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Sample records for teratogenesis

  1. Misoprostol and teratogenesis in neonates

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    Mariana Beatriz Scabora da Silva

    2009-09-01

    Full Text Available This paper is focused in some aspects of maternal exposure to misoprostol during perinatal period, and the abortive and teratogenesis effects on the fetus. The causes of malformations were revised, taking into account chemical, physical and environmental factors as well as the interaction between them. There are evidences that the practice of abortion tripled in Southern and Northeastern Brazil in 15 years, and one of the most frequent forms of abortion is through the use of misoprostol. In Brazil, 1991, 288,700 women were hospitalized as a consequence of complications induced by abortion attempt with this medicine. This fact resulted in the ban of misoprostol across our country, by Decree 344/98 determined by the Health Ministry. The use of misoprostol requires special control and it is allowed only in hospitals, with supervision of the municipal health surveillance. Among the more severe problems affecting the non-aborted child is the injury on the central nervous system, which frequently results in the Moebius syndrome. This is a congenital and non-progressive paralysis of the VI and VII cranial nerves, frequently bilateral, which produces a unexpressive facial appearance and convergent Strabismus. Even banned in our country, abortion is illegally practiced, being deprived of proper knowledge about misoprostol teratogenic effects on the fetus as well as the risks involving mothers.Este trabalho enfoca aspectos relativos à exposição ao misoprostol no período perinatal como abortificante e agente teratogênico, assim como as causas das malformações, considerando-se fatores químicos, físicos e ambientais. A prática do aborto triplicou nas regiões Sul e Nordeste em 15 anos, sendo que entre os métodos mais freqüentes está o uso do medicamento com o princípio ativo do misoprostol. Em 1991 no Brasil, 288.700 mulheres foram socorridas em hospitais devido a complicações por indução de aborto com este medicamento. Isso resultou na

  2. Transgenerational teratogenesis and carcinogenesis by radiation

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    Nomura, Taisei [Osaka Univ., Suita (Japan). Graduate School of Medicine

    2000-07-01

    This paper thoroughly reviews studies on transgenerational teratogenesis and carcinogenesis induced by radiation and summarizes currently available data from animal studies. The discussions focus on the incidence of tumors, malformations, and mutations in the offspring after parental exposure to radiation, as well as estimated relative risks of congenital malformations and stillbirths in the offspring after parental X-ray exposure. The data suggest that different types of tumors are induced in offspring, because of strain differences in the experimental animals. The results of epidemiological studies in human populations, such as the children of atomic bomb survivors, conflict with the findings in animal studies. The author points to the following reasons for the differences between the results in animals and humans: differences in radiation doses, timing of exposure, and genetic predisposition, etc. While pointing out issues that need to be investigated further, the author indicates that clear strain differences exist in types of tumors induced and in tumor incidences in the offspring of animals that were irradiated before the offspring were conceived, and that genetic predisposition is therefore important in transgenerational carcinogenesis. (K.H.)

  3. Further Development and Validation of the Frog Embryo Teratogenesis Assay-Xenopus (FETAX).

    Science.gov (United States)

    1992-11-23

    high osmosis water to culture the adults with no temperature bake oven in which glassware can be apparent adverse effects on results. Only non- heated...Toxicol 14(1&2):143-160, 199 1. Laevis. Bull Environ Contain Toxicol 22:159-166, 1979. Friedman M, Rayburn JR, Bantle JA: Developmental toxicology of potato ...160. Friedman, M., Rayburn, J.R., and Bantle, J.A. 1990. Developmental toxicology of potato alkaloids in the Frog Embryo Teratogenesis Assay-Xenopus

  4. Lethality and teratogenesis in F{sub 1} offspring mice following paternal fission neutron irradiation

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    Shoji, Shuneki [Hiroshima Univ., Research Institute for Radiation Biology and Medicine, Hiroshima (Japan)

    2003-07-01

    Studies were conducted to determine whether following genetic damage at germ cell stages induced by paternal exposure to {sup 252}Cf fission neutron could lead to teratogenesis in the offspring. Seven-week-old C3H male mice were irradiated with graded doses of {sup 252}Cf fission neutrons and then were mated with nine-week-old C57BL females two weeks after the exposure. Three weeks later, it was found that testis and epididymal weight losses as well as the proportions of caudal epididymal sperm abnormalities in irradiated males were significantly greater than those in non-irradiated groups. Pregnant dams were sacrificed on day 18 of gestation and their fetuses were examined for the number of resorptions, intrauterine deaths and teratogenesis in F{sub 1} surviving offspring. Embryo lethality among the F{sub 1} offspring was found to be significantly higher in the irradiated group than in the non-irradiated group (p < 0.01), while the incidence of congenital malformations among the F{sub 1} offspring significantly increased in the irradiated groups. These results suggest that the paternal radiation exposure may have caused genetic transmission of DNA damage and genetic instability, which is in line with findings that show increases in incidence of teratogenesis in B{sub 6}C{sub 3}F{sub 1}. (author)

  5. Fishing for Fetal Alcohol Spectrum Disorders: Zebrafish as a Model for Ethanol Teratogenesis.

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    Lovely, Charles Ben; Fernandes, Yohaan; Eberhart, Johann K

    2016-10-01

    Fetal Alcohol Spectrum Disorders (FASD) describes a wide array of ethanol-induced developmental defects, including craniofacial dysmorphology and cognitive impairments. It affects ∼1 in 100 children born in the United States each year. Due to the pleiotropic effects of ethanol, animal models have proven critical in characterizing the mechanisms of ethanol teratogenesis. In this review, we focus on the utility of zebrafish in characterizing ethanol-induced developmental defects. A growing number of laboratories have focused on using zebrafish to examine ethanol-induced defects in craniofacial, cardiac, ocular, and neural development, as well as cognitive and behavioral impairments. Growing evidence supports that genetic predisposition plays a role in these ethanol-induced defects, yet little is understood about these gene-ethanol interactions. With a high degree of genetic amenability, zebrafish is at the forefront of identifying and characterizing the gene-ethanol interactions that underlie FASD. Because of the conservation of gene function between zebrafish and humans, these studies will directly translate to studies of candidate genes in human populations and allow for better diagnosis and treatment of FASD.

  6. Application of frog embryo teratogenesis assay-Xenopus to ecological risk assessment.

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    Hoke, Robert A; Ankley, Gerald T

    2005-10-01

    An expert workshop recently was convened to consider the frog embryo teratogenesis assay-Xenopus (FETAX) as a screening method for identifying the potential developmental toxicity of single chemicals and chemical mixtures. One recommendation from the workshop was that, in order to determine the utility of FETAX for ecological risk assessments, additional consideration of how the assay is conducted is necessary. In addition, a comparative evaluation would be useful of FETAX endpoints (i.e., survival, malformations, growth) versus each other, endpoints from aquatic toxicity tests using more commonly tested species of cladocerans and fish, and tests with other amphibian species. This review provides an evaluation and critique of the current FETAX protocol from two perspectives: Practical considerations relative to conducting the test and sensitivity of the assay (and associated endpoints) compared to tests with other species. Several aspects of the current standard protocol, including test temperature, diet, loading rates, and chemical exposure options, need to be modified to ensure that the assay is robust technically. Evaluation of FETAX data from the open literature indicates that growth is the most sensitive endpoint in the assay, followed by malformations and then survival; unfortunately, the growth endpoint often is not considered or reported in the assay. Comparison of FETAX data with acute toxicity data from tests with other amphibians or traditional aquatic test species indicates FETAX is relatively insensitive. This suggests that environmental risk assessments using acute hazard data from tests with traditional aquatic test species usually would be more protective of native amphibian species than risk assessments that use hazard data from FETAX.

  7. Use of the enhanced frog embryo teratogenesis assay-Xenopus (FETAX) to determine chemically-induced phenotypic effects.

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    Hu, Lingling; Zhu, Jingmin; Rotchell, Jeanette M; Wu, Lijiao; Gao, Jinjuan; Shi, Huahong

    2015-03-01

    The frog embryo teratogenesis assay-Xenopus (FETAX) is an established method for the evaluation of the developmental toxicities of chemicals. To develop an enhanced FETAX that is appropriate for common environmental contaminants, we exposed Xenopus tropicalis embryos to eight compounds, including tributyltin, triphenyltin, CdCl2, pyraclostrobin, picoxystrobin, coumoxystrobin, all-trans-retinoic acid and 9-cis-retinoic acid. Multiple malformations were induced in embryos particularly following exposure to tributyltin, triphenyltin and pyraclostrobin at environmentally relevant concentrations. Based on the range of observed malformations, we proposed a phenotypic assessment method with 20 phenotypes and a 0-5 scoring system. This derived index exhibited concentration-dependent relationships for all of the chemicals tested. Furthermore, the phenotype profiles were characteristic of the different tested chemicals. Our results indicate that malformation phenotypes can be quantitatively integrated with the primary endpoints in conventional FETAX assessments to allow for increased sensitivity and measurement of quantitative effects and to provide indicative mechanistic information for each tested chemical. Copyright © 2014 Elsevier B.V. All rights reserved.

  8. The history and development of FETAX (ASTM standard guide, E-1439 on conducting the frog embryo teratogenesis Assay-Xenopus)

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    Dumont, J.N.; Bantle, J.A.; Linder, G.; ,

    2003-01-01

    The energy crisis of the 1970's and 1980's prompted the search for alternative sources of fuel. With development of alternate sources of energy, concerns for biological resources potentially adversely impacted by these alternative technologies also heightened. For example, few biological tests were available at the time to study toxic effects of effluents on surface waters likely to serve as receiving streams for energy-production facilities; hence, we began to use Xenopus laevis embryos as test organisms to examine potential toxic effects associated with these effluents upon entering aquatic systems. As studies focused on potential adverse effects on aquatic systems continued, a test procedure was developed that led to the initial standardization of FETAX. Other .than a limited number of aquatic toxicity tests that used fathead minnows and cold-water fishes such as rainbow trout, X. laevis represented the only other aquatic vertebrate test system readily available to evaluate complex effluents. With numerous laboratories collaborating, the test with X. laevis was refined, improved, and developed as ASTM E-1439, Standard Guide for the Conducting Frog Embryo Teratogenesis Assay-Xenopus (FETAX). Collabrative work in the 1990s yielded procedural enhancements, for example, development of standard test solutions and exposure methods to handle volatile organics and hydrophobic compounds. As part of the ASTM process, a collaborative interlaboratory study was performed to determine the repeatability and reliability of FETAX. Parallel to these efforts, methods were also developed to test sediments and soils, and in situ test methods were developed to address "lab-to-field extrapolation errors" that could influence the method's use in ecological risk assessments. Additionally, a metabolic activation system composed of rat liver microsomes was developed which made FETAX more relevant to mammalian studies.

  9. Airport noise and teratogenesis

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    Edmonds, L.D.; Layde, P.M.; Erickson, J.D.

    1979-07-01

    It has been suggested that exposure to high-noise levels near major airports may cause increased incidence of birth defects in the offspring of parents residing near these airports. Using data gathered in Metropolitan Atlanta during 1970 to 1972, we compared the rates of seventeen categories of defects in high- and low-noise census tracts. No significant differences were observed. However, when we subdivided the category of central nervous system defects into several subcategories of specific defects, we noted a significantly increased incidence of spina bifida without hydrocephalus in the high-noise areas. Because of the small number of cases associated with this finding we did a matched case-control study using all cases of central nervous system defects born during the years 1968 to 1976. No significantly increased risk for residents in the high-noise areas was noted in this study. It is our opinion that noise or other factors associated with residence near airports are unlikely to be important environmental teratogens.

  10. In vivo phenytoin-initiated oxidative damage to proteins and lipids in murine maternal hepatic and embryonic tissue organelles: potential molecular targets of chemical teratogenesis.

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    Liu, L; Wells, P G

    1994-04-01

    The widely used anticonvulsant drug phenytoin may be bioactivated by peroxidases such as prostaglandin H synthase (PHS) to a reactive free radical intermediate that initiates teratogenesis. This in vivo study evaluated the potential molecular targets mediating phenytoin teratogenicity. In vivo phenytoin-induced oxidative tissue damage following bioactivation was quantified in both maternal hepatic and embryonic tissues from pregnant CD-1 mice using lipid peroxidation and protein oxidation and degradation as indices. Pregnant mice were injected with a teratogenic dose of phenytoin, 65 mg/kg ip, during organogenesis on Gestational Day 12. alpha-Phenyl-N-t-butylnitrone (PBN), a free radical spin trapping agent, 41.5 mg/kg, or acetylsalicylic acid (ASA), an inhibitor of the cyclooxygenase component of PHS, 10 mg/kg, were injected ip 2 hr before phenytoin treatment, and maternal hepatic and embryonic tissues were obtained at 0, 3, 6, 8, and 24 hr. Phenytoin enhanced lipid peroxidation in maternal plasma, hepatic microsomes, cytosol, mitochondria, and nuclei and in embryonic microsomes, cytosol, and mitochondria (p teratogenicity by PBN and ASA, suggest that peroxidase-catalyzed bioactivation of phenytoin may initiate oxidative damage to lipids and proteins in embryonic tissues, with teratological consequences.

  11. Oxidative stress is increased in women with epilepsy: Is it a potential mechanism of anti-epileptic drug-induced teratogenesis?

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    Damayanthi Deepa

    2012-01-01

    Full Text Available Context: Oxidative stress can be a final common pathway for AED-induced teratogenesis. Aims: To compare the oxidative stress of women with epilepsy (WWE and unfavorable pregnancy outcome (fetal malformation or spontaneous abortion - group EM with that of WWE with normal pregnancy outcome (group ENM and healthy women with normal pregnancy outcome (group C. Materials and Methods: We identified WWE under group EM (n = 43 and group ENM (n = 22 from the Kerala Registry of Epilepsy and Pregnancy (KREP. Group C was constituted of healthy volunteers (N = 20. Oxidative stress was assessed by estimating serum levels of malondialdehyde (MDA and isoprostane (ISP. The antioxidant profile was evaluated as activity of superoxide dismutase (SOD, glutathione reductase (GR, catalase (CAT, total antioxidant status (TAO, and glutathione (GSH content. Results: The MDA and ISP levels for group EM (3.46 + 0.82 and 17.77 + 3.0 were higher than that of group ENM (3.07 + 1.02 and 14.0 + 5.3, and both were significantly higher than that of group C (2.42 + 0.51 and 10.77 + 4.1. Their levels of SOD (146.82 + 42.64 vs. 175.81 + 42.61 and GSH (0.98 + 0.98 vs. 1.55 + 1.3 were significantly lower than those of controls. No significant changes were seen in TAO and GR. WWE on polytherapy showed significant increase in MDA when compared to monotherapy group. Conclusion: WWE (group EM and ENM had higher oxidative stress and reduced antioxidant activity. The subgroup of WWE with unfavorable pregnancy outcome (group EM had higher oxidative stress. Excess oxidative stress can be a final common pathway, by which AEDs exert teratogenic effects.

