyte growth factor was investigated on the sections, and cardiotrophin-1, hepatocyte growth factor and myocyte enhancer factor 2 mRNA expression was examined by reverse transcriptase,polymerase chain reaction. Myocardial DNA synthesis was investigated using 5-bromo-2,-deoxyuridine and the labeling index was calculated for each heart. Apoptosis was also analyzed using TUNEL reaction and electrophoresis of DNA fragmentation. RESULTS The embryos treated with bis-diamine had conotruncal anomalies associated with thin left ventricular wall in the later stage. The labeling index on embryonic day 15.5 and 16.5 was significantly lower than those in the controls. Hepatocyte growth factor and cardiotrophin-1 mRNA expression was upregulated on embryonic day 12.5 and 15.5 in bis-diamine,treated hearts. Fewer apoptotic cells were detected in the hearts of bis-diamine,treated embryos than in control hearts from embryonic day 14.5 to 16.5. CONCLUSIONS The ventricular disproportion in the bis-diamine,treated heart may be caused by the early myocardial differentiation delay and poor proliferation and reduced apoptosis associated with anomalous circulatory condition in the later stage. Birth Defects Research (Part A), 2004. © 2004 Wiley-Liss, Inc. [source]

Busulfan-induced central polydactyly, syndactyly and cleft hand or foot: A common mechanism of disruption leads to divergent phenotypes

DEVELOPMENT GROWTH & DIFFERENTIATION, Issue 6 2007
Takuji Naruse
The prevalence of clinical phenotypes that exhibit combinations of central polydactyly, syndactyly, or cleft hand or foot is higher than would be expected for random independent mutations. We have previously demonstrated that maternal ingestion of a chemotherapeutic agent, busulfan, at embryonic day 11 (E11) induces these defects in various combinations in rat embryo limbs. In an effort to determine the mechanism by which busulfan disrupts digital development, we examined cell death by Nile Blue staining and TdT-mediated dUTP nick end labeling (TUNEL) assays; we also carried out whole mount in situ hybridization for fibroblast growth factor-8 (Fgf8), bone morphogenetic protein-4 (Bmp4), and sonic hedgehog (Shh) to examine developmental pathways linked to these defects. In busulfan-treated embryos, diffuse cell death was evident in both ectoderm and mesoderm, peaking at E13. The increased cell death leads to regression of Fgf8 in the apical ectodermal ridge (AER) and Bmp4 and Shh in the underlying mesoderm. The subsequent pattern of interdigital apoptosis and cartilage condensation was variably disrupted. These results suggest that busulfan manifests its teratogenic effects by inducing cell death of both ectoderm and mesoderm, with an associated reduction in tissue and a disruption in the generation of patterning molecules during critical periods of digit specification. [source]

Effect of elevated homocysteine on cardiac neural crest migration in vitro

DEVELOPMENTAL DYNAMICS, Issue 2 2002
Philip R. Brauer
Abstract A positive correlation between elevated maternal homocysteine (Hcys) and an increased risk of neural tube, craniofacial, and cardiac defects is well known. Studies suggest Hcys perturbs neural crest (NC) development and may involve N-methyl-D-aspartate (NMDA) receptors (Rosenquist et al., 1999). However, there is no direct evidence that Hcys alters NC cell behavior. Here, we evaluated the effect of Hcys on cardiac NC cell migratory behavior in vitro. Neural tube segments from chick embryos treated in ovo with or without Hcys were placed in culture and the migratory behavior of emigrating NC cells was monitored. Hcys significantly increased in vitro NC cell motility at all embryonic stages examined. NC cell surface area and perimeter were also increased. However, the relative distance NC cells migrated from their original starting point only increased in NC cells treated in ovo at stage 6 or at the time neural tube segments were cultured. Cysteine had no effect. NMDA mimicked Hcys' effect on NC motility and migration distance but had no effect on cell area or perimeter. The noncompetitive inhibitor of NMDA receptors, MK801+, significantly inhibited NC cell motility, reduced migration distance, and also blocked the effects of NMDA and Hcys on NC motility and migratory distance in vitro. A monoclonal antibody directed against the NMDA receptor immunostained NC cells in vitro and, in western blots, bound a single protein with the appropriate molecular weight for the NMDA receptor in NC cell lysates. These data are consistent with the hypothesis that a Hcys-sensitive NMDA-like receptor is expressed by early emigrating NC cells or their precursors, which is important in mediating their migratory behavior. Perturbation of this receptor may be related to some of the teratogenic effects observed with elevated Hcys. © 2002 Wiley-Liss, Inc. [source]

Teratogenic Effects of Antiepileptic Drugs: Use of an International Database on Malformations and Drug Exposure (MADRE)

Ethanol Teratogenesis in Five Inbred Strains of Mice

ALCOHOLISM, Issue 7 2009
Chris Downing
Background:, Previous studies have demonstrated individual differences in susceptibility to the detrimental effects of prenatal ethanol exposure. Many factors, including genetic differences, have been shown to play a role in susceptibility and resistance, but few studies have investigated the range of genetic variation in rodent models. Methods:, We examined ethanol teratogenesis in 5 inbred strains of mice: C57BL/6J (B6), Inbred Short-Sleep, C3H/Ibg, A/Ibg, and 129S6/SvEvTac (129). Pregnant dams were intubated with either 5.8 g/kg ethanol (E) or an isocaloric amount of maltose,dextrin (MD) on day 9 of pregnancy. Dams were sacrificed on day 18 and fetuses were weighed, sexed, and examined for gross morphological malformations. Every other fetus within a litter was then either placed in Bouin's fixative for subsequent soft-tissue analyses or eviscerated and placed in ethanol for subsequent skeletal analyses. Results:, B6 mice exposed to ethanol in utero had fetal weight deficits and digit, kidney, brain ventricle, and vertebral malformations. In contrast, 129 mice showed no teratogenesis. The remaining strains showed varying degrees of teratogenesis. Conclusions:, Differences among inbred strains demonstrate genetic variation in the teratogenic effects of ethanol. Identifying susceptible and resistant strains allows future studies to elucidate the genetic architecture underlying prenatal alcohol phenotypes. [source]

Central and Peripheral Timing Variability in Children With Heavy Prenatal Alcohol Exposure

ALCOHOLISM, Issue 3 2009
Roger W. Simmons
Background:, The study examined whether prenatal alcohol exposure is associated with increased motor timing variability when the timing response is partitioned into central clock variability, which indexes information processing at the central nervous system (CNS) level and motor delay variability, which reflects timing processes at the level of the peripheral nervous system. Methods:, Eighteen children with histories of prenatal alcohol exposure and 22 control children were assigned to young (7 to 11 years) or older (12 to 17 years) groups. Children tapped a single response key with the index finger in synchrony with a series of externally generated tones (the paced phase). At the conclusion of these tones, children continued tapping (the continuation phase) while attempting to maintain the same rate of tapping imposed by the paced phase. Two blocks of tapping were completed with inter-tone-intervals set at either 400 or 900 milliseconds. Inter-response interval, central clock variability, and motor delay variability produced during the continuation phase were the dependent variables. Results:, Mean inter-response interval for the 4 groups did not differ for either time interval. Central clock variability produced by the young alcohol-exposed group was significantly greater than the two older groups for the 400 millisecond interval and all other groups for the 900 millisecond interval. Motor delay variability produced by the young alcohol-exposed group was significantly greater than the other three groups for both time intervals. Central and motor delay variability in children with and without alcohol exposure was directly related to the duration of the interval to be reproduced. Conclusions:, Central and peripheral timing variability was significantly greater for the young alcohol-exposed children. This atypical timing may be related to the teratogenic effects of alcohol, although the negative effects are limited to younger alcohol-exposed children since there were no differences in central and peripheral timing variability between the older alcohol-exposed children and controls. [source]

Maternal Oral Intake Mouse Model for Fetal Alcohol Spectrum Disorders: Ocular Defects as a Measure of Effect