  12. Embryo transfers between C57BL/6J and DBA/2J mice: Examination of a maternal effect on ethanol teratogenesis

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    David eGilliam

    2014-12-01

    Full Text Available Genetic factors influence Fetal Alcohol Spectrum Disorders (FASD in both humans and animals. Experiments using inbred and selectively bred mouse stocks that controlled for 1 ethanol dose, 2 maternal and fetal blood ethanol levels, and 3 fetal developmental exposure stage, show genotype can affect teratogenic outcome. Other experiments distinguish the teratogenic effects mediated by maternal genotype from those mediated by fetal genotype. One technique to distinguish maternal versus fetal genotype effect is to utilize embryo transfers. This study is the first to examine ethanol teratogenesis - fetal weight deficits and mortality, and digit, kidney, and vertebral malformations - in C57BL/6J (B6 and DBA/2J (D2 fetuses that were transferred as blastocysts into B6 and D2 dams. We hypothesized that, following maternal alcohol exposure, B6 and D2 fetuses gestating within B6 mothers, as compared to D2 mothers, will exhibit a higher frequency of malformations. On day 9 of pregnancy, females were intubated (IG with either 5.8 g/kg ethanol (E or maltose dextrin (MD. Other females were mated within strain and treated with either ethanol or maltose, or were not exposed to either treatment. Implantation rates were affected by genotype. Results show more B6 embryos implanted into D2 females than B6 females (p<.05; 47% vs 23%, respectively. There was no difference in the percentage of D2 embryos implanting into B6 and D2 females (14% and 16%, respectfully. Litter mortality averaged 24% across all experimental groups. Overall, in utero ethanol exposure reduced mean litter weight compared to maltose treatment (E=1.01 g; MD=1.19 g; p<.05; but maltose exposed litters with transferred embryos weighed more than similarly treated natural litters (1.30 g vs 1.11 g; p<.05. Approximately 50% of all ethanol exposed B6 fetuses exhibited some malformation (digit, vertebral, and/or kidney regardless of whether they were transferred into a B6 or D2 female, or were naturally

  13. Neutron induced teratogenesis and spermatogenesis inhibitor fertilysin induced fetal bis-diamine syndrome in the rat. An animal model for DiGeorge and CATCH22 syndromes

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    Shoji, Shuneki [Hiroshima Univ., Research Institute for Radiation Biology and Medicine, Hiroshima (Japan)

    2003-07-01

    To develop preventive and regenerative medicine measures and to clarify the effect of neutron-irradiation and Fertilysin on vasculogenesis and teratogenesis, we decided to investigate the pathogenesis of these abnormalities in this study and compare them to abnormalities reported in humans. Pregnant rats were exposed to graded doses of 14.1 MeV neutron irradiation or Fertilysin on day 10 of gestation. The rats were sacrificed on day 18 of gestation, examined for lethality and surviving fetuses, and were microdissected for malformations. Our studies showed that neutron irradiation of rats commonly induced abnormalities whose types included eye, limb and tail defects, transposition of the great arteries, riding aorta, right aortic arch and aortic arch anomalies. These results suggest that maternal exposure to neutron-irradiation may have caused DNA damage and neural crest deficiency in offspring. These results are similar to those found in animal models with Retinoic acid syndrome and human fetuses with DiGeorge syndrome, a condition considered as a pharyngeal arch syndrome related to a cephalic neurocristopathy. In addition, multi-organ malformations associated with the highest incidences of abnormal vasculogenesis, cardiac outflow tracts and aortic arch anomalies such as right aortic arch and aberrant subclavian artery were found to be consistently produced following maternal exposure to Fertilysin on day 10 of gestation. Evidently the crucial scenario for administering Fertilysin to cause the cardiovascular defects of all surviving fetuses, in which over 80% of the fetuses were persistent truncus arteriosus (PTA) and the remainder was tetralogy of Fallot (TOF), is 200 mg for day 10 of gestation. This corresponds in humans to approximately day 21 after conception. A mechanism involving DNA damage, disruption of neural crest cells and growth and transcription factors, as well as growth failure of the branchial arches from apoptosis and neurocristopathy of the third

  14. Thalidomide Analogs in Brazil: Concern About Teratogenesis / Análogos da Talidomida no Brasil: Preocupação com a Teratogênese

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    Fernanda Sales Luiz Vianna

    2014-05-01

    Full Text Available It has been more than 50 years since thalidomide was withdrawn from the world market due to its teratogenic potential. However, its widespread use around the world resumed due to its immunomodulatory and anti-angiogenic properties. The drug established itself in new therapies, and interest continued with the emergence of more potent analogs, the most notable being lenalidomide and pomalidomide, which are not approved in Brazil. The question that arises after analog synthesis is: Do these drugs also have the same teratogenic potential? The answer to this question is based only on experimental studies because exposure to humans is not authorized and has not yet been descri-bed. Although thalidomide has been recognized as a powerful human teratogen for many years, its molecular mechanisms of teratogenesis remain to be fully explained. Efforts with animal models and human genetic studies have clarified some important pathways that are most likely involved in the teratogenic action of thalidomide. However, it has not yet been possible to identify the teratogenic domain of the molecule from the therapeutic ones. Moreover, there are species-specific differences that must be taken into consideration when teratogenicity is evaluated. -------------------------------------------------------------- Faz mais de 50 anos que a talidomida foi retirada do mercado mundial devido ao seu potencial teratogênico. Entretanto, seu uso disseminado em todo o mundo foi retomado devido às suas propriedades imunomodulatórias e antiangiogênicas. A droga foi utilizada em novas terapias e o interesse continuou com a emergência de análogos mais potentes, os mais notáveis deles sendo a lenalidomida e a pomalidomida, que não estão aprovados no Brasil. A questão que surge após a síntese dos análogos é: Estas drogas também têm o mesmo potencial teratogênico? A resposta a esta pergunta baseia-se apenas em estudos experimentais, pois a exposição a humanos não est

  15. Thalidomide‐induced teratogenesis: History and mechanisms

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    2015-01-01

    Nearly 60 years ago thalidomide was prescribed to treat morning sickness in pregnant women. What followed was the biggest man‐made medical disaster ever, where over 10,000 children were born with a range of severe and debilitating malformations. Despite this, the drug is now used successfully to treat a range of adult conditions, including multiple myeloma and complications of leprosy. Tragically, a new generation of thalidomide damaged children has been identified in Brazil. Yet, how thalidomide caused its devastating effects in the forming embryo remains unclear. However, studies in the past few years have greatly enhanced our understanding of the molecular mechanisms the drug. This review will look at the history of the drug, and the range and type of damage the drug caused, and outline the mechanisms of action the drug uses including recent molecular advances and new findings. Some of the remaining challenges facing thalidomide biologists are also discussed. Birth Defects Research (Part C) 105:140–156, 2015. © 2015 The Authors Birth Defects Research Part C: Embryo Today: Reviews Published by Wiley Periodicals, Inc. PMID:26043938

  16. On categorizations in analyses of alcohol teratogenesis.

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    Sampson, P D; Streissguth, A P; Bookstein, F L; Barr, H M

    2000-06-01

    In biomedical scientific investigations, expositions of findings are conceptually simplest when they comprise comparisons of discrete groups of individuals or involve discrete features or characteristics of individuals. But the descriptive benefits of categorization become outweighed by their limitations in studies involving dose-response relationships, as in many teratogenic and environmental exposure studies. This article addresses a pair of categorization issues concerning the effects of prenatal alcohol exposure that have important public health consequences: the labeling of individuals as fetal alcohol syndrome (FAS) versus fetal alcohol effects (FAE) or alcohol-related neurodevelopmental disorder (ARND), and the categorization of prenatal exposure dose by thresholds. We present data showing that patients with FAS and others with FAE do not have meaningfully different behavioral performance, standardized scores of IQ, arithmetic and adaptive behavior, or secondary disabilities. Similarly overlapping distributions on measures of executive functioning offer a basis for identifying alcohol-affected individuals in a manner that does not simply reflect IQ deficits. At the other end of the teratological continuum, we turn to the reporting of threshold effects in dose-response relationships. Here we illustrate the importance of multivariate analyses using data from the Seattle, Washington, longitudinal prospective study on alcohol and pregnancy. Relationships between many neurobehavioral outcomes and measures of prenatal alcohol exposure are monotone without threshold down to the lowest nonzero levels of exposure, a finding consistent with reports from animal studies. In sum, alcohol effects on the developing human brain appear to be a continuum without threshold when dose and behavioral effects are quantified appropriately.

  17. A case of partial sirenomelia and possible vitamin A teratogenesis.

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    Von Lennep, E; El Khazen, N; De Pierreux, G; Amy, J J; Rodesch, F; Van Regemorter, N

    1985-01-01

    Prenatal echographical findings of a partial sirenomelic fetus are described. An attempt was made to terminate pregnancy by administration of prostaglandin F2 alpha, but uterine rupture occurred. The teratogenic role of vitamin A ingested by the mother in the periconceptional period is discussed.

  18. Anticonvulsant teratogenesis 5: observer bias in a cohort study.

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    Harvey, Elizabeth A; Coull, Brent A; Holmes, Lewis B

    2003-06-01

    The most common physical effects of prenatal exposure to the anticonvulsant drugs phenytoin and phenobarbital are midface and digit hypoplasia. These features are subjective in nature, which makes their detection vulnerable to any bias the examiner has, such as an increased expectation that the infant being examined has been exposed prenatally to an anticonvulsant drug. The purpose of this analysis was to determine whether or not there was evidence of observer bias in the detection of presumed anticonvulsant drug-related physical features. The presence or absence of three groups of features were compared: 1) midface hypoplasia, such as anteverted nostrils; 2) digit hypoplasia, e.g., tapered fingers, and 3) other features, e.g., prominent occiput, not known to be affected by exposure to anticonvulsants. These infants were examined by one masked physician examiner, using a study protocol, in three time periods: in two similar time periods, the masked examiner knew that one in four (25%) of the infants to be examined had been exposed to an anticonvulsant drugs; in the third time period, the chance was 50%. The frequencies of the subjective features of midface (odds ratio [OR] = 2.6) and digit hypoplasia (OR = 3.9), but not the other features, were significantly more common in the time periods when the masked examiner knew that there was a 50% chance of exposure to anticonvulsant drugs, compared to the time periods when there was a 25% chance. The findings suggest the effect of observer bias. In addition, there was evidence of context bias, meaning that a study that focuses on determining the presence of specific features will identify them more often.

  19. Protective effect of [6]-gingerol on the ethanol-induced teratogenesis of cultured mouse embryos.

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    Yon, Jung-Min; Baek, In-Jeoung; Lee, Se-Ra; Kim, Mi-Ra; Hong, Jin Tae; Yong, Hwanyul; Lee, Beom Jun; Yun, Young Won; Nam, Sang-Yoon

    2012-01-01

    Excessive ethanol consumption during pregnancy causes fetal alcohol syndrome. We investigated the effect of [6]-gingerol on ethanol-induced embryotoxicity using a whole embryo culture system. The morphological changes of embryos and the gene expression patterns of the antioxidant enzymes cytosolic glutathione peroxidase (cGPx), cytoplasmic Cu/Zn superoxide dismutase (SOD1), and Mn-SOD (SOD2), and SOD activity were examined in the cultured mouse embryos exposed to ethanol (5 μL/3 mL) and/or [6]-gingerol (1×10(-8) or 1×10(-7) μg/mL) for 2 days. In ethanol-exposed embryos, the standard morphological score of embryos was significantly decreased compared with those of the control (vehicle) group. However, cotreatment of embryos with [6]-gingerol and ethanol significantly improved all of the developmental parameters except crownrump length and head length, compared with those of the ethanol alone group. The mRNA expression levels of cGPx and SOD2, not SOD1, were decreased consistently, SOD activity were significantly decreased compared with the control group. However, the decreases in mRNA levels of antioxidant enzymes and SOD activity were significantly restored to the control levels by [6]-gingerol supplement. These results indicate that [6]-gingerol has a protective effect against ethanol-induced teratogenicity during mouse embryogenesis.

  20. Further Development and Validation of the frog Embryo Teratogenesis Assay - Xenopus (FETAX)

    Science.gov (United States)

    1991-02-28

    al. (42) reported teratogenic responses in rabbits, chickens , mice and rats when DMSO was administered at very high doses. However, at low doses few...species (120 hrs or 5 days) and for similar embryological events to occur during exposure. The fathead minnow (Pimephales promelas) has been established in... embryological stages. Differing exposure periods (time) can strongly influence bioassay results as the assumption that internal toxicant levels are equal to the

  1. The effect of intermittent dosing of Nicotiana glauca on teratogenesis in goats

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    Sustained inhibition of fetal movement in livestock species, induced by several poisonous plants, can result in numerous skeletal-contracture malformations. Lupines are responsible for a condition in cattle referred to as “crooked calf syndrome” that occurs when pregnant cattle graze teratogenic lup...

  2. Anagyrine desensitization of peripheral nicotinic acetylcholine receptors. A potential biomarker of quinolizidine alkaloid teratogenesis in cattle.

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    Anagyrine, a teratogenic quinolizidine alkaloid found in certain Lupinus spp., has been proposed to undergo metabolism by pregnant cattle to a piperidine alkaloid which acts inhibit fetal movement, the putative mechanism behind crooked calf syndrome. The objective of this study was to test the hypot...

  3. Valproate-induced teratogenesis in Japanese rice fish (Oryzias latipes) embryogenesis.

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    Wu, Mengmeng; Khan, Ikhlas A; Dasmahapatra, Asok K

    2012-04-01

    Fertilized eggs of Japanese rice fish (medaka) at three developmental stages (Iwamatsu stages 4-30) were exposed to waterborne valproic acid (VPA) (0-80 mM) in hatching solution for 48 h. The amount of valproate to cause 50% mortality (IC(50)) is found to be developmental stage-specific. The embryos were more sensitive to valproate at early stages of development (Iwamatsu stages 4-10) than in the embryos in late stages (Iwamatsu stages 17-30). Valproate exposed embryos have microcephaly and disrupted cardiovasculature with delayed vessel circulation, thrombus formation, and slow heart rate. The hatching efficiency is also reduced by valproate exposure due to developmental delay. The mRNA analysis of nine genes belong to oxidative stress (catalase, gsr, gst), neurogenesis (iro3, wnt1, shh, otx2, nlgn3b) and cell cycle regulation (ccna2) have been done. It was observed that the genes belong to oxidative stress remained unaltered after valproate exposure. However, some of the genes belong to neurogenesis (wnt1,shh, otx2 and nlgn3b) and cell cycle (ccna2) showed developmental stage-specific alteration after valproate exposure. This study indicates that valproate is able to induce some of the phenotypic features which are analogous to human fetal valproate syndrome (FVS). Modulation of genes expressed in neural tissues indicates that this fish can be used to analyze the mechanisms of many neurobehavioral disorders like Autism spectrum disorder (ASD) in human. Published by Elsevier Inc.

  4. Embryonic oxidative stress as a mechanism of teratogenesis with special emphasis on diabetic embryopathy.

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    Ornoy, Asher

    2007-07-01

    Reactive oxygen species (ROS) are involved in the etiology of numerous diseases including cardio-vascular diseases and diabetes mellitus. There is evidence that several teratogens affect the developing embryo by increasing its oxidative stress and, because of its relatively weak antioxidant defense, especially at the early stages of organogenesis, result in severe embryonic damage. This mechanism seems to operate in diabetes-induced embryonic damage as well as in the mechanism of teratogenicity caused by ionizing radiation, hypoxia, alcohol and cocaine use and cigarette smoking. We studied the role of oxidative stress in diabetic induced embryopathy, both in vivo and in vitro. Under diabetic condition there was a significant decrease in the activity of endogenous antioxidant enzymes and of vitamins C and E in the embryos and their yolk sacs. The lowest activity was observed in the malformed experimental embryos when compared to experimental embryos without anomalies. Similar results were obtained in the Cohen diabetic rats, where the diabetic prone (CDs) rats were unable to increase their antioxidant enzyme activity in spite of the diabetes. Studies performed by other investigators show similar results. Human and animal studies show that the main mechanism of fetal damage induced by high levels of ionizing irradiation, cocaine and alcohol abuse, hypoxia and cigarette smoking is also by increased embryonic oxidative stress. Similarly, several drugs exert their teratogenic activity via embryonic oxidative stress. Abnormal placentation may also cause enhanced placental oxidative stress, resulting in embryonic death, preeclampsia or congenital anomalies. Inability of the developing embryo to cope with that stress may result in embryonic death and/or congenital anomalies. Animal studies also show that a variety of antioxidants are effective in decreasing the damaging effects of heightened oxidative stress induced by teratogens. Effective antioxidants, which might also be of clinical use, include vitamins C and E, carotenoids, folic acid, as well as synthetic products. Appropriate clinical studies with antioxidants in pregnancies of high risk to develop oxidative stress are needed, since non-toxic antioxidants might prove an efficient and inexpensive way to reduce the rate of some serious and sometimes fatal congenital anomalies.

  5. Pharmacological safety during pregnancy: the principles of teratogenesis and teratogenicity of drugs

    Directory of Open Access Journals (Sweden)

    O. V. Reshet’ko

    2016-01-01

    Full Text Available Drugs used during pregnancy simultaneously have an impact on 2 populations — fetal and maternal. The article is devoted to teratogenic drugs exposition; it points out the need for further research in the field of pharmaceutical safety during pregnancy. Authors analyzed the multiplicity of the congenital disorders in infants, including birth defects cuased by drug application. For ethical reasons, researchers can not conduct any studies on the safety of medicines during pregnancy. Authors suppose that collection of additional information during the marketing phase as a part of the routine pharmacovigilance program and the targeted pharmacoepidemiological trials with the current evaluation of the teratogenic risk of drugs will help to achieve the goals.

  6. Using Zebrafish to Implement a Course-Based Undergraduate Research Experience to Study Teratogenesis in Two Biology Laboratory Courses.