ALCOHOLISM, Issue 10 2006
Scott E. Parnell
Background: This work was conducted in an effort to establish an oral intake model system in which the effects of ethanol insult that occur during early stages of embryogenesis can be easily examined and in which agents that may modulate ethanol's teratogenicity can be readily tested in vivo. The model system described utilizes the alcohol deprivation effect to obtain teratogenic levels of maternal ethanol intake on days 7 and 8 of pregnancy in C57Bl/6J mice. Ocular defects including microphthalmia and uveal coloboma, which have previously been shown to result from ethanol administered by gavage or via intraperitoneal injection on these days, served as the developmental end point for this study. The ocular defects are readily identifiable and their degree of severity is expected to correlate with concurrently developing defects of the central nervous system (CNS). Methods: Female C57Bl/6J mice were maintained on an ethanol-containing (4.8% v/v) liquid diet for 14 days and then mated during a subsequent abstinence period. Mice were then reexposed to ethanol on days 7 and 8 of pregnancy only. Control as well as ethanol-exposed dams were killed on their 14th day of pregnancy. Fetuses were then weighed, measured for crown rump length, photographed, and analyzed for ocular abnormalities. Globe size, palpebral fissure length, and pupil size and shape were noted for both the right and left eyes of all fetuses and informative comparisons were made. Results: This exposure paradigm resulted in peak maternal blood alcohol concentrations that ranged from 170 to 220 mg/dL on gestational day (GD) 8. Compared with the GD 14 fetuses from the normal control group, the pair-fed, acquisition controls, as well as the ethanol-exposed fetuses, were developmentally delayed and had reduced weights. Confirming previous studies, comparison of similarly staged control and treated GD 8 embryos illustrated reductions in the size of the forebrain in the latter. Subsequent ocular malformations were noted in 33% of the right eyes and 25% of the left eyes of the 103 GD 14 ethanol-exposed fetuses examined. This incidence of defects is twice that observed in the control groups. Additionally, it was found that the palpebral fissure length is directly correlated with globe size. Conclusions: The high incidence of readily identifiable ocular malformations produced by oral ethanol intake in this model and their relevance to human fetal alcohol spectrum disorders (FASD) makes this an excellent system for utilization in experiments involving factors administered to the embryo that might alter ethanol's teratogenic effects. Additionally, the fact that early ethanol insult yields ocular and forebrain abnormalities that are developmentally associated allows efficient specimen selection for subsequent detailed analyses of CNS effects in this in vivo mammalian FASD model. [source]

Rapid Induction of Apoptosis in Gastrulating Mouse Embryos by Ethanol and Its Prevention by HB-EGF

ALCOHOLISM, Issue 1 2006
Brian A. Kilburn
Background: Ethanol exposure during gastrulation and early neurulation induces apoptosis within certain embryonic cell populations, leading to craniofacial and neurological defects. There is currently little information about the initial kinetics of ethanol-induced apoptosis, and interest in the ability of endogenous survival factors to moderate apoptosis is growing. Ethanol alters intracellular signaling, leading to cell death in chick embryos, suggesting that apoptosis could occur rapidly and that signaling pathways activated by survival factors might reduce apoptosis. Methods: Pregnant mice were intubated with 1, 2, or 4 g/kg ethanol on day 7.5 of embryogenesis (E7.5) 1, 3, or 6, hours before harvesting gastrulation-stage embryos. Control animals received maltose/dextran. Blood alcohol concentrations (BAC) were determined by gas chromatography. E7.5 embryos isolated from untreated dams were cultured in vitro for 1 or 3 hr with 0 or 400 mg% ethanol and 0 or 5 nM heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF). Apoptosis was quantified using fluorescence microscopy to detect annexin V binding and DNA fragmentation [terminal deoxynucleotidyl transferase-mediated dUTP-X nick end labeling (TUNEL)] in whole-mount or sectioned embryos. Results: Both annexin V binding and TUNEL were elevated (p<0.05) in embryos exposed in utero to 1 g/kg ethanol for 3 hours, increasing linearly with time and ethanol concentration. Apoptosis increased (p<0.05) in all germ cell layers. Mice treated with 4 g/kg sustained BAC of 400 mg% for nearly 3 hours, significantly increasing apoptosis within the first hour. Cultured embryos exposed to 400 mg% ethanol displayed 2- to 3-fold more TUNEL than vehicle-treated embryos (p<0.05); however, exogenous HB-EGF prevented apoptosis. Conclusions: Ethanol rapidly produced apoptosis in gastrulation-stage embryos, consistent with induction by intracellular signaling. The ethanol-induced apoptotic pathway was blocked by the endogenous survival factor, HB-EGF. Differences in the expression of survival factors within individual embryos could be partly responsible for variations in the teratogenic effects of ethanol among offspring exposed prenatally. [source]

Alcohol-Induced Lipid and Morphological Changes in Chick Retinal Development

ALCOHOLISM, Issue 5 2004
Yolanda Aguilera
Abstract: Background: Alcohol exposure causes alterations in the lipid content of different organs and a reduction of long-chain fatty acids. During embryo development, the central nervous system is extremely vulnerable to the teratogenic effects of alcohol, and the visual system is particularly sensitive. Methods: White Leghorn chick embryos were injected with 10- and 20-,l alcohol doses into the yolk sac at day 6 of incubation. The lipid composition of the retina was analyzed in embryos at day 7 of incubation (E7), E11, E15, and E18. The percentages of phospholipids, free cholesterol, esterified cholesterol, diacylglycerides, and free fatty acids were estimated by using an Iatroscan thin layer chromatography flame ionization detector. Gas chromatography and mass spectrometry were used to determine fatty acid composition. The morphological study was performed at E7, E11, and E19 by means of semithin and immunohistochemical techniques. Results: In the retina, alcohol causes the total lipid content to change, with a remarkable increase in free cholesterol and a dramatic decrease in esterified cholesterol. Diacylglycerides and free fatty acids tend to increase. Phosphatidylcholine and phosphatidylethanolamine decrease, whereas phosphatidylserine, sphingomyelin, and phosphatidylinositol increase. The main fatty acids of the retina also undergo changes. At E7, myriotic acid increases, and oleic acid and polyunsaturated fatty acids such as arachidonic acid and docosahexaenoic acid decrease. From E18 onward, there is some recovery, except for fatty acids, which recover earlier. From a morphological point of view, alcohol effects on retinal development are various: increase of intercellular spaces in all cell layers, pyknosis with loss of cellularity in the inner nuclear cell layer and ganglion cell layer, retarded or disorderly cell migration, early cell differentiation, and loss of immunoreactivity for myelin oligodendrocyte,specific protein. Conclusions: Acute alcohol exposure during embryo development causes the lipid composition of the retina to change, with a trend to recovery in the last stages. These alterations are in line with the changes observed at a morphological level. [source]

Free tissue transfer in pregnancy: Guidelines for perioperative management

MICROSURGERY, Issue 5 2001
G. Robert Meger M.D.
A successful free tissue transfer of serratus anterior muscle, to provide coverage for an open ankle defect in a pregnant patient, is described. Microvascular surgery in the presence of a viable pregnancy demands considerations unique to this situation. Although rarely possible, an attempt should be made to plan surgery to coincide with the second trimester, to lessen the risk of anesthesia to the fetus. Maternal positioning, fluid balance, and aspiration precautions need to be critically addressed. Close perioperative monitoring by an obstetrician is essential. The condition of pregnancy results in a hypercoagulable state that may lead to an increased risk of anastomotic failure. The use of anticoagulants results in increased risk of bleeding, not only for the patient but also for the fetus, as well as risk of teratogenic effects. Closely monitored heparin is considered safe in pregnancy as is low-molecular-weight dextran and low-dose aspirin. Additional considerations include the use of narcotics and sedatives for comfort postoperatively, as well as antibiotic choices, if indicated. © 2001 Wiley-Liss, Inc. Microsurgery 21:202,207 2001 [source]

Fetal alcohol syndrome and developing craniofacial and dental structures , a review