    Science.gov (United States)

    Sarmah, Swapnalee; Chism, Grady W; Vaughan, Martin A; Muralidharan, Pooja; Marrs, Jim A; Marrs, Kathleen A

    2016-08-01

    A course-based undergraduate research experience (CURE) spanning three semesters was introduced into freshman and sophomore biology classes, with the hypothesis that participation in a CURE affects skills in research, communication, and collaboration, which may help students persist in science. Student research projects were centered on the hypothesis that nicotine and caffeine exposure during early development affects gastrulation and heart development in zebrafish. First, freshmen generated original data showing distinct effects of embryonic nicotine and caffeine exposure on zebrafish heart development and function. Next, Cell Biology laboratory students continued the CURE studies and identified novel teratogenic effects of nicotine and caffeine during gastrulation. Finally, new freshmen continued the CURE research, examining additional toxicant effects on development. Students designed new protocols, made measurements, presented results, and generated high-quality preliminary data that were studied in successive semesters. By implementing this project, the CURE extended faculty research and provided a scalable model to address national goals to involve more undergraduates in authentic scientific research. In addition, student survey results support the hypothesis that CUREs provide significant gains in student ability to (1) design experiments, (2) analyze data, and (3) make scientific presentations, translating into high student satisfaction and enhanced learning.

  7. Maternal use of antiepileptic drugs and the risk of major congenital malformations: a joint European prospective study of human teratogenesis associated with maternal epilepsy.

    NARCIS (Netherlands)

    E.B. Samren (Bettina); C.M. van Duijn (Cornelia); S. Koch; V.K. Hiilesma; H. Klepel; A.H. Bardy; B. Mannegetta; A.W. Deichl; E. Gaily; M.L. Granstrom; H. Meinardi; D.E. Grobbee (Diederick); D. Lindhout (Dick); A. Hofman (Albert)

    1997-01-01

    textabstractPURPOSE: To quantify the risks of intrauterine antiepileptic drug (AED) exposure in monotherapy and polytherapy. METHODS: Data from five prospective European studies totaling 1,379 children were pooled and reanalyzed. Data were available for 1,221 children exposed to AED during pregnancy

  8. Hyperglycemia induces embryopathy, even in the absence of systemic maternal diabetes: an in vivo test of the fuel mediated teratogenesis hypothesis.

    Science.gov (United States)

    Baack, Michelle L; Wang, Chunlin; Hu, Shanming; Segar, Jeffrey L; Norris, Andrew W

    2014-07-01

    Embryonic exposure to excess circulating fuels is proposed to underlie diabetic embryopathy. To isolate the effects of hyperglycemia from the many systemic anomalies of diabetes, we infused 4 mg/min glucose into the left uterine artery of non-diabetic pregnant rats on gestation days (GD) 7-9. Right-sided embryos and dams exhibited no glucose elevation. Embryos were assessed on GD13, comparing the left versus right uterine horns. Hyperglycemic exposure increased rates of embryopathy, resorptions, and worsened embryopathy severity. By contrast, saline infusion did not affect any of these parameters. To assess for possible embryopathy susceptibility bias between uterine horns, separate dams were given retinoic acid (25mg/kg, a mildly embryopathic dose) systemically on GD7.5. The resultant embryopathy rates were equivalent between uterine horns. We conclude that hyperglycemia, even in the absence of systemic maternal diabetes, is sufficient to produce in vivo embryopathy during organogenesis. Copyright © 2014 Elsevier Inc. All rights reserved.

  9. Hyperglycemia Induces Embryopathy, Even in the Absence of Systemic Maternal Diabetes: An In Vivo Test of the Fuel Mediated Teratogenesis Hypothesis

    OpenAIRE

    Baack, Michelle L.; Wang, Chunlin; Hu, Shanming; Segar, Jeffrey L.; Norris, Andrew W.

    2014-01-01

    Embryonic exposure to excess circulating fuels is proposed to underlie diabetic embryopathy. To isolate the effects of hyperglycemia from the many systemic anomalies of diabetes, we infused 4 mg/min glucose into the left uterine artery of non-diabetic pregnant rats on gestation days (GD) 7–9. Right-sided embryos and dams exhibited no glucose elevation. Embryos were assessed on GD13, comparing the left versus right uterine horns. Hyperglycemic exposure increased rates of embryopathy, resorptio...

  10. L-cysteine, N-acetyl-L-cysteine, and glutathione protect xenopus laevis embryos against acrylamide-induced malformations and mortality in the frog embryo teratogenesis assay (FETAX)

    Science.gov (United States)

    Dietary acrylamide is largely derived from heat-induced reactions between the amino group of the free amino acid asparagine and carbonyl groups of glucose and fructose during heat processing (baking, frying) of plant-derived foods such as potato fries and cereals. After consumption, acrylamide is a...

  11. Mycotoxin Contamination of Agricultural Products in the Southern United States and Approaches to Reducing it from Pre-harvest to Final Food Products

    Science.gov (United States)

    Mycotoxins represent >300 fungal natural products. Some, notably aflatoxins, trichothecenes, zearalenones, ochratoxins, patulin and fumonisins frequently contaminate cereal grains, causing acute and chronic illnesses in livestock and humans, including teratogenesis, carcinogenesis, endocrine disrup...

  12. USAFSAM (USAF School of Aerospace Medicine) Review and Analysis of Radiofrequency Radiation Bioeffects Literature: Third Report.

    Science.gov (United States)

    1984-03-01

    Rosenbaum, and W.F. Pickard THE RELATION OF TERATOGENESIS IN TENEBRIO MOLITOR TO THE INCIDENCE OF LOW-LEVEL MICROWAVES IEEE Trans. ictowave Theory and Tech...TERATOGENESIS IN TENEBRIO MOLITOR TO THE INCIDENCE OF LOW-LEVEL MICROWAVES IEEE Trans. Microwave Theory and Tech., Vol. 23, No. II, pp. 929-931 (1975) (11...RFR EVOKED-POTENTIAL STRESS EXPOSURE-SYSTEM TENEBRIO GUINEA-PIG TERATOGENIC HAMSTER THERMOREGULATION HAPLOTYPE THRESHOLD HFMATOLOGY TRACER HISTOLOGY

  13. Characterization of the Pathological and Biochemical Markers that Correlate to the Clinical Features of Autism

    Science.gov (United States)

    2012-10-01

    teratogenesis, neuro- developmental deficits, and cancer . Toxicol Sci 108:4–18 56. Wells PG, Bhuller Y, Chen CS, Jeng W, Kasapinovic S, Kennedy JC...Hetzler BE, Griffin JL (1981) Infantile autism and the temporal lobe of the brain. J Autism Dev Disord 11:317–330 64. Zilbovicius M, Boddaert N, Belin P

  14. Potential protective effect of L-cysteine against the toxicity of acrylamide and furan in exposed Xenopus laevis embryos: an interaction study

    Science.gov (United States)

    The embryo toxicities of two food-processing-induced toxic compounds, acrylamide and furan, with and without added L-cysteine were examined individually and in mixtures using the frog embryo teratogenesis assay-Xenopus (FETAX). The following measures of developmental toxicity were used (a) 96-h LC5...

  15. Quantitative indicators of teratological variability of Kazakhstan tulips in nature and in culture

    Directory of Open Access Journals (Sweden)

    Anna Ivashchenko

    2014-04-01

    Full Text Available Тhe various ability to form anomalies in 26 species of wild tulips based on years of research was established. Species with minimal (less than 1.5% and the maximum inclination to teratogenesis (≤ 3.5% were identified. Also the different degrees of increasing in the number of teratomas (from double to ten times in the conditions of introduction of different species were found.

  16. Regulation of Electromagnetic Radiation: A Confusing Course through Modulating E and H Waves.

    Science.gov (United States)

    1982-02-15

    developmental abnormali- ties. Teratogenesis involves those abnormalities induced while the fetus is being carried in the womb . Mutagenic Effects There is...of 10,000 human fetuses which have been exposed to RFR while in the womb . For several years Jose Daels, a Belgian obstetrician, has used 2450 MHz CW...the spectrum to be used efficiently (and for the related industries to be profitable), emitters and their uses should not be limited by artificial man

  17. Safety of irradiated foods

    Energy Technology Data Exchange (ETDEWEB)

    Iwahara, Shigeo (Foods Medicines Safety Center (Japan)); Kobayashi, Kazuo

    1983-01-01

    The safety of 7 irradiated foods (potato, onion, rice, wheat, vienna sausage, fish paste and mandarine orange), in terms of 2-year long-term toxic effect, reproductive physiology and possible teratogenesis, was studied using 3 generations of rats, mice and monkeys. The genetic toxicity was studied by means of various mutagenicity tests. The details of the studies conducted by the authors to date and some overseas data were reported. The available data showed no toxic effect.

  18. USAFSAM Review and Analysis of Radiofrequency Radiation Bioeffects Literature: Second Report.

    Science.gov (United States)

    1982-05-01

    Rosenbaum, and W. F. Pickard THE RELATION OF TERATOGENESIS IN TENEBRIO MOLITOR TO THE INCIDENCE OF LOW-LEVEL MICROWAVES IEEE Trans. Microwave Theory...Teratogenic and developmental abnormalities; ’N VIVO; TENEBRIO MOLITOR (DARKLING BEETLE) Effect type: Abnormalities in emergent adult beetles due to RFR...early pupae of the mealworm beetle, Tenebrio molitor . Each pupa was inserted in a waveguide and irradiated therein at waveguide powers of 80 mW for

  19. USAFSAM (USAF School of Aerospace Medicine) Review and Analysis of Radiofrequency Radiation Bioeffects Literature: Fourth Report.

    Science.gov (United States)

    1984-05-01

    TENEBRIO MOLITOR TO THE INCIDENCE OF LOW-LEVEL MICROWAVES IEEE Trans. Microwave Theory and Tech., Vol. 23, No. 11, pp. 929-931 (1975) (II-44) 57 McRee...OF TERATOGENESIS IN TENEBRIO MOLITOR TO THE INCIDENCE OF LOW-LEVEL MICROWAVES IEEE Trans. Microwave Theory and Tech., Vol. 23, No. 11, pp. 929-931...EKG RAT EMBRYO RECTAL ENDOCRINOLOGIC REPEATED-ACQUISITION ENVIRONMENTAL REVIEW EPIDEMIOLOGIC RFR ESTRUS STRESS EVOKED-POTENTIAL TENEBRIO EXPOSURE

  20. Critical pneumonia complicating early-stage pregnancy.

    Science.gov (United States)

    Mercieri, Marco; Di Rosa, Roberta; Pantosti, Annalisa; De Blasi, Roberto Alberto; Pinto, Giovanni; Arcioni, Roberto

    2010-03-01

    We present a case of community-acquired methicillin-resistant Staphylococcus aureus necrotizing pneumonia, Panton-Valentine leukocidin positive, in a woman at 14 weeks of pregnancy. To our knowledge, this is the first case reporting this critical lung infection occurring during an early phase of pregnancy. This case study alerts physicians to the increasing worldwide spread of these uncommon yet virulent and potentially lethal infections. In our patient, antibiotic therapy with linezolid plus rifampin started at 14 weeks of pregnancy had a successful outcome without inducing toxicity or teratogenesis in the fetus.

  1. The Impact of Proposed Radio Frequency Radiation Standards on Military Operations.

    Science.gov (United States)

    1985-03-01

    Teratogenesis in Tenebrio Molitor to the Incidence of Low-Level Microwaves," IEEE Trans. Microwave The- ory and Tech., 23(11):929-931, 1975. 47. Green, D.R...F.J. Rosenbaum, and W.F. Pickard, "Intensity of Microwave Irradia- tion and the Teratogenic Response of Tenebrio molitor ," Radio Sol., Vol. 14, No. 6S...pp. 181-185 (1979). 48. Pickard, W.F., and R.G. Olsen, "Developmental Effects of MIcrowaves on Tenebrio ; Influences of Culturing Protocol and of

  2. Draft Supplement to Final Environmental Statement on Continental United States (CONUS) Over-the-Horizon Backscatter (OTH-B) Radar System, Penobscot, Washington, Somerset Counties, Maine.

    Science.gov (United States)

    1981-08-01

    development of eggs of birds and the pupae of the darkling beetle, Tenebrio molitor , have also been performed with RFR. Although the term uiually refers... Tenebrio Molitor ," Radio Sci., Vol. 14, No. 6S, pp. 165-171 (1979). Greene, F. M., "Development of Magnetic Near-Field Probes," U.S. Department of...Liu, L. M., F. J. Rosenbaum, and W. F. Pickard, "The Relation of Teratogenesis in Tenebrio Molitor to the Incidence of Low-Level Microwaves," IEEE

  3. Prevention of valproic acid-induced neural tube defects by sildenafil citrate.

    Science.gov (United States)

    Tiboni, Gian Mario; Ponzano, Adalisa

    2015-08-15

    This study was undertaken to test the effects of sildenafil citrate (SC), a type 5 phosphodiesterase inhibitor, on valproic acid (VPA)-induced teratogenesis. On gestation day (GD) 8, ICR (CD-1) mice were treated by gastric intubation with SC at 0 (vehicle), 1.0, 2.5, 5.0 or 10mg/kg. One hour later, animals received a teratogenic dose of VPA (600mg/kg) or vehicle. Developmental endpoints were evaluated near the end of gestation. Twenty-eighth percent of fetuses exposed to VPA had neural tube defects (exencephaly). Pretreatment with SC at 2.5, 5.0 or 10mg/kg significantly reduced the rate of VPA-induced exencephaly to 15.9%, 13.7%, and 10.0%, respectively. Axial skeletal defects were observed in 75.8% of VPA-exposed fetuses. Pre-treatment with SC at 10mg/kg, but not at lower doses, significantly decreased the rate of skeletally affected fetuses to 61.6%. These results show that SC, which prolongs nitric oxide (NO) signaling action protects from VPA-induced teratogenesis. Copyright © 2015 Elsevier Inc. All rights reserved.

  4. Streptozotocin-Induced Diabetes Models: Pathophysiological Mechanisms and Fetal Outcomes

    Directory of Open Access Journals (Sweden)

    D. C. Damasceno

    2014-01-01

    Full Text Available Glucose homeostasis is controlled by endocrine pancreatic cells, and any pancreatic disturbance can result in diabetes. Because 8% to 12% of diabetic pregnant women present with malformed fetuses, there is great interest in understanding the etiology, pathophysiological mechanisms, and treatment of gestational diabetes. Hyperglycemia enhances the production of reactive oxygen species, leading to oxidative stress, which is involved in diabetic teratogenesis. It has also been suggested that maternal diabetes alters embryonic gene expression, which might cause malformations. Due to ethical issues involving human studies that sometimes have invasive aspects and the multiplicity of uncontrolled variables that can alter the uterine environment during clinical studies, it is necessary to use animal models to better understand diabetic pathophysiology. This review aimed to gather information about pathophysiological mechanisms and fetal outcomes in streptozotocin-induced diabetic rats. To understand the pathophysiological mechanisms and factors involved in diabetes, the use of pancreatic regeneration studies is increasing in an attempt to understand the behavior of pancreatic beta cells. In addition, these studies suggest a new preventive concept as a treatment basis for diabetes, introducing therapeutic efforts to minimize or prevent diabetes-induced oxidative stress, DNA damage, and teratogenesis.