ORTHODONTICS & CRANIOFACIAL RESEARCH, Issue 4 2006
LB Sant'Anna
Structured abstract Authors ,, Sant'Anna LB, Tosello DO Objectives ,, Fetal alcohol syndrome (FAS) is a collection of signs and symptoms seen in children exposed to alcohol in the prenatal period. It is characterized mainly by a distinct pattern of craniofacial malformations, physical and mental retardation. However, with the increased incidence of FAS, there is a great variation in the clinical features of FAS. Design ,, Narrative review. Results ,, This review describes data from clinical and experimental studies, and in vitro models. Experimental studies have shown that alcohol has a direct toxic effect on the ectodermal and mesodermal cells of the developing embryo, particularly in the cells destined to give rise to dentofacial structures (i.e. cranial neural crest cells). Other effects, such as, abnormal pattern of cranial and mandibular growth and altered odontogenesis are described in detail. The exact mechanism by which alcohol induces its teratogenic effects remains still unknown. The possible mechanisms are outlined here, with an emphasis on the developing face and tooth. Possible future research directions and treatment strategies are also discussed. Conclusion ,, Early identification of children affected by prenatal alcohol exposure leads to interventions, services, and improved outcomes. FAS can be prevented with the elimination of alcohol consumption during pregnancy. We need to provide education, target high-risk groups, and make this issue a high priority in terms of public health. [source]

The potential of the European network of congenital anomaly registers (EUROCAT) for drug safety surveillance: a descriptive study,

PHARMACOEPIDEMIOLOGY AND DRUG SAFETY, Issue 9 2006
Willemijn M. Meijer PharmD
Abstract Background European Surveillance of Congenital Anomalies (EUROCAT) is a network of population-based congenital anomaly registries in Europe surveying more than 1 million births per year, or 25% of the births in the European Union. This paper describes the potential of the EUROCAT collaboration for pharmacoepidemiology and drug safety surveillance. Methods The 34 full members and 6 associate members of the EUROCAT network were sent a questionnaire about their data sources on drug exposure and on drug coding. Available data on drug exposure during the first trimester available in the central EUROCAT database for the years 1996,2000 was summarised for 15 out of 25 responding full members. Results Of the 40 registries, 29 returned questionnaires (25 full and 4 associate members). Four of these registries do not collect data on maternal drug use. Of the full members, 15 registries use the EUROCAT drug code, 4 use the international ATC drug code, 3 registries use another coding system and 7 use a combination of these coding systems. Obstetric records are the most frequently used sources of drug information for the registries, followed by interviews with the mother. Only one registry uses pharmacy data. Percentages of cases with drug exposure (excluding vitamins/minerals) varied from 4.4% to 26.0% among different registries. The categories of drugs recorded varied widely between registries. Conclusions Practices vary widely between registries regarding recording drug exposure information. EUROCAT has the potential to be an effective collaborative framework to contribute to post-marketing drug surveillance in relation to teratogenic effects, but work is needed to implement ATC drug coding more widely, and to diversify the sources of information used to determine drug exposure in each registry. Copyright © 2006 John Wiley & Sons, Ltd. [source]

Prospective studies of exposure to an environmental contaminant: The challenge of hypothesis testing in a multivariate correlational context

PSYCHOLOGY IN THE SCHOOLS, Issue 6 2004
Joseph L. Jacobson
In this paper, we respond to the criticisms and concerns raised by D.V. Cicchetti, A.S. Kaufman, & S.S. Sparrow (this issue) in their review of the PCB literature, with particular attention to our own research in Michigan. We agree that multiple comparisons and functional significance are issues that would benefit from more discussion. However, because the effects associated with exposure to environmental contaminants are generally subtle, the risk of Type II error would be unacceptably high if researchers were to adopt the authors' recommendation to use a Bonferroni correction. We describe the hierarchical approach we have used to deal with the issue of multiple comparisons, which emphasizes the need to base interpretation on consistent patterns in the data and on replicated findings. The issue of confounding is one that has received considerable attention in the PCB studies and, given that one can never measure every possible confounder, the range of control variables that have been evaluated is impressive. We disagree with the authors' assertion that only standardized test scores are sufficiently reliable for use in these studies; behavioral teratogens often involve subtle effects, which can be identified most effectively by innovative, narrow-band tests that have not yet been normed. Moreover, longitudinal statistical analysis is not necessarily the method of choice for the issues being addressed in this literature. One important new development that Cicchetti et al. fail to note is the emergence of evidence from both the Michigan and Dutch cohorts indicating that breast-fed children are markedly less vulnerable. It is not yet clear to what degree this protective effect is attributable to nutrients in breast milk or to more optimal intellectual stimulation by nursing mothers, or both. However, the discovery of effect modifiers that can explain individual differences in vulnerability marks an important advance in our growing understanding of the teratogenic effects of exposure to environmental contaminants on child development. © 2004 Wiley Periodicals, Inc. Psychol Schs 41: 625,637, 2004. [source]