  5. The radiation protection effect of propolis to embryonic effects in ICR mice

    Energy Technology Data Exchange (ETDEWEB)

    Suzuki, Sachiyo; Gu, Yeunhwa; Suzuki, Ikukatsu; Hasegawa, Takeo; Yamamoto, Youichi; Muto, Hroe; Yanagisawa, Takaharu; Iwasa, Toshihiro [Suzuka University, Mie (Japan)

    1999-07-01

    The profit which radiation brought to the Homo sapiens is very big. But, radiation has even harmful parameter for the human besides one case. After effect on man to the radiation is thought about, the individiual of which sensibility is the highest is a fetus. As for the embryonic death rate, propolis was administered, and obviously embryonic death rate was poorer than the 1.5Gy independent exposure group, and significant difference was recognized by a 1.5Gy radiation exposure group (p<0.001). It had a 1.5Gy radiation exposure group made clear by this research fetal death rate propolis administer more only 1.5Gy exposure fetal death rate development low (p<0.001). Fetal death rate wasn't recognized by propolis administration group (Sham control). As for the teratogenesis rate, propolis was administered, and the teratogenesis rate of the 1.5Gy radiation exposure group was higher than the 1.5Gy radiation independent exposure group. But, this is thought anamorphosis appear by propolis administration so long as there was much number of the survival fetuses. The modality of the external malformation which appeared was exencephaly, anaomalise of tail, anophthalmia, cleft palate, hydrcephaly, and so on. As for the fetal body weight were recognized, a 1.5Gy group and propolis administered 1.5Gy radiation exposure group decreased in comparison with the control as for significant difference (p<0.001)

  6. Pregestational Obesity-Induced Embryopathy.

    Science.gov (United States)

    Suárez-Román, Gipsis; Fernández-Romero, Tammy; Perera-Calderín, Alfredo J; Rodríguez-Sosa, Víctor M; Arranz, Celeste; Hernández, Sonia Clapés

    2016-09-01

    Several epidemiologic studies in humans have shown a relationship between pregestational obesity and congenital malformations in offsprings. However, there are no experimental evidence in animal models of obesity and pregnancy that reproduce the teratogenesis induced by this pathological condition. To evaluate the effect of monosodium glutamate-induced obesity on embryonic development. Female rats received subcutaneously (4 mg/g body weight) monosodium glutamate (MSG) solution or saline solution 0.9% (vehicle control) at days 2, 4, 6, 8, and 10 of life. At 90 days of age, all animals were mated, and on day 11 of pregnancy, the animals were killed. Biochemical variables (glucose, triglycerides, total cholesterol, and insulin) were determined in plasma of dams and embryo homogenates (DNA and protein content, advanced oxidation protein products). Embryos were evaluated for malformations, crown-rump length, and somite number. Obese rats presented higher triglyceride levels as compared to nonobese rats. Increased proportion of malformed embryos, decreased crown-rump length, somite number, DNA, and protein content were observed in offspring of obese rats. The model of obesity induced with MSG reproduces the maternal obesity-induced teratogenesis. The hypertriglyceridemia observed in MSG obese pregnant rats could be related to increased birth defect. © The Author(s) 2016.

  7. Role of selenium toxicity and oxidative stress in aquatic birds

    Science.gov (United States)

    Hoffman, D.J.

    2002-01-01

    Adverse effects of selenium (Se) in wild aquatic birds have been documented as a consequence of pollution of the aquatic environment by subsurface agricultural drainwater and other sources. These effects include mortality, impaired reproduction with teratogenesis, reduced growth, histopathological lesions and alterations in hepatic glutathione metabolism. A review is provided, relating adverse biological effects of Se in aquatic birds to altered glutathione metabolism and oxidative stress. Laboratory studies, mainly with an organic form of Se, selenomethionine, have revealed oxidative stress in different stages of the mallard (Anas platyrhynchos) life cycle. As dietary and tissue concentrations of Se increase, increases in plasma and hepatic GSH peroxidase activities occur, followed by dose-dependent increases in the ratio of hepatic oxidized to reduced glutathione (GSSG:GSH) and ultimately hepatic lipid peroxidation measured as an increase in thiobarbituric acid reactive substances (TBARS). One or more of these oxidative effects were associated with teratogenesis (4.6 ppm wet weight Se in eggs), reduced growth in ducklings (15 ppm Se in liver), diminished immune function (5 ppm Se in liver) and histopathological lesions (29 ppm Se in liver) in adults. Manifestations of Serelated effects on glutathione metabolism were also apparent in field studies in seven species of aquatic birds. Reduced growth and possibly immune function but increased liver:body weight and hepatic GSSG:GSH ratios were apparent in American avocet (Recurvirostra americana) hatchlings from eggs containing 9 ppm Se. In blacknecked stilts (Himantopus mexicanus), which contained somewhat lower Se concentrations, a decrease in hepatic GSH was apparent with few other effects. In adult American coots (Fulica americana), signs of Se toxicosis included emaciation, abnormal feather loss and histopathological lesions. Mean liver concentrations of 28 ppm Se (ww) in the coots were associated with elevated

  8. The study of the radiation protection of propolis to the radiation effects in mice

    Energy Technology Data Exchange (ETDEWEB)

    Gu, Y.H.; Suzuki, Ikukatsu; Hasegawa, Takeo; Muto, H. [Suzuka Univ. of Medical Science, Mie (Japan); Yanagisawa, Takaharu; Iwasa, Toshihiro; Bamen, K.

    2000-05-01

    The profit which radiation brought to the Homo sapiens is very big. But, radiation has even harmful parameter for the human besides one case. After effect on man to the radiation is thought about, the individual of which sensibility is the highest is a fetus. Therefore, even an effects to this fetus is grasped precisely, and protection criterion and resource are decided from the viewpoint of the protection of radiation as well. If it does so, a child and maturitas aren't so difficult as in the protection of radiation and the managerial side. It was examined about control group, propolis administration chisels for medical use group, 1.5 Gy independent exposure group and propolis pluse 1.5 Gy group in this study. It was examined about the protection of radiation of propolis which to malformation, fetal death, arrested development, and so on in the organogenesis (8 days post conception) being done when sensibility is the highest against the teratogenesis. Preimplantation death rate was compared with the control group and the sham control group, and statistical significant difference wasn't recognized by a 1.5 Gy radiation independent exposure group, propolis administration 1.5 Gy radiation exposure group. As for the embryonic death rate, propolis was administered, and obviously embryonic death rate was poorer than the 1.5 Gy independent exposure group, and significant difference was recognized by a 1.5 Gy radiation exposure group (p<0.001). It has a 1.5 Gy radiation exposure group made clear by this research fetal death rate propolis administer more only 1.5 Gy exposure fetal death rate development low (p<0.001). Fetal death rate wasn't recognized by propolis administration group (Sham control). As for the teratogenesis rate, propolis was administered, and the teratogenesis rate of the 1.5 Gy radiation exposure group was higher than the 1.5 Gy radiation independent exposure group. But, this is thought anamorphosis appear by propolis administration so

  9. Teratogenic mechanisms associated with prenatal medication exposure.

    Science.gov (United States)

    van Gelder, Marleen M H J; van Rooij, Iris A L M; de Jong-van den Berg, Lolkje T W; Roeleveld, Nel

    2014-01-01

    Birth defects may originate through multiple mechanisms and may be caused by a variety of possible exposures, including medications in early pregnancy. In this review, we describe six principal teratogenic mechanisms suspected to be associated with medication use: folate antagonism, neural crest cell disruption, endocrine disruption, oxidative stress, vascular disruption, and specific receptor- or enzyme-mediated teratogenesis. Knowledge about these mechanisms, for some of which evidence is mainly derived from animal models, may not only be relevant for etiologic and post-marketing research, but may also have implications for prescribing behavior for women of reproductive age. Since combinations of seemingly unrelated medications may have effects through similar teratogenic mechanisms, the risk of birth defects may be strongly increased in multi-therapy. © 2014 Société Française de Pharmacologie et de Thérapeutique.

  10. Oxidative Stress, Unfolded Protein Response, and Apoptosis in Developmental Toxicity

    Science.gov (United States)

    Kupsco, Allison; Schlenk, Daniel

    2016-01-01

    Physiological development requires precise spatiotemporal regulation of cellular and molecular processes. Disruption of these key events can generate developmental toxicity in the form of teratogenesis or mortality. The mechanism behind many developmental toxicants remains unknown. While recent work has focused on the unfolded protein response (UPR), oxidative stress, and apoptosis in the pathogenesis of disease, few studies have addressed their relationship in developmental toxicity. Redox regulation, UPR, and apoptosis are essential for physiological development and can be disturbed by a variety of endogenous and exogenous toxicants to generate lethality and diverse malformations. This review examines the current knowledge of the role of oxidative stress, UPR, and apoptosis in physiological development as well as in developmental toxicity, focusing on studies and advances in vertebrates model systems. PMID:26008783

  11. Initial evaluation of developmental malformation as an end point in mixture toxicity hazard assessment for aquatic vertebrates

    Energy Technology Data Exchange (ETDEWEB)

    Dawson, D.A.; Wilke, T.S. (Department of Animal Science, College of Veterinary Medicine, University of Tennessee, Knoxville (USA))

    1991-04-01

    The joint toxic action of three binary mixtures was determined for the embryo malformation endpoint of the aquatic FETAX (frog embryo teratogenesis assay: Xenopus) test system. Osteolathyrogenic compounds and short-chain carboxylic acids, representing separate, distinct modes of action for induction of malformation, were selected for testing in 96-hr, static-renewal tests. Three mixtures were tested for each combination, with each combination being tested on three separate occasions. Using toxic unit analysis, the combination of osteolathyrogens and the combination of carboxylic acids produced strictly additive (concentration addition) rates of malformation, while the combination of an osteolathyrogen and a carboxylic acid was less-than-additive (response addition) for induction of malformation. Therefore, developmental malformation may have value as an endpoint in mixture toxicity hazard assessment.

  12. Selective Serotonin Reuptake Inhibitor (SSRI) Antidepressants in Pregnancy and Congenital Anomalies

    DEFF Research Database (Denmark)

    Jordan, Sue; Morris, Joan K.; Davies, Gareth I.

    2016-01-01

    of first day of last menstrual period (LMP). Methods and Findings:Three population-based EUROCAT congenital anomaly registries- Norway (2004–2010), Wales (2000–2010) and Funen, Denmark (2000–2010)—were linked to the electronic healthcare databases holding prospectively collected prescription information...... of anomalies and severe CHD was reduced when SSRI prescriptions were stopped or paused preconception, and increased when >1 prescription was recorded, but differences were not statistically significant. The dose-response relationship between severe CHD and SSRI dose (meta-regression OR 1.49, 1.......12–1.97) was consistent with SSRI-exposure related risk. Analyses in Wales suggested no associations between anomalies and diagnosed depression. Conclusion: The additional absolute risk of teratogenesis associated with SSRIs, if causal, is small. However, the high prevalence of SSRI use augments its public health...

  13. Pharmacogenetic evaluation of ABCB1, Cyp2C9, Cyp2C19 and methylene tetrahydrofolate reductase polymorphisms in teratogenicity of anti-epileptic drugs in women with epilepsy

    Directory of Open Access Journals (Sweden)

    Manna Jose

    2014-01-01

    Full Text Available Aim: Pregnancy in women with epilepsy (WWE who are on anti-epileptic drugs (AEDs has two- to three-fold increased risk of fetal malformations. AEDs are mostly metabolized by Cyp2C9, Cyp2C19 and Cyp3A4 and transported by ABCB1. Patients on AED therapy can have folate deficiency. We hypothesize that the polymorphisms in ABCB1, Cyp2C9, Cyp2C19 and methylene tetrahydrofolate reductase (MTHFR might result in differential expression resulting in differential drug transport, drug metabolism and folate metabolism, which in turn may contribute to the teratogenic impact of AEDs. Materials and Methods: The ABCB1, Cyp2C9, Cyp2C19 and MTHFR polymorphisms were genotyped for their role in teratogenic potential and the nature of teratogenecity in response to AED treatment in WWE. The allelic, genotypic associations were tested in 266 WWE comprising of 143 WWE who had given birth to babies with WWE-malformation (WWE-M and 123 WWE who had normal offsprings (WWE-N. Results: In WWE-M, CC genotype of Ex07 + 139C/T was overrepresented (P = 0.0032 whereas the poor metabolizer allele FNx012 and FNx012 FNx012 genotype of CYP2C219 was significantly higher in comparison to WWE-N group (P = 0.007 and P = 0.005, respectively. All these observations were independent of the nature of malformation (cardiac vs. non cardiac malformations. Conclusion: Our study indicates the possibility that ABCB1 and Cyp2C19 may play a pivotal role in the AED induced teratogenesis, which is independent of nature of malformation. This is one of the first reports indicating the pharmacogenetic role of Cyp2C19 and ABCB1 in teratogenesis of AED in pregnant WWE.

  14. A role for glutathione, independent of oxidative stress, in the developmental toxicity of methanol

    Energy Technology Data Exchange (ETDEWEB)

    Siu, Michelle T.; Shapiro, Aaron M. [Division of Biomolecular Sciences, Faculty of Pharmacy, University of Toronto, Toronto, Ontario (Canada); Wiley, Michael J. [Division of Anatomy, Faculty of Medicine, University of Toronto, Toronto, Ontario (Canada); Wells, Peter G., E-mail: pg.wells@utoronto.ca [Division of Biomolecular Sciences, Faculty of Pharmacy, University of Toronto, Toronto, Ontario (Canada); Department of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, Toronto, Ontario (Canada)

    2013-12-15

    Oxidative stress and reactive oxygen species (ROS) have been implicated in the teratogenicity of methanol (MeOH) in rodents, both in vivo and in embryo culture. We explored the ROS hypothesis further in vivo in pregnant C57BL/6J mice. Following maternal treatment with a teratogenic dose of MeOH, 4 g/kg via intraperitoneal (ip) injection on gestational day (GD) 12, there was no increase 6 h later in embryonic ROS formation, measured by 2′,7′-dichlorodihydrofluorescin diacetate (DCFH-DA) fluorescence, despite an increase observed with the positive control ethanol (EtOH), nor was there an increase in embryonic oxidatively damaged DNA, quantified as 8-oxo-2′-deoxyguanosine (8-oxodG) formation. MeOH teratogenicity (primarily ophthalmic anomalies, cleft palate) also was not altered by pre- and post-treatment with varying doses of the free radical spin trapping agent alpha-phenyl-N-tert-butylnitrone (PBN). In contrast, pretreatment with L-buthionine-(S,R)-sulfoximine (BSO), an inhibitor of glutathione (GSH) synthesis, depleted maternal hepatic and embryonic GSH, and enhanced some new anomalies (micrognathia, agnathia, short snout, fused digits, cleft lip, low set ears), but not the most common teratogenic effects of MeOH (ophthalmic anomalies, cleft palate) in this strain. These results suggest that ROS did not contribute to the teratogenic effects of MeOH in this in vivo mouse model, in contrast to results in embryo culture from our laboratory, and that the protective effect of GSH in this model may arise from its role as a cofactor for formaldehyde dehydrogenase in the detoxification of formaldehyde. - Highlights: • In vivo, a free radical scavenger did not block methanol (MeOH) teratogenesis. • MeOH did not increase embryonic reactive oxygen species formation or DNA oxidation. • MeOH teratogenesis was enhanced by glutathione (GSH) depletion. • GSH may protect as the cofactor for formaldehyde dehydrogenase (ADH3). • Formaldehyde may be a ROS

  15. Strain differences in developmental vulnerability to alcohol exposure via embryo culture in mice.

    Science.gov (United States)

    Chen, Yuanyuan; Ozturk, Nail Can; Ni, Lijun; Goodlett, Charles; Zhou, Feng C

    2011-07-01

    Prenatal alcohol exposure can result in varying degrees of neurodevelopmental deficits, growth retardation, and facial dysmorphology. Variation in these adverse outcomes not only depends on the dose and pattern of alcohol exposure but also on less well understood interactions among environmental, genetic, and maternal factors. The current study tested the hypothesis that fetal genotype is an important determinant of ethanol teratogenesis by evaluating effects of ethanol exposure via embryo culture in 3 inbred strains of mice known to differ in the vulnerability of prenatal alcohol exposure in vivo. Three strains of mice, C57BL/6N (B6), DBA/2 (D2), and 129S6/SvEvTac (129S6) were assessed in a whole embryo culture beginning on embryonic day 8.25, with or without alcohol administration at 88 mM for 6 hours followed by 42 hours culture in ethanol-free media. Contrasting strain differences in susceptibility were observed for the brain, the face, and other organ systems using the Maele-Fabry and Picard scoring system. The forebrain, midbrain, hindbrain, heart, optic vesicle, caudal neural tube, and hindlimbs of the B6 mice were severely delayed in growth, whereas compared to the respective controls, only the forebrain and optic vesicle were delayed in the D2 mice, and no effects were found in the 129S6 mice. A large number of cleaved (c)-caspase 3 positive (+) cells were found in regions of the brain, optic vesicles, cranial nerve nuclei V, VII, VIII, and IX as well as the craniofacial primordial; only a few were found in corresponding regions of the B6 controls. In contrast, only a small number of c-caspase 3 immunostaining cells were found in either the alcohol treated or the controls of the D2 embryos and in 129S6 embryos. The independent apoptotic markers TUNEL and Nile blue staining further confirmed the strain differences in apoptotic responses in both the neural tube and craniofacial primordia. Under embryo culture conditions, in which alcohol exposure factors

  16. Effect of chronic maternal ethanol administration on nitric oxide synthase activity in the hippocampus of the mature fetal guinea pig.

    Science.gov (United States)

    Kimura, K A; Parr, A M; Brien, J F

    1996-08-01

    Nitric oxide is a novel messenger that is involved in neuronal cell-cell communication and seems to play a neurotrophic role in normal brain development. Chronic prenatal ethanol exposure can produce central nervous system (CNS) teratogenesis, in which one of the target sites is the hippocampus. The main objective of our study was to test the following hypothesis: chronic maternal administration of an ethanol dosage regimen that produces CNS teratogenesis decreases nitric oxide synthase (NOS) activity in the fetal hippocampus. The ontogeny of NOS activity in the hippocampus of the developing guinea pig was further elucidated at two prenatal and two postnatal ages. The effects of chronic maternal oral administration of 4 g of ethanol/kg maternal body weight/day, isocaloric sucrose and pair feeding, or water [given as two equally divided doses 2 hr apart from gestational day (GD) 2 to GD 61] on body, brain, and hippocampal weights and hippocampal NOS activity were determined in the mature fetal guinea pig at GD 62 (term, about GD 68). NOS activity in the 25,000 x g supernatant fraction of hippocampal homogenate was measured using an optimized radiometric assay, based on the oxidation of L-[14C]arginine to L-[14C]citrulline. For the chronic ethanol regimen, the maternal blood ethanol concentration at 1 hr after the second divided dose on GD 57 was 157 +/- 45 mg/dl. Chronic maternal administration of ethanol decreased fetal body, brain, and hippocampal weights, compared with the isocaloric-sucrose/pair-fed and water treatment groups. The rate of L-[14C]citrulline formation and NOS activity in the fetal hippocampus were decreased in the ethanol treatment group, compared with the isocaloric-sucrose/ pair-fed and water treatment groups. There was no difference in the rate of L-[14C]citrulline formation, NOS activity, and fetal hippocampal and body weights between the isocaloric-sucrose/pair-fed and water treatment groups; however, fetal brain weight was decreased in the

  17. Gene expression changes in C57BL/6J and DBA/2J mice following prenatal alcohol exposure.

    Science.gov (United States)

    Downing, Chris; Flink, Stephen; Florez-McClure, Maria L; Johnson, Thomas E; Tabakoff, Boris; Kechris, Katerina J

    2012-09-01

    Prenatal alcohol exposure can result in fetal alcohol spectrum disorders (FASD). Not all women who consume alcohol during pregnancy have children with FASD and studies have shown that genetic factors can play a role in ethanol teratogenesis. We examined gene expression in embryos and placentae from C57BL/6J (B6) and DBA/2J (D2) mice following prenatal alcohol exposure. B6 fetuses are susceptible to morphological malformations following prenatal alcohol exposure while D2 are relatively resistant. Male and female B6 and D2 mice were mated for 2 hours in the morning, producing 4 embryonic genotypes: true-bred B6B6 and D2D2, and reciprocal B6D2 and D2B6. On gestational day 9, dams were intubated with 5.8 g/kg ethanol, an isocaloric amount of maltose dextrin, or nothing. Four hours later, dams were sacrificed and embryos and placentae were harvested. RNA was extracted, labeled and hybridized to Affymetrix Mouse Genome 430 v2 microarray chips. Data were normalized, subjected to analysis of variance and tested for enrichment of gene ontology molecular function and biological process using the Database for Annotation, Visualization and Integrated Discovery (DAVID). Several gene classes were differentially expressed in B6 and D2 regardless of treatment, including genes involved in polysaccharide binding and mitosis. Prenatal alcohol exposure altered expression of a subset of genes, including genes involved in methylation, chromatin remodeling, protein synthesis, and mRNA splicing. Very few genes were differentially expressed between maltose-exposed tissues and tissues that received nothing, so we combined these groups for comparisons with ethanol. While we observed many expression changes specific to B6 following prenatal alcohol exposure, none were specific for D2. Gene classes up- or down-regulated in B6 following prenatal alcohol exposure included genes involved in mRNA splicing, transcription, and translation. Our study identified several classes of genes with altered

  18. Evaluation of means used to access the impacts of energy production on human health. LASL third life sciences symposium, Los Alamos, New Mexico, October 15--17, 1975

    Energy Technology Data Exchange (ETDEWEB)

    Anderson, E.C.; Sullivan, E.M. (eds.)

    1976-01-01

    The symposium explored the various techniques and methods available to study the potential effects that various energy-producing industries may have on human health. Three papers presented at Session I dealt with national energy needs, resources, and future developments; responsibilities and capabilities in ERDA as related to the health and environmental impacts of energy productions; and health hazards associated with alternate energy sources. Four papers presented at Session II reviewed standards setting for the worker and for the public; the radiation experience; and developing health policies and standards as the responsibility of the scientist. Eight papers in Sessions III and IV, Sources of Information, dealt with developing a health standard from epidemiological and clinical data and from laboratory animal data; carcinogenesis, mutagenesis, teratogenesis, and behavior changes as end points in health impact assessments; new methods and approaches to health impact assessment; problems in sampling for health impact; and the application of scientific data to worker/workplace health decision making. Two papers at Session V covered bases for the application of scientific data to health standards and health and environmental standards from a legal viewpoint. A final discussion, Room for Controversy, was conducted by four panelists. (MCW)

  19. Effect of dolomite oral exposure in Wistar rats during organogenesis period of pregnancy.

    Science.gov (United States)

    Lagarto, Alicia; Bellma, Addis; Tillán, Juana; Gabilondo, Tatiana; Guerra, Isbel; Ocanto, Zuleira; Couret, Micaela; González, Ricardo

    2008-09-01

    The potential of oral exposure to dolomite, a natural product that contains calcium and magnesium, to initiate teratogenesis was analyzed in Wistar rats. Animals received dolomite oral dosages of 500 and 1500mg/kg during the period of gestation from day 6-15 post conceptionem (p.c.). Maternal, embryo and fetal toxicity were evaluated. Dolomite exposure did not produce maternal toxicity assessed by clinical observations, body weight gain, hematology parameters and relative organs weight. Signs of embryo-fetal toxicity were not observed. Skeletal malformations and visceral variations were similar in control and dolomite-treated groups. On the other hand, slight increase was observed in fetal body weight in the dolomite-treated group. Treatment with dolomite resulted in significantly decreased incidences of unossified xiphisternum, incomplete ossification of xiphisternum and sternebrae. These effects could be caused by a beneficial influence of calcium and magnesium salts present in dolomite on ossification process. In conclusion, in this study we found that the oral exposure to rats of up to 1500mg/kg of dolomite during organogenesis did not induce significant maternal and embryo-fetal toxicity.

  20. [Time and obstetric anesthesia: from chaotic cosmology to chronobiology].

    Science.gov (United States)

    Vale, Nilton Bezerra do; Vale, Lúcio Flávio Bezerra do; Cruz, José Rômulo

    2009-01-01

    Temporal cycles (dark/light; birth/death; etc.), along with environmental conditions (synchronizers), influence labor physiology because of the presence of endogenous clocks (oscillators) that interact with social diuturnal clues. In this review, the most important cyclic anesthetic-obstetric parameters in parturient care are listed. Chronobiological analysis of the main events in the obstetric pathophysiology of Mulier sapiens: I) Embryogenesis - risk of teratogenesis; II) From prematurity to post-didacticism: from eutocic labor to cervical cerclage; III) Night and labor: higher incidence of nocturnal labor (physiological facilitation) and daylight cesarean section (choice of the obstetrician); IV) The moon and labor - non-conclusive results; V) The night shift in obstetric anesthesia: riskier professional contingency; VI) Phases of cesarean section: removal of the fetus: UD stage (uterotomy - delivery) as brief as possible; effective correction of hypotension and valorize pre-anesthetic fasting; VII) circadian variation of dystocia: pain; uterine contraction; blood loss; hypertension (HTN); risk of allergy and asthma. In the nocturnal phase, the intensity of contraction and risk of hemorrhage, allergy, and asthma are greater. On the other hand, HTN in eclampsia does not show circadian variation; VIII) Obstetric chronopharmacology: local anesthetics, analgesics, hypnotics, general anesthetics, and neuromuscular blockers. Chronoenergy explains the matinal peak of opioid analgesia, vespertine of local anesthetic, and nocturnal of inhalational anesthetics. The chronobiological approach of labor anesthesia emphasizes the obstetric importance of circadian rhythmicity in labor humanization and safety.

  1. The rationale for use of Ulipristal Acetate as first line in emergency contraception: biological and clinical evidence.

    Science.gov (United States)

    Glasier, Anna

    2014-10-01

    Ulipristal acetate (UPA) was licensed as an emergency contraceptive (EC) in Europe in 2009. By the end of May 2013, over 1.4 million courses had been used. The rationale for using UPA for EC in favor of the much more commonly used levonorgestrel (LNG) is based on data on efficacy, safety and side effects. In two large clinical trials among women presenting for EC up to 120 hours after unprotected sex, UPA was as effective as LNG at preventing pregnancy. When the two trials were combined in a meta analysis UPA was superior, almost halving the risk of pregnancy compared with LNG. Biomedical studies have shown that UPA inhibits or delays ovulation more effectively than LNG at a stage of the cycle when the risk of pregnancy is highest. Safety and side effects: UPA and LNG have similar side effect profiles and to date no serious adverse events have been attributed to use of UPA for EC. Data on pregnancies conceived in association with UPA use are reassuring. There is no evidence for teratogenesis or for any increased risk of ectopic pregnancy or miscarriage. Use of UPA will remain limited until it is available without a doctor's prescription.

  2. Effects of a 4.7 T static magnetic field on fetal development in ICR mice

    Energy Technology Data Exchange (ETDEWEB)

    Okazaki, Ryuji; Ootsuyama, Akira; Uchida, Soshi; Norimura, Toshiyuki [Univ. of Occupational and Environmental Health, Kitakyushu, Fukuoka (Japan). School of Medicine

    2001-09-01

    In order to determine the effects of a 4.7 T static magnetic field (SMF) on fetal development in mice, we evaluated fetal teratogenesis and endochondral ossification following exposure in utero. Pregnant ICR mice were exposed to a 4.7 T SMF from day 7.5 to 9.5 of gestation in a whole-body dose, and sacrificed on day 18.5 of gestation. We examined with incidence of prenatal death, external malformations and fetal skeletal malformations. There were no significant differences observed in the incidence of prenatal death and/or malformations between SMF-exposed mice and control mice. Further, we evaluated the immunoreactivity for the vascular endothelial growth factor (VEGF), which is implicated in angiogenesis and osteogenesis, in the sternum of fetal mice following magnetic exposure. Our studies also indicated that on day 16.5 of gestation following SMF exposure, the immunoreactivity for VEGF was increased compared to unexposed controls. However, it was decreased in the exposed group compared to the control group on day 18.5 of gestation. DNA and proteoglycan (PG) synthesis were also measured in rabbit costal growth plate chondrocytes in vitro. No significant differences were observed in DNA synthesis between the SMF exposed chondrocytes and the control chondrocytes; however, PG synthesis in SMF exposed chondrocytes increased compared to the controls. Based on these results, we suggest that while SMF exposure promoted the endochondral ossification of chondrocytes, it did not induce any harmful effects on fetal development in ICR mice. (author)

  3. [Adverse events of psychotropic drugs].

    Science.gov (United States)

    Watanabe, Koichiro; Kikuchi, Toshiaki

    2014-01-01

    The authors discuss adverse events which are often missed but clinicians should pay attention to in order to preserve patients'quality of life(QOL). Among mood stabilizers, lithium may cause a urinary volume increase, hyperparathyroidism, and serum calcium elevation; sodium valproate possibly increases androgenic hormone levels and the risk of polycystic ovary syndrome (PCOS) as well as hypothyroidism. Moreover, in addition to teratogenesis, it has been reported that fetal exposure to a higher dose of valproate is associated with a lower intelligence quotient and higher incidence of autism spectrum disorders in children. Antidepressants with a higher affinity for serotonin transporters might induce gastrointestinal bleeding, and some antidepressants cause sexual dysfunction more frequently than others. Activation syndrome is still a key side effect which should be noted. Regarding the adverse events of antipsychotics, subjective side effects unpleasant to patients such as dysphoria and a lower subjective well-being should not be overlooked. We clinicians have to cope with adverse events worsening the QOL of patients with psychiatric disorders and, therefore, we need to adopt appropriate counter-measures.

  4. Sodium valproate-induced congenital cardiac abnormalities in mice are associated with the inhibition of histone deacetylase

    Science.gov (United States)

    2010-01-01

    Background Valproic acid, a widely used anticonvulsant drug, is a potent teratogen resulting in various congenital abnormalities. However, the mechanisms underlying valproic acid induced teratogenesis are nor clear. Recent studies indicate that histone deacetylase is a direct target of valproic acid. Methods In the present study, we have used histological analysis and RT-PCR assays to examine the cardiac abnormalities in mice treated with sodium valproate (NaVP) and determined the effects of NaVP on histone deacetylase activity and the expression of heart development-related genes in mouse myocardial cells. Results The experimental data show that NaVP can induce cardiac abnormalities in fetal mice in a dose-dependent manner. NaVP causes a dose-dependent inhibition of hitone deacetylase (HDAC) activity in mouse myocardial cells. However, the expression levels of HDAC (both HDAC1 and HDAC2) are not significantly changed in fetal mouse hearts after administration of NaVP in pregnant mice. The transcriptional levels of other heart development-related genes, such as CHF1, Tbx5 and MEF2, are significantly increased in fetal mouse hearts treated with NaVP. Conclusions The study indicates that administration of NaVP in pregnant mice can result in various cardiac abnormalities in fetal hearts, which is associated with an inhibition of histone deacetylase without altering the transcription of this enzyme. PMID:20219112

  5. Baller-Gerold syndrome: Further evidence for association with prenatal exposure to valproate

    Directory of Open Access Journals (Sweden)

    Iype Mary

    2008-01-01

    Full Text Available Baller Gerold Syndrome (BGS is a rare autosomal recessive disorder that is apparent at birth. The disorder is characterized by distinctive malformations of the skull and facial area and bones of the forearms and hands. We are reporting a new case of BGS in a 10-month-old female child born of an epileptic mother who was on sodium valproate during the initial months of pregnancy. The baby was born with premature closure of the metopic suture, unilateral radial aplasia with limb malformation and other congenital anomalies that conformed with the description of BGS. The parents and other family members were unaffected, karyotyping was normal and there was no history of consanguinity. Fetal valproate exposure has been previously reported as the cause of this fetal malformation syndrome, which is generally inherited as an autosomal recessive trait. The peculiar pregnancy history and the supporting literature on the effects of valproic acid on the fetus exposed in utero to it with numerous case reports in the literature referring to BGS as a result of fetal exposure to valproate made us conclude that this is indeed a case of BGS secondary to valproate-induced teratogenesis.

  6. Sodium valproate-induced congenital cardiac abnormalities in mice are associated with the inhibition of histone deacetylase

    Directory of Open Access Journals (Sweden)

    Rollo Johnathon C

    2010-03-01

    Full Text Available Abstract Background Valproic acid, a widely used anticonvulsant drug, is a potent teratogen resulting in various congenital abnormalities. However, the mechanisms underlying valproic acid induced teratogenesis are nor clear. Recent studies indicate that histone deacetylase is a direct target of valproic acid. Methods In the present study, we have used histological analysis and RT-PCR assays to examine the cardiac abnormalities in mice treated with sodium valproate (NaVP and determined the effects of NaVP on histone deacetylase activity and the expression of heart development-related genes in mouse myocardial cells. Results The experimental data show that NaVP can induce cardiac abnormalities in fetal mice in a dose-dependent manner. NaVP causes a dose-dependent inhibition of hitone deacetylase (HDAC activity in mouse myocardial cells. However, the expression levels of HDAC (both HDAC1 and HDAC2 are not significantly changed in fetal mouse hearts after administration of NaVP in pregnant mice. The transcriptional levels of other heart development-related genes, such as CHF1, Tbx5 and MEF2, are significantly increased in fetal mouse hearts treated with NaVP. Conclusions The study indicates that administration of NaVP in pregnant mice can result in various cardiac abnormalities in fetal hearts, which is associated with an inhibition of histone deacetylase without altering the transcription of this enzyme.

  7. Hyperemesis gravidarum: pathogenesis and the use of antiemetic agents.

    Science.gov (United States)

    Sanu, Olaleye; Lamont, Ronald F

    2011-04-01

    Nausea and vomiting in pregnancy remains the most common cause of hospitalization in the first half of pregnancy. Although the exact cause is largely unknown, an interaction of genetic, biological and psychological factors is plausible. An endocrine trigger for hyperemesis has been linked with both ovarian and placental hormones, but this association requires further clarification. The use of type-3 serotonin receptor antagonists is increasing but as yet there are no convincing data to demonstrate their superiority over the other antiemetics. A computerized search was conducted using PubMed, Embase, Cinahl, Lilacs, ISI Web of Science, the Cochrane Central Register of Controlled Trials (all from inception or 1960 to October 2010), and Research Registries of ongoing trials. The key words used were nausea, vomiting, emesis, hyperemesis gravidarum, morning sickness, pregnancy, pregnancy complications, treatment, efficacy, effectiveness, antiemetics, safety and teratogenesis. The precise mechanism underlying hyperemesis gravidarum remains unclear, but appears to be multifactorial. As yet there is no evidence that any antiemetic class is superior to another with respect to effectiveness.