Investigation of Direct Toxic and Teratogenic Effects of Anticoagulants on Rat Embryonic Development Using In Vitro Culture Method and Genotoxicity Assay

Fetal cardiac effects of maternal hyperglycemia during pregnancy

BIRTH DEFECTS RESEARCH, Issue 6 2009
Niamh Corrigan
Maternal diabetes mellitus is associated with increased teratogenesis, which can occur in pregestational type 1 and type 2 diabetes. Cardiac defects and with neural tube defects are the most common malformations observed in fetuses of pregestational diabetic mothers. The exact mechanism by which diabetes exerts its teratogenic effects and induces embryonic malformations is unclear. Whereas the sequelae of maternal pregestational diabetes, such as modulating insulin levels, altered fat levels, and increased reactive oxygen species, may play a role in fetal damage during diabetic pregnancy, hyperglycemia is thought to be the primary teratogen, causing particularly adverse effects on cardiovascular development. Fetal cardiac defects are associated with raised maternal glycosylated hemoglobin levels and are up to five times more likely in infants of mothers with pregestational diabetes compared with those without diabetes. The resulting anomalies are varied and include transposition of the great arteries, mitral and pulmonary atresia, double outlet of the right ventricle, tetralogy of Fallot, and fetal cardiomyopathy. A wide variety of rodent models have been used to study diabetic teratogenesis. Both genetic and chemically induced models of type 1 and 2 diabetes have been used to examine the effects of hyperglycemia on fetal development. Factors such as genetic background as well as confounding variables such as obesity appear to influence the severity of fetal abnormalities in mice. In this review, we will summarize recent data on fetal cardiac effects from human pregestational diabetic mothers, as well as the most relevant findings in rodent models of diabetic cardiac teratogenesis. Birth Defects Research (Part A), 2009. © 2009 Wiley-Liss, Inc. [source]

Tetramethylcyclopropyl analogue of the leading antiepileptic drug, valproic acid: Evaluation of the teratogenic effects of its amide derivatives in NMRI mice,

Plasma vitamin values and antiepileptic therapy: Case reports of pregnancy outcomes affected by a neural tube defect

BIRTH DEFECTS RESEARCH, Issue 1 2007
Mirande Candito
Abstract BACKGROUND: Folic acid supplementation reduces the occurrence of neural tube defects (NTDs); however, it is not clear whether it protects against teratogenic effects of antiepileptic drugs. METHODS: We report the cases of four pregnant women receiving valproic acid therapy, who all had NTD-affected offspring, despite periconceptional 5 mg/day of folic acid supplementation (cases), and investigated homocysteine metabolism, linked with folate metabolism. Their plasma homocysteine, folates, and vitamin B6 and B12 results were compared with values of two other women, who were also receiving valproic acid and folic acid complement, but who had normal pregnancies (valproic acid controls), and values of 40 pregnant women who had normal pregnancies and were not receiving any therapy (controls without therapy). Because of the possible existence of a genetic susceptibility, polymorphisms in homocysteine metabolism were sought. RESULTS: Two cases showed a decreased phosphopyridoxal level, compared with levels in the controls not receiving therapy. The genotype TT (C677T) is an NTD genetic susceptibility, but it was observed in only one valproic acid control. Various polymorphisms were observed in the cases, but were also common in the controls. Several studies have reported that valproic acid therapy lowers vitamin B6 levels. Our case with the greatest decrease in plasma phosphopyridoxal, who was taking periconceptional folic acid plus pyridoxine therapy, had a normal second pregnancy outcome. CONCLUSIONS: In addition to folates, other vitamins, such as vitamin B6, may have played a role in NTDs in our patients taking an antiepileptic drug. Birth Defects Research (Part A) 2007. © 2006 Wiley-Liss, Inc. [source]