  8. Synergistic interaction of glycoalkaloids alpha-chaconine and alpha-solanine on developmental toxicity in Xenopus embryos.

    Science.gov (United States)

    Rayburn, J R; Friedman, M; Bantle, J A

    1995-12-01

    The embryo toxicities of two major potato glycoalkaloids, alpha-chaconine and alpha-solanine, were examined individually and in mixtures using the frog embryo teratogenesis assay-Xenopus. Calculations of toxic units (TUs) were used to assess possible antagonism, synergism or response addition of several mixtures ranging from approximately 3:1 to 1:20 TUs of alpha-chaconine to alpha-solanine. Some combinations exhibited strong synergism in the following measures of developmental toxicity: (a) 96-hr LC50, defined as the median concentration causing 50% embryo lethality; (b) 96-hr EC50 (malformation), defined as the concentration causing 50% malformation of the surviving embryos; and (c) teratogenic index which is equal to LC50/EC50 (malformation). The results indicated that each of the mixtures caused synergistic mortality or malformation. Furthermore, these studies suggested that the synergism observed for a specific mixture cannot be used to predict possible synergism of other mixtures with different ratios of the two glycoalkaloids; toxicities observed for individual glycoalkaloids may not be able to predict toxicities of mixtures; and specific combinations found in different potato varieties need to be tested to assess the safety of a particular cultivar.

  9. Variations of sediment toxicity in a tidal estuary: a case study of the South Passage, Changjiang (Yangtze) Estuary.

    Science.gov (United States)

    Gao, Jinjuan; Shi, Huahong; Dai, Zhijun; Mei, Xuefei

    2015-06-01

    Sediments in estuaries, especially those containing a large reservoir of contaminants released from urban and industrial activities, have had great impacts on benthic fauna and associated species. A better understanding of the toxicity of contaminants in estuarine sediments is of great significance to ecological assessments. Here, based on the collected sediments from neap to spring tides in the South Passage, Changjiang Estuary, the toxicity of the sediments was first studied using the frog embryo teratogenesis assay-Xenopus (FETAX). The results showed that the extracts of estuarine sediments induced multiple malformations in the embryos and that the phenotypes of malformation had two distinct patterns of variations corresponding to the tidal cycles. The phenotypes in the first pattern were dominated by hypopigmentation and edema of the heart, and the pattern was mainly controlled by fine-grained fractions. The phenotypes in the second pattern were dominated by edema of the heart and enlarged proctodeum, and it was mostly controlled by coarse-grain fractions. The sediment toxicity was higher during the spring and flood tides, which may be influenced by the grain size and sediment resuspension. Furthermore, obvious periodicities existed in the changes of the percentages of hatching (14-16 h and 6 h), enlarged proctodeum (15-18 h), and bent tail (5-7 h) due to the influence of tidal cycles. Moreover, our results also suggested that FETAX is an appropriate cost-effective biological monitoring tool to assess estuarine ecological health in contaminated sediments. Copyright © 2015 Elsevier Ltd. All rights reserved.

  10. Teratogens: a public health issue – a Brazilian overview

    Directory of Open Access Journals (Sweden)

    Thiago Mazzu-Nascimento

    2017-05-01

    Full Text Available Abstract Congenital anomalies are already the second cause of infant mortality in Brazil, as in many other middle-income countries in Latin America. Birth defects are a result of both genetic and environmental factors, but a multifactorial etiology has been more frequently observed. Here, we address the environmental causes of birth defects – or teratogens – as a public health issue and present their mechanisms of action, categories and their respective maternal-fetal deleterious effects. We also present a survey from 2008 to 2013 of Brazilian cases involving congenital anomalies (annual average of 20,205, fetal deaths (annual average of 1,530, infant hospitalizations (annual average of 82,452, number of deaths of hospitalized infants (annual average of 2,175, and the average cost of hospitalizations (annual cost of $7,758. Moreover, we report on Brazilian cases of teratogenesis due to the recent Zika virus infection, and to the use of misoprostol, thalidomide, alcohol and illicit drugs. Special attention has been given to the Zika virus infection, now proven to be responsible for the microcephaly outbreak in Brazil, with 8,039 cases under investigation (from October 2015 to June 2016. From those cases, 1,616 were confirmed and 324 deaths occurred due to microcephaly complications or alterations on the central nervous system. Congenital anomalies impact life quality and raise costs in specialized care, justifying the classification of teratogens as a public health issue.

  11. Concentration and Spatial Distribution of Polycyclic Aromatic Hydrocarbons in Surface Roadside Soils, Shanghai

    Science.gov (United States)

    Pan, Zhaoyu; Liu, Ying; He, Yao; Chen, Ling

    2010-11-01

    Polycyclic aromatic hydrocarbons (PAHs) are persistent organic pollutants that may lead to mutagenesis, carcinogenesis or teratogenesis. Vehicular traffic pollution is one of the important sources for PAHs in soils. Concentrations of 19 PAHs were detected in soils along nine roads in Shanghai by automatic Soxhlet extraction and high performance liquid chromatography. Concentration and spatial distribution of PAHs in surface soils beside nine target roads in Shanghai were investigated and a preliminary migration regularity of PAHs was proposed based on data analysis of Cheting Highway (NO.320 Chinese National Highway). The result showed that the total concentrations of PAHs in the target roadside soils ranged from undetectable to 34.6μg/g-dw, with a mean of 7.77μg/g-dw. In comparison with the level of PAHs in urban or suburban roadside soils, the results showed significantly that Σ PAHs concentration in roadside soils inside industrial areas was higher. The study on the migration regularity of PAHs in soils along roads demonstrated that surface runoff had a more significant effect on the PAHs transportation than air-borne transportation.

  12. Do Nanoparticle Physico-Chemical Properties and Developmental Exposure Window Influence Nano ZnO Embryotoxicity in Xenopus laevis?

    Directory of Open Access Journals (Sweden)

    Patrizia Bonfanti

    2015-07-01

    Full Text Available The growing global production of zinc oxide nanoparticles (ZnONPs suggests a realistic increase in the environmental exposure to such a nanomaterial, making the knowledge of its biological reactivity and its safe-by-design synthesis mandatory. In this study, the embryotoxicity of ZnONPs (1–100 mg/L specifically synthesized for industrial purposes with different sizes, shapes (round, rod and surface coatings (PEG, PVP was tested using the frog embryo teratogenesis assay-Xenopus (FETAX to identify potential target tissues and the most sensitive developmental stages. The ZnONPs did not cause embryolethality, but induced a high incidence of malformations, in particular misfolded gut and abdominal edema. Smaller, round NPs were more effective than the bigger, rod ones, and PEGylation determined a reduction in embryotoxicity. Ingestion appeared to be the most relevant exposure route. Only the embryos exposed from the stomodeum opening showed anatomical and histological lesions to the intestine, mainly referable to a swelling of paracellular spaces among enterocytes. In conclusion, ZnONPs differing in shape and surface coating displayed similar toxicity in X. laevis embryos and shared the same target organ. Nevertheless, we cannot exclude that the physico-chemical characteristics may influence the severity of such effects. Further research efforts are mandatory to ensure the synthesis of safer nano-ZnO-containing products.

  13. Effect of allyl isothiocyanate on developmental toxicity in exposed Xenopus laevis embryos

    Directory of Open Access Journals (Sweden)

    John Russell Williams

    2015-01-01

    Full Text Available The pungent natural compound allyl isothiocyanate isolated from the seeds of Cruciferous (Brassica plants such as mustard is reported to exhibit numerous beneficial health-promoting antimicrobial, antifungal, anticarcinogenic, cardioprotective, and neuroprotective properties. Because it is also reported to damage DNA and is toxic to aquatic organisms, the objective of the present study was to determine whether it possesses teratogenic properties. The frog embryo teratogenesis assay-Xenopus (FETAX was used to determine the following measures of developmental toxicity of the allyl isothiocyanate: (a 96-h LC50, defined as the median concentration causing 50% embryo lethality; (b 96-h EC50, defined as the median concentration causing 50% malformations of the surviving embryos; and (c teratogenic malformation index (TI, equal to 96-h LC50/96-h EC50. The quantitative results and the photographs of embryos before and after exposure suggest that allyl isothiocyanate seems to exhibit moderate teratogenic properties. The results also indicate differences in the toxicity of allyl isothiocyanate toward exposed embryos observed in the present study compared to reported adverse effects of allyl isothiocyanate in fish, rodents, and humans. The significance of the results for food safety and possible approaches to protect against adverse effects of allyl isothiocyanate are discussed.

  14. Compounds used to produce cloned animals are genotoxic and mutagenic in mammalian assays in vitro and in vivo

    Energy Technology Data Exchange (ETDEWEB)

    Oliveira, R.J. [Programa de Pós-Graduação em Biologia Celular e Molecular, Instituto de Biociências de Rio Claro, Universidade Estadual Paulista, Rio Claro, SP (Brazil); Centro de Estudos em Células Tronco, Terapia Celular e Genética Toxicológica, Núcleo de Hospital Universitário, Universidade Federal de Mato Grosso do Sul, Campo Grande, MS (Brazil); Programa de Pós-Graduação em Saúde em Desenvolvimento na Região Centro-Oeste, Faculdade de Medicina “Dr. Hélio Mandetta”, Universidade Federal de Mato Grosso do Sul, Campo Grande, MS (Brazil); Programa de Mestrado em Farmácia, Centro de Ciências Biológicas e da Saúde, Universidade Federal de Mato Grosso do Sul, Campo Grande, MS (Brazil); Mantovani, M.S.; Silva, A.F. da [Departamento de Biologia Geral, Universidade Estadual de Londrina, Londrina, PR (Brazil); Pesarini, J.R. [Centro de Estudos em Células Tronco, Terapia Celular e Genética Toxicológica, Núcleo de Hospital Universitário, Universidade Federal de Mato Grosso do Sul, Campo Grande, MS (Brazil); Programa de Pós-Graduação em Saúde em Desenvolvimento na Região Centro-Oeste, Faculdade de Medicina “Dr. Hélio Mandetta”, Universidade Federal de Mato Grosso do Sul, Campo Grande, MS (Brazil); Mauro, M.O. [Centro de Estudos em Células Tronco, Terapia Celular e Genética Toxicológica, Núcleo de Hospital Universitário, Universidade Federal de Mato Grosso do Sul, Campo Grande, MS (Brazil); Programa de Doutorado em Biotecnologia e Biodiversidade - Rede Pró Centro-Oeste, Universidade Federal de Mato Grosso do Sul, Campo Grande, MS (Brazil); Ribeiro, L.R. [Programa de Pós-Graduação em Biologia Celular e Molecular, Instituto de Biociências de Rio Claro, Universidade Estadual Paulista, Rio Claro, SP (Brazil); Programa de Pós-Graduação em Patologia, Faculdade de Medicina de Botucatu, Universidade Estadual Paulista, Botucatu, SP (Brazil)

    2014-03-28

    The compounds 6-dimethylaminopurine and cycloheximide promote the successful production of cloned mammals and have been used in the development of embryos produced by somatic cell nuclear transfer. This study investigated the effects of 6-dimethylaminopurine and cycloheximide in vitro, using the thiazolyl blue tetrazolium bromide colorimetric assay to assess cytotoxicity, the trypan blue exclusion assay to assess cell viability, the comet assay to assess genotoxicity, and the micronucleus test with cytokinesis block to test mutagenicity. In addition, the comet assay and the micronucleus test were also performed on peripheral blood cells of 54 male Swiss mice, 35 g each, to assess the effects of the compounds in vivo. The results indicated that both 6-dimethylaminopurine and cycloheximide, at the concentrations and doses tested, were cytotoxic in vitro and genotoxic and mutagenic in vitro and in vivo, altered the nuclear division index in vitro, but did not diminish cell viability in vitro. Considering that alterations in DNA play important roles in mutagenesis, carcinogenesis, and morphofunctional teratogenesis and reduce embryonic viability, this study indicated that 6-dimethylaminopurine and cycloheximide utilized in the process of mammalian cloning may be responsible for the low embryo viability commonly seen in nuclear transfer after implantation in utero.

  15. Aryl hydrocarbon receptor (AHR): "pioneer member" of the basic-helix/loop/helix per-Arnt-sim (bHLH/PAS) family of "sensors" of foreign and endogenous signals.

    Science.gov (United States)

    Nebert, Daniel W

    2017-07-01

    The basic-helix/loop/helix per-Arnt-sim (bHLH/PAS) family comprises many transcription factors, found throughout all three kingdoms of life; bHLH/PAS members "sense" innumerable intracellular and extracellular "signals" - including endogenous compounds, foreign chemicals, gas molecules, redox potential, photons (light), gravity, heat, and osmotic pressure. These signals then initiate downstream signaling pathways involved in responding to that signal. The term "PAS", abbreviation for "per-Arnt-sim" was first coined in 1991. Although the mouse Arnt gene was not identified until 1991, evidence of its co-transcriptional binding partner, aryl hydrocarbon receptor (AHR), was first reported in 1974 as a "sensor" of foreign chemicals, up-regulating cytochrome P450 family 1 (CYP1) and other enzyme activities that usually metabolize the signaling chemical. Within a few years, AHR was proposed also to participate in inflammation. The mouse [Ah] locus was shown (1973-1989) to be relevant to chemical carcinogenesis, mutagenesis, toxicity and teratogenesis, the mouse Ahr gene was cloned in 1992, and the first Ahr(-/-) knockout mouse line was reported in 1995. After thousands of studies from the early 1970s to present day, we now realize that AHR participates in dozens of signaling pathways involved in critical-life processes, affecting virtually every organ and cell-type in the animal, including many invertebrates. Copyright © 2017 Elsevier Ltd. All rights reserved.

  16. Teratogenic effects of selenium in natural populations of freshwater fish.

    Science.gov (United States)

    Lemly, A D

    1993-10-01

    The prevalence of abnormalities and associated tissue selenium residues were assessed for the fish population of Belews Lake, North Carolina, and two reference lakes in 1975, 1978, 1982, and 1992. Teratogenic defects identified included lordosis, kyphosis, scoliosis, and head, mouth, and fin deformities. Many fish exhibited multiple malformations and some were grossly deformed and distorted in appearance. Other abnormalities observed were edema, exophthalmus, and cataracts. Whole-body tissue residues of selenium in the fishes of Belews Lake were up to 130 times those in the reference lakes and the incidence of abnormalities was some 7 to 70 times greater. Teratogenic defects increased as selenium levels rose between 1975 and 1982 and fell with declining selenium levels between 1982 and 1992 as selenium inputs into Belews Lake were curtailed. The relationship between selenium residues and prevalence of malformations approximated an exponential function (R2 = 0.881, P selenium and 0-70% deformities. This relationship could be useful in evaluating the role of teratogenic effects in warm-water fish populations suspected of having selenium-related reproductive failure. Unique conditions may have existed in Belews Lake which led to the high frequency and persistence of deformities in juvenile and adult fish. In other, less-contaminated locations competition and predation may eliminate malformed individuals in all but the larval life stage. Teratogenesis could be an important, but easily overlooked phenomenon contributing to fishery reproductive failure in selenium-contaminated aquatic habitats.

  17. Common increase of GATA-3 level in PC-12 cells by three teratogens causing autism spectrum disorders.

    Science.gov (United States)

    Rout, Ujjwal K; Clausen, Pete

    2009-06-01

    Autism spectrum disorder (ASD) is a disease of neuro-developmental origin of uncertain etiology. The current understanding is that both genetic and environmental factors contribute to the development of ASD. Exposure to valproate, thalidomide and alcohol during gestation are amongst the environmental triggers that are associated with the development of ASD. These teratogens may disturb the ontogeny of the brain by altering the expression pattern of genes that regulate the normal development of the brain. In this study, a neuron-like PC-12 cell model was used to examine the effects of these compounds on the binding potential of 50 different transcription factors to understand the molecular mechanism/s that may be involved in the teratogenesis caused by these agents. Cells in culture were treated with low or high concentrations of teratogens within a range that are reported in the blood of individuals. A pronounced increase in GATA transcription factor binding was observed for all three teratogens. Furthermore, Western blot analysis showed that GATA-3 level in the nuclear fractions was enhanced by each of the three teratogens. Results suggest that altered gene expression pattern due to heightened GATA-3 activities in the fetral brains following exposure to these teratogens may contribute to the development of ASD.

  18. Teratogenic effects of organic extracts from the Pearl River sediments on Xenopus laevis embryos.

    Science.gov (United States)

    Zhang, Cong; Liu, Xinhui; Wu, Dan; Liu, Guannan; Tao, Li; Fu, Wenjun; Hou, Jing

    2014-01-01

    Toxicity of organic extracts from the Pearl River sediments was investigated with Xenopus laevis embryos. The effects of sediment organic extracts on the mortality, body length and malformation of X. laevis embryos were tested by the Frog Embryo Teratogenesis Assay-Xenopus (FETAX). The 96-h LC₅₀ values for X. laevis embryos ranged from 62 to 137 g/L (g extracted sediment per L), and the toxicity effect on body length of larvae was not significant under 20 g/L. However, the teratogenic effects produced by sediment organic extracts were diverse, including edema, hypopigmentation, cardiac and ocular malformations, abdomen recurved and curved spine. The percentage of malformations increased with increasing sediment organic extracts, and even reached almost 100% at 10 and 20 g/L in Guangzhou district. A gradient of pollution in the Pearl River sediments was discerned from the teratogenic toxicity. Guangzhou district showed higher teratogenic toxicity compared with Panyu and Nansha districts as a possible consequence of high levels of PAHs, PCBs, OCPs and NP in the sediments. The teratogenic effects of organic extracts from the Pearl River sediments were successfully assessed which indicated the feasibility of teratogenic potential studies of sediments using X. laevis embryos. Copyright © 2013. Published by Elsevier B.V.

  19. Safety and efficacy of immunomodulators and biologics during pregnancy and lactation for the treatment of inflammatory bowel disease.

    Science.gov (United States)

    Saha, Sumona; Wald, Arnold

    2012-11-01

    The inflammatory bowel diseases (IBD) are chronic, idiopathic, inflammatory conditions of the gastrointestinal tract, that peak in incidence during the reproductive years. Therefore, the safety of IBD medications during pregnancy and lactation is of significant interest to patients. Unfortunately, the current pregnancy labeling used by the United States Food and Drug Association (FDA) is often misinterpreted and may mislead healthcare providers and their patients to believe that risk increases from Category A to B to C to D to X, which in fact, is not the case. In addition, the FDA categories do not always distinguish between risks based on human versus animal data, or between differences in frequency, severity, and type of fetal developmental toxicities. This article provides an in-depth review of the available safety data during pregnancy and lactation for the more potent immunosuppressants used to treat IBD: the immunomodulators and biologics. It also includes the authors' expert opinions on the use of these medications during these critical periods. The benefit-to-risk ratio for most immunomodulators and biologics used in the treatment of IBD favors medication continuation during pregnancy. Certain immunomodulators, however, can cause extreme fetal harm and should be used with caution. While human safety data regarding teratogenesis and some data on pregnancy outcomes exist for most IBD medications, long-term follow-up studies of children and young adults exposed to these drugs in utero are lacking. These studies are needed to determine if these drugs are of sufficiently low risk to be considered safe.

  20. Potential uses of sea urchin embryos for identifying toxic chemicals: description of a bioassay incorporating cytologic, cytogenetic and embryologic endpoints

    Energy Technology Data Exchange (ETDEWEB)

    Hose, J.E.

    1985-08-01

    A method for evaluating pollutant genotoxicity, embryotoxicity and teratogenicity using sea urchin embryos has been developed and was tested using benzo(a)pyrene (BP). Initial results suggested that the bioassay may be a sensitive indicator of pollutant toxicity and mutagenicity since several endpoints can be simultaneously assessed. The bioassay is rapid, inexpensive and appears applicable to a variety of toxicants and delivery methods. The test is based upon the standard 48 h sea urchin development assay and incorporates cytologic-cytogenetic analysis of embryos. Following toxic exposure of gametes, fertilization success is assessed. Embryos then develop for 48 h at which time survival and teratogenesis are evaluated. A subsample of embryos is stained and dissociated into monolayers and mitotic configurations are examined using light microscopy. Embryo mitotic rates are used as an indicator of overall embryonic health. Cytotoxic effects are concomitantly evaluated. Genotoxicity is measured using two methods: (1) anaphase aberration analysis, a technique which assesses abnormalities in the chromosome configurations (such as bridges and fragments) as the groups of chromosomes move to opposite poles and (2) micronucleus formation, a procedure examining the incidence of smaller, secondary nuclei composed of whole chromosomes or chromatid fragments.

  1. PSK, a biological response modifier, modifies p53 expression, mitosis and apoptosis in X-ray irradiated mouse embryos. Possible cellular mechanism of the anti-teratogenic effect

    Energy Technology Data Exchange (ETDEWEB)

    Kagohashi, Yukiko; Naora, Hiroyuki; Otani, Hiroki [Shimane Medical Univ., Izumo (Japan)

    2002-03-01

    We previously showed that PSK, a biological response modifier, suppressed X-ray irradiation induced ocular anomalies in mouse embryos. In the present study, in mouse embryos irradiated at E7.5, PSK, when administered immediately after irradiation, suppressed mitosis and increased apoptosis as compared with embryos not treated with PSK at 12 hrs after irradiation. In the irradiated embryos, p53, which is normally expressed at a high level in early embryos, increased at 6 hrs and decreased at 12 hrs after irradiation. In the irradiated and PSK-treated embryos, the p53 level did not change at 6 hrs, increased at 12 hrs and decreased at 24 hrs after irradiation. This timing of PSK-induced delayed increase of p53 coincided with that of the PSK-induced decrease in mitosis and increase in apoptosis. These results suggested that PSK modified the p53 level and affected cell proliferation and apoptosis, which might contribute to the suppression of teratogenesis. (author)

  2. Radioprotective agents to prevent cellular damage due to ionizing radiation.

    Science.gov (United States)

    Smith, Tyler A; Kirkpatrick, Daniel R; Smith, Sean; Smith, Trevor K; Pearson, Tate; Kailasam, Aparna; Herrmann, Kortney Z; Schubert, Johanna; Agrawal, Devendra K

    2017-11-09

    Medical imaging has become a central component of patient care to ensure early and accurate diagnosis. Unfortunately, many imaging modalities use ionizing radiation to generate images. Ionizing radiation even in low doses can cause direct DNA damage and generate reactive oxygen species and free radicals, leading to DNA, protein, and lipid membrane damage. This cell damage can lead to apoptosis, necrosis, teratogenesis, or carcinogenesis. As many as 2% of cancers (and an associated 15,000 deaths annually) can be linked to computed tomography exposure alone. Radioprotective agents have been investigated using various models including cells, animals, and recently humans. The data suggest that radioprotective agents working through a variety of mechanisms have the potential to decrease free radical damage produced by ionizing radiation. Radioprotective agents may be useful as an adjunct to medical imaging to reduced patient morbidity and mortality due to ionizing radiation exposure. Some radioprotective agents can be found in high quantities in antioxidant rich foods, suggesting that a specific diet recommendation could be beneficial in radioprotection.

  3. FETAX interlaboratory validation study: Phase 2 testing

    Energy Technology Data Exchange (ETDEWEB)

    Bantle, J.A. (Oklahoma State Univ., Stillwater, OK (United States). Dept. of Zoology); Burton, D.T. (WYE Research and Educational Center, Queenstown, MD (United States)); Dawson, D.A. (Ashland Univ., OH (United States). Dept. of Biology and Toxicology) (and others)

    1994-10-01

    The Frog Embryo Teratogenesis Assay-Xenopus (FETAX) is a 96-h whole embryo developmental toxicity screening assay that can be used in ecotoxicology and in detecting mammalian developmental toxicants when an in vitro metabolic activation system is employed. A standardized American Society for Testing and Materials (ASTM) guide for the conduct of FETAX has been published along with a companion atlas that helps in embryo staging and identifying malformations. As part of the ASTM process, an interlaboratory validation study was undertaken to evaluate the repeatability and reliability of FETAX. Six different laboratories participated in the study. Each laboratory utilized one technician with the exception of one laboratory, which utilized two independent technicians. In Phase 1, FETAX proved to be more repeatable and reliable than many other bioassays. However, some excessive variation was observed in a few laboratories. Some of this variation may have been due to an initial lack of experience with the assay by some technicians. Phase 2, which is reported here, showed far less intralaboratory and interlaboratory variability than did Phase 1. Nonteratogens such as saccharin and sodium cyclamate showed the most consistent results, whereas more variability was observed for the teratogens caffeine and 5-fluorouracil. Interlaboratory coefficient of variation values for all FETAX end points ranged from 7.3 to 54.7%. The minimum concentration to inhibit growth proved to be the most variable end point for three of the four test chemicals, whereas the LC50 and EC50 (malformation) proved to be less variable.

  4. Sublethal Toxic Effects and Induction of gGutathione S-transferase by Short-Chain Chlorinated Paraffins (SCCPs and C-12 alkane (dodecane in Xenopus laevis Frog Embryos

    Directory of Open Access Journals (Sweden)

    B. Burýšková

    2006-01-01

    Full Text Available Short chain chlorinated paraffins (SCCPs are important industrial chemicals with high persistence in the environment but poorly characterized ecotoxicological effects. We studied embryotoxic effects of commercial mixture of SCCP (carbon length C-12, 56% of chlorine; CP56-12 and non-chlorinated n-alkane (dodecane, C-12 in the 96h Frog Embryo Teratogenesis Assay - Xenopus (FETAX. Only weak lethal effects were observed for both substances (the highest tested concentration 500 mg/L of both chemicals caused up to 11% mortality. On the other hand, we observed developmental malformations and reduced embryo growth at 5 mg/l and higher concentrations. However, the effects were not related to chlorination pattern as both SCCPs and dodecane induced qualitatively similar effects. SCCPs also significantly induced phase II detoxification enzyme glutathione S-transferase (GST in Xenopus laevis embryos even at 0.5 mg/L, and this biomarker might be used as another early warning of chronic toxic effects. Our results newly indicate significant developmental toxicity of both SCCPs and n-dodecane to aquatic organisms along with inductions of specific biochemical toxicity mechanisms.

  5. Free radical-mediated oxidative DNA damage in the mechanism of thalidomide teratogenicity.

    Science.gov (United States)

    Parman, T; Wiley, M J; Wells, P G

    1999-05-01

    The sedative drug thalidomide ([+]-alpha-phthalimidoglutarimide), once abandoned for causing birth defects in humans, has found new therapeutic license in leprosy and other diseases, with renewed teratological consequences. Although the mechanism of teratogenesis and determinants of risk remain unclear, related teratogenic xenobiotics are bioactivated by embryonic prostaglandin H synthase (PHS) to a free-radical intermediates that produce reactive oxygen species (ROS), which cause oxidative damage to DNA and other cellular macromolecules. Similarly, thalidomide is bioactivated by horseradish peroxidase, and oxidizes DNA and glutathione, indicating free radical-mediated oxidative stress. Furthermore, thalidomide teratogenicity in rabbits is reduced by the PHS inhibitor acetylsalicylic acid, indicating PHS-catalyzed bioactivation. Here, we show in rabbits that thalidomide initiates embryonic DNA oxidation and teratogenicity, both of which are abolished by pre-treatment with the free radical spin trapping agent alpha-phenyl-N-t-butylnitrone (PBN). In contrast, in mice, a species resistant to thalidomide teratogenicity, thalidomide does not enhance DNA oxidation, even at a dose 300% higher than that used in rabbits, providing insight into an embryonic determinant of species-dependent susceptibility. In addition to their therapeutic implications, these results constitute direct evidence that the teratogenicity of thalidomide may involve free radical-mediated oxidative damage to embryonic cellular macromolecules.

  6. Inhibition of isotretinoin teratogenicity by acetylsalicylic acid pretreatment in mice.

    Science.gov (United States)

    Kubow, S

    1992-01-01

    Although isotretinoin (ITR) has been suggested to cause malformations via cytopathic effects on embryonic cells, the molecular mechanisms of ITR cytotoxicity in teratogenesis are not clear. Since ITR undergoes metabolism by prostaglandin synthase to a potentially cytotoxic peroxyl free radical, the possible role of prostaglandin synthase metabolism as a modulator of ITR teratogenicity was evaluated. Craniofacial and limb abnormalities were noted in fetuses on day 18.5 of gestation following administration of ITR to pregnant CD-1 mice in a three dose regimen of 100 mg/kg at 4 hr intervals on day 10.5 of gestation (plug day = day 0.5 of gestation). Mice were also treated with acetylsalicylic acid (ASA), an irreversible inhibitor of the cyclooxygenase component of prostaglandin synthase, at doses of 20 and 60 mg/kg body weight 2 hr prior to each ITR dose. ASA pretreatment of mice receiving ITR treatment showed a dose-dependent decrease in the overall incidence of malformations, number of defects per fetus, and the incidence of specific craniofacial and limb defects. Equivalent doses of ASA given to control mice did not cause malformations or alter the incidence of resorptions. These results demonstrate that ASA is able to ameliorate the teratogenic effects of ITR observed in fetal mice near term and indicate that prostaglandin metabolism could play a mechanistic role in ITR teratogenicity.

  7. Modulation of cupric ion activity by pH and fulvic acid as determinants of toxicity in Xenopus laevis embryos and larvae

    Energy Technology Data Exchange (ETDEWEB)

    Buchwalter, D.B. [Oregon State Univ., Corvallis, OR (United States). Toxicology Program]|[ManTech Environmental Technology, Inc., Corvallis, OR (United States); Linder, G. [ManTech Environmental Technology, Inc., Corvallis, OR (United States); Curtis, L.R. [East Tennessee State Univ., Johnson City, TN (United States). Dept. of Environmental Health

    1996-04-01

    An ion-specific electrode measured cupric ion activity modulated by fulvic acid (FA) and pH in a series of modified Frog Embryo Teratogenesis Assay--Xenopus (FETAX) toxicity assays. Hydrogen ion concentration was the primary determinant of cupric ion activity, while FA played a smaller but significant role. Fulvic acid was a weak copper complexing agent at pH 5.50. At pH 5.50 there was slight reduction of ionic activity and a subsequent attenuation of copper toxicity with 5.0 mg/L FA. At pH 7.50, FA also had a mild attenuating effect on copper toxicity. At pH 6.50, copper was strongly complexed by FA at total copper (TCu) concentrations below its pH-dependent solubility limit. At TCu concentrations above the solubility limit FA enhanced toxicity. There was more cupric ion activity measured in the presence of 0.5 and 5.0 mg/L FA than without it at TCu concentrations above the solubility limit. The proposed mechanism for this behavior was FA action as a nucleation inhibitor. Under the chemical conditions of the pH 6.50 experiments, a stable supersaturation of copper was formed, resulting in a more toxic aqueous matrix.

  8. Ochratoxin A from a toxicological perspective.

    Science.gov (United States)

    Petzinger, E; Ziegler, K

    2000-04-01

    Ochratoxin A (OTA) is a widespread mycotoxin which is produced mainly by the mould fungi Aspergillus ochraceus and Penicillum verrucosum during the storage of cereals, cereal products and other plant-derived products such as herbs, spices, grapes, etc. By carry over from mouldy fodder, ochratoxin A is also found in pork meat, offal and sausages containing pork blood. When ingested as a food contaminant, OTA is very persistent in human beings with a blood half-life of 35 days after a single oral dosage due to unfavourable elimination toxicokinetics. This renders the toxin among the most frequent mycotoxin contaminants in human blood in the EU, the US, Canada, and elsewhere, where it has been investigated. OTA is neither stored nor deposited in the body, but heterogeneous body distribution may impose serious damage to the kidneys. The toxin was classified a 2B cancer compound, being possibly carcinogenic for humans. It was among the strongest carcinogenic compounds in rats and mice. As the toxicological profile also includes teratogenesis, nephrotoxicity, and immunotoxicity, legislation authorities are currently discussing maximal residue levels (MRL) for OTA in various foodstuffs. In the present article arguments are presented which suggest an acceptable daily intake (ADI) of 1.5 ng OTA/kg body weight and a much lower MRL than 5 microgram OTA/kg cereals and cereal products as has been postulated by the EU commission.

  9. Evaluation of the teratogenic potential and reproductive toxicity of coal-derived naphtha.

    Science.gov (United States)

    McKee, R H; Hinz, J P; Traul, K A

    1986-06-15

    Liquids which are derived from coal liquefaction processes and boil above approximately 250 degrees C have induced terata in rats. However, few studies have addressed the teratogenic potential of coal liquids which boil below 250 degrees C. The present studies evaluated the reproductive and teratogenic potential of EDS hydrotreated naphtha, a refined coal liquid boiling below 177 degrees C. These studies were conducted by inhalation exposures with Sprague-Dawley rats at target vapor concentrations of 0.2, 1.0, and 5.0 g/m3. The first study assessed teratogenesis. There was no evidence that inhalation exposures for 6 hr per day between Days 6 and 19 of gestation induced maternal toxicity, fetal toxicity, or malformation. In a second study, rats were exposed for 6 hr per day, 5 days per week for 13 weeks, and then mated to assess reproductive toxicity. There was little evidence that inhalation exposure to EDS hydrotreated naphtha adversely affected reproductive performance or fetal development in Sprague-Dawley rats. A low incidence of malformations was observed in treated groups, but these malformations were probably not treatment related.

  10. Do Nanoparticle Physico-Chemical Properties and Developmental Exposure Window Influence Nano ZnO Embryotoxicity in Xenopus laevis?

    Science.gov (United States)

    Bonfanti, Patrizia; Moschini, Elisa; Saibene, Melissa; Bacchetta, Renato; Rettighieri, Leonardo; Calabri, Lorenzo; Colombo, Anita; Mantecca, Paride

    2015-01-01

    The growing global production of zinc oxide nanoparticles (ZnONPs) suggests a realistic increase in the environmental exposure to such a nanomaterial, making the knowledge of its biological reactivity and its safe-by-design synthesis mandatory. In this study, the embryotoxicity of ZnONPs (1–100 mg/L) specifically synthesized for industrial purposes with different sizes, shapes (round, rod) and surface coatings (PEG, PVP) was tested using the frog embryo teratogenesis assay-Xenopus (FETAX) to identify potential target tissues and the most sensitive developmental stages. The ZnONPs did not cause embryolethality, but induced a high incidence of malformations, in particular misfolded gut and abdominal edema. Smaller, round NPs were more effective than the bigger, rod ones, and PEGylation determined a reduction in embryotoxicity. Ingestion appeared to be the most relevant exposure route. Only the embryos exposed from the stomodeum opening showed anatomical and histological lesions to the intestine, mainly referable to a swelling of paracellular spaces among enterocytes. In conclusion, ZnONPs differing in shape and surface coating displayed similar toxicity in X. laevis embryos and shared the same target organ. Nevertheless, we cannot exclude that the physico-chemical characteristics may influence the severity of such effects. Further research efforts are mandatory to ensure the synthesis of safer nano-ZnO-containing products. PMID:26225989

  11. New Findings in eNOS gene and Thalidomide Embryopathy Suggest pre-transcriptional effect variants as susceptibility factors.

    Science.gov (United States)

    Kowalski, Thayne Woycinck; Fraga, Lucas Rosa; Tovo-Rodrigues, Luciana; Sanseverino, Maria Teresa Vieira; Hutz, Mara Helena; Schuler-Faccini, Lavínia; Vianna, Fernanda Sales Luiz

    2016-03-23

    Antiangiogenic properties of thalidomide have created an interest in the use of the drug in treatment of cancer. However, thalidomide is responsible for thalidomide embryopathy (TE). A lack of knowledge regarding the mechanisms of thalidomide teratogenesis acts as a barrier in the aim to synthesize a safer analogue of thalidomide. Recently, our group detected a higher frequency of alleles that impair the pro-angiogenic mechanisms of endothelial nitric oxide synthase (eNOS), coded by the NOS3 gene. In this study we evaluated variable number tandem repeats (VNTR) functional polymorphism in intron 4 of NOS3 in individuals with TE (38) and Brazilians without congenital anomalies (136). Haplotypes were estimated for this VNTR with previously analyzed polymorphisms, rs2070744 (-786C > T) and rs1799983 (894T > G), in promoter region and exon 7, respectively. Haplotypic distribution was different between the groups (p = 0.007). Alleles -786C (rs2070744) and 4b (VNTR), associated with decreased NOS3 expression, presented in higher frequency in TE individuals (p = 0.018; OR = 2.57; IC = 1.2-5.8). This association was not identified with polymorphism 894T > G (p = 0.079), which influences eNOS enzymatic activity. These results suggest variants in NOS3, with pre-transcriptional effects as susceptibility factors, influencing the risk TE development. This finding generates insight for a new approach to research that pursues a safer analogue.

  12. Congenital Malformations Associated with Maternal Diabetes

    Directory of Open Access Journals (Sweden)

    Chih-Ping Chen

    2005-03-01

    Full Text Available Maternal diabetes has toxic effects on the development of the embryo and significantly increases the risk of congenital malformations in humans. The incidence of fetal structural defects caused by maternal pregestational diabetes is three- to fourfold higher than that caused by non-diabetic pregnancy. The congenital malformations associated with diabetic pregnancy arise before the seventh gestational week. Diabetic embryopathy can affect any developing organ system, including the central nervous system (CNS (anencephaly, spina bifida, microcephaly, and holoprosencephaly, skeletal system (caudal regression syndrome, sacral agenesis, and limb defects, renal system (renal agenesis, hydronephrosis, and ureteric abnormalities, cardiovascular system (transposition of the great vessels, ventricular septal defects, atrial septal defects, coarctation of the aorta, cardiomyopathy, and single umbilical artery, and gastrointestinal system (duodenal atresia, anorectal atresia, and small left colon syndrome. Pregnant women with fetuses with diabetic embryopathy may have chronic or unrecognized hyperglycemia and elevated levels of glycerated hemoglobin. This review emphasizes the necessity to consider hyperglycemia-induced teratogenesis during genetic counseling of parents with prenatally detected fetal malformations. Successful preconception counseling for women with diabetes mellitus and metabolic control will reduce birth defects and maternal morbidity.

  13. Catalytic activity and quantitation of cytochrome P-450 2E1 in prenatal human brain.

    Science.gov (United States)

    Brzezinski, M R; Boutelet-Bochan, H; Person, R E; Fantel, A G; Juchau, M R

    1999-06-01

    Cytochrome P-450 2E1 (CYP2E1) is a readily inducible hemoprotein that catalyzes the oxidation of endogenous compounds and many low molecular weight xenobiotics. As the major component of the microsomal ethanol oxidizing system, it contributes significantly to ethanol metabolism and the formation of the highly reactive metabolite acetaldehyde. The leaky property of this enzyme results in the generation of reactive oxygen species that can induce oxidative stress and cytotoxic conditions deleterious to development. To further investigate the proposed role of CYP2E1 in the etiology of alcohol teratogenesis, the current study focused on the quantification of CYP2E1 in prenatal human brain, a tissue that is highly vulnerable to the damaging effects of ethanol throughout gestation. In microsomal samples prepared from pools of brain tissues, immunoreactive protein was detected by Western blot analysis using enhanced chemiluminescence, whereas functional protein was estimated with an enzymatic assay using p-nitrophenol and an electrochemical detection system. CYP2E1 transcript was consistently detected in RNA samples prepared from individual brain tissues using the ribonuclease protection assay. Quantitative data were collected by scanning densitometry and phosphorimaging technology. There was a dramatic increase in human brain CYP2E1 content around gestational day 50 and a fairly constant level was maintained throughout the early fetal period, until at least day 113. The relatively low levels of the P-450 isoform present in conceptal brain may be sufficient to generate reactive intermediates that elicit neuroembryotoxicity following maternal alcohol consumption.

  14. 2004 Environmental Mutagen Society Annual Meeting - Genes, Mutations and Disease: The Environmental Connection

    Energy Technology Data Exchange (ETDEWEB)

    Samson, Leona D.

    2004-08-23

    The Meeting consisted of 9 Symposia, 4 Keynote Lectures, 3 Platform Sessions and 4 Poster Sessions. In addition there were Breakfast Meetings for Special Interest Groups designed to inform attendees about the latest advances in environmental mutagenesis research. Several of the topics to be covered at this broad meeting will be of interest to the Department of Energy, Office of Science. The relevance of this meeting to the DOE derives from the fact that low dose radiation may represent one of the most significant sources of human mutations that are attributable to the environment. The EMS membership, and those who attended the EMS Annual Meeting were interested in both chemical and radiation induced biological effects, such as cell death, mutation, teratogenesis, carcinogenesis and aging. These topics thate were presented at the 2004 EMS Annual meeting that were of clear interest to DOE include: human variation in cancer susceptibility, unusual mechanisms of mutation, germ and stem cell mutagenesis, recombination and the maintenance of genomic stability, multiple roles for DNA mismatch repair, DNA helicases, mutation, cancer and aging, Genome-wide transcriptional responses to environmental change, Telomeres and genomic stability: when ends don?t meet, systems biology approach to cell phenotypic decision processes, and the surprising biology of short RNAs. Poster and platform sessions addressed topics related to environmental mutagen exposure, DNA repair, mechanisms of mutagenesis, epidemiology, genomic and proteomics and bioinformatics. These sessions were designed to give student, postdocs and more junior scientists a chance to present their work.

  15. Developmental toxicity and DNA damage from exposure to parking lot runoff retention pond samples in the Japanese medaka (Oryzias latipes).

    Science.gov (United States)

    Colton, Meryl D; Kwok, Kevin W H; Brandon, Jennifer A; Warren, Isaac H; Ryde, Ian T; Cooper, Ellen M; Hinton, David E; Rittschof, Daniel; Meyer, Joel N

    2014-08-01

    Parking lot runoff retention ponds (PLRRP) receive significant chemical input, but the biological effects of parking lot runoff are not well understood. We used the Japanese medaka (Oryzias latipes) as a model to study the toxicity of water and sediment samples from a PLRRP in Morehead City, NC. Medaka exposed in ovo to a dilution series of PLRRP water had increased odds of death before hatching, but not teratogenesis or delayed hatching. Next, we adapted a long-amplicon quantitative PCR (LA-QPCR) assay for DNA damage for use with the Japanese medaka. We employed LA-QPCR to test the hypotheses that PLRRP water and sediments would cause nuclear and mitochondrial DNA damage with and without full-spectrum, natural solar radiation. Fluoranthene with and without natural sunlight was a positive control for phototoxic polycyclic aromatic hydrocarbon-induced DNA damage. Fluoranthene exposure did not result in detectable DNA damage by itself, but in combination with sunlight caused significant DNA damage to both genomes. PLRRP samples caused DNA damage to both genomes, and this was not increased by sunlight exposure, suggesting the DNA damage was unlikely the result of PAH phototoxicity. We report for the first time that PLRRP-associated pollutants cause both nuclear and mitochondrial DNA damage, and that fluoranthene-mediated phototoxicity results in similar levels of damage to the nuclear and mitochondrial genomes. These effects may be especially significant in sensitive marine ecosystems. Copyright © 2014 Elsevier Ltd. All rights reserved.

  16. Minimizing AED adverse effects: improving quality of life in the interictal state in epilepsy care.

    Science.gov (United States)

    St Louis, Erik K; Louis, Erik K

    2009-06-01

    The goals of epilepsy therapy are to achieve seizure freedom while minimizing adverse effects of treatment. However, producing seizure-freedom is often overemphasized, at the expense of inducing adverse effects of treatment. All antiepileptic drugs (AEDs) have the potential to cause dose-related, "neurotoxic" adverse effects (i.e., drowsiness, fatigue, dizziness, blurry vision, and incoordination). Such adverse effects are common, especially when initiating AED therapy and with polytherapy. Dose-related adverse effects may be obviated in most patients by dose reduction of monotherapy, reduction or elimination of polytherapy, or substituting for a better tolerated AED. Additionally, all older and several newer AEDs have idiosyncratic adverse effects which usually require withdrawal in an affected patient, including serious rash (i.e., Stevens-Johnson Syndrome, toxic epidermal necrolysis), hematologic dyscrasias, hepatotoxicity, teratogenesis in women of child bearing potential, bone density loss, neuropathy, and severe gingival hyperplasia. Unfortunately, occurrence of idiosyncratic AED adverse effects cannot be predicted or, in most cases, prevented in susceptible patients. This article reviews a practical approach for the definition and identification of adverse effects of epilepsy therapies, and reviews the literature demonstrating that adverse effects result in detrimental quality of life in epilepsy patients. Strategies for minimizing AED adverse effects by reduction or elimination of AED polytherapy, appropriately employing drug-sparing therapies, and optimally administering AEDs are outlined, including tenets of AED selection, titration, therapeutic AED laboratory monitoring, and avoidance of chronic idiosyncratic adverse effects.

  17. Psychomotor development and general movements in offspring of women with epilepsy and anticonvulsant therapy.

    Science.gov (United States)

    Parisi, Pasquale; Francia, Ada; Vanacore, Nicola; Fiore, Stefania; Giallonardo, Anna Teresa; Manfredi, Mario

    2003-11-01

    While the role of antiepileptic drug (AED) therapy in teratogenesis has widely been investigated, there are few prospective studies on later postnatal development in offspring of epileptic women in utero exposed. The aim of this study was a prospective investigation of the psychomotor development in a selected population of infant born to women with epilepsy on AED therapy during pregnancy. Children were assessed at various times until 30 months of age by general movement (GMs) observation (at 7 days and 4 and 13 weeks), traditional neurologic examination (at 7 days and 4 and 13 weeks, 6, 9 and 12 months) and Brunet-Lezine (B-L) administration (at 30 months). We present the preliminary results of our study conducted on 11 children. Psychomotor delay in children was confirmed by traditional neurological examinations scores at 7 days, 4 weeks, 13 weeks and 6 months and by B-L score at 30 months. Between 9 and 12 months of age, traditional neurologic examination became "silent". GM assessment was found to be a better predictor of psychomotor development. In fact, GM analysis, particularly at 4 weeks, was strongly correlated with the Brunet-Lezine score at 30 months. In conclusion, on the basis of these data we suggest a psychomotor delay in the offspring of epileptic women and that GMs and neurologic evaluation provide complementary information concerning psychomotor development and later outcome of these children.

  18. Teratogenic effects of five anticancer drugs on Xenopus laevis embryos.

    Science.gov (United States)

    Isidori, Marina; Piscitelli, Concetta; Russo, Chiara; Smutná, Marie; Bláha, Luděk

    2016-11-01

    In recent years, the environmental presence of pharmaceuticals - including anticancer drugs - is an emerging issue. Because of the lack of appropriate critical studies about anticancer drug effects in frogs, the aim of the present study was to investigate lethal and teratogenic effects of five anticancer drugs widely used in large quantities, i.e. 5-flourouracil, capecitabine, cisplatin, etoposide, and imatinib, in the embryos of the South African clawed frog, Xenopus laevis, using FETAX - Frog Embryo Teratogenesis Assay in Xenopus. None of the studied anticancer drugs induced statistically significant mortality within the concentrations tested (0.01-50mg/L, depending on the studied compound), and no growth inhibition of embryos after a 96-h exposure was observed. Except for cisplatin, the other pharmaceuticals induced an increase of developmental malformations such as abdominal edema, axial flexure, head, eyes, gut and heart malformations with statistically significant effects observed at the highest concentrations tested (50mg/L for 5-flourouracil; 30mg/L for etoposide and 20mg/L for capecitabine and imatinib). The results indicate that anticancer drugs can affect embryogenesis mechanisms. Copyright © 2016 Elsevier Inc. All rights reserved.

  19. Effects of ethanol and NAP on cerebellar expression of the neural cell adhesion molecule L1.

    Directory of Open Access Journals (Sweden)

    Devon M Fitzgerald

    Full Text Available The neural cell adhesion molecule L1 is critical for brain development and plays a role in learning and memory in the adult. Ethanol inhibits L1-mediated cell adhesion and neurite outgrowth in cerebellar granule neurons (CGNs, and these actions might underlie the cerebellar dysmorphology of fetal alcohol spectrum disorders. The peptide NAP potently blocks ethanol inhibition of L1 adhesion and prevents ethanol teratogenesis. We used quantitative RT-PCR and Western blotting of extracts of cerebellar slices, CGNs, and astrocytes from postnatal day 7 (PD7 rats to investigate whether ethanol and NAP act in part by regulating the expression of L1. Treatment of cerebellar slices with 20 mM ethanol, 10(-12 M NAP, or both for 4 hours, 24 hours, and 10 days did not significantly affect L1 mRNA and protein levels. Similar treatment for 4 or 24 hours did not regulate L1 expression in primary cultures of CGNs and astrocytes, the predominant cerebellar cell types. Because ethanol also damages the adult cerebellum, we studied the effects of chronic ethanol exposure in adult rats