An in ovo chicken model to study the systemic and localized teratogenic effects of valproic acid

BIRTH DEFECTS RESEARCH, Issue 4 2002
Amy I. Whitsel
Background The antiepileptic valproic acid (VPA) is a teratogen whose embryopathic mechanism(s) remain uncertain. Elucidating potential cellular and molecular effects of VPA is complicated by systemic application paradigms. We developed an in ovo model to reproduce the teratogenic effects of VPA and a localized VPA application procedure to determine whether VPA can selectively effect abnormal development in one region of the embryo. Methods VPA was applied topically to chicken embryos in ovo at different embryonic stages. Embryos were later evaluated for gross and skeletal anomalies. Pax-2 and Pax-6 protein expression in the developing eye was also evaluated because VPA-induced eye anomalies are similar to those seen by the disruption of Pax-2 and Pax-6. For localized application, a thin sheet of the synthetic polymer Elvax was impregnated with VPA. A small piece of the VPA-impregnated polymer was applied directly to the presumptive wing bud region in Stage 10,17 embryos. Embryos were examined for gross and skeletal anomalies. Sham controls were employed for all experiments. Results Chicken embryos exposed to VPA in ovo demonstrated increased mortality, growth delay and anomalies similar to ones previously seen in humans: neural tube, cardiovascular, craniofacial, limb and skeletal. Pax-2 and Pax-6 protein expression was qualitatively diminished in the eye. Localized wing bud VPA exposure caused structural abnormalities in the developing wing in the absence of other anomalies in the embryos. These wing defects were similar to those observed after topical whole-embryo VPA application. Conclusions These results indicate that at least one mechanism for the teratogenicity of VPA involves a direct effect on developing tissue. The nature of the abnormalities observed implies that this effect may be mediated by disruption of genes that regulate pattern formation. Teratology 66:153,163, 2002. © 2002 Wiley-Liss, Inc. [source]

Effects of cadmium on formation of the ventral body wall in chick embryos and their prevention by zinc pretreatment

BIRTH DEFECTS RESEARCH, Issue 2 2001
Jennifer Thompson
Background Cadmium (Cd) is an established experimental teratogen whose effects can be reversed by pretreatment with zinc. Mesodermal development is a frequently reported target for Cd teratogenicity. The aim of this study was to examine the mechanisms of Cd induced body wall defects in chick embryos. Methods Chick embryos in shell-less culture were treated with 50 ,l of cadmium acetate (8.9 × 10,5 M Cd2+) at 60-hr incubation (H.-H. stages 16,17). Controls received equimolar sodium acetate. Other embryos were treated with various concentrations of zinc acetate and then with Cd or NaAc 1 hrs later. Development was evaluated 48 hrs later. Resin-embedded 1-,m sections were examined at earlier stages. Results Cd caused embryolethality (35%), ventral body wall defect with malpositioned lower limbs (40%), and weight reduction in survivors. After 4-hr treatment with Cd, breakdown of junctions between peridermal cells with rounding up and desquamation occurred. Shape changes were also seen in the basal layer of the ectoderm. At 4 hr, cell death was evident in lateral plate mesoderm, somites, and neuroepithelium; the lateral plate mesoderm began to grow dorsally, carrying the attached limb buds with it. Zn pretreatment protected against the lethal, teratogenic, and growth-retarding effects of Cd, as well as ectodermal changes and cell death. Conclusions Cd disrupts peridermal cell adhesion and induces cell death in the mesoderm. This may result in abnormal growth of lateral plate mesoderm and in a body wall defect. Zn pretreatment prevents both the gross teratogenic effects and the cellular changes, most likely by competition with Cd. Teratology 64:87,97, 2001. © 2001 Wiley-Liss, Inc. [source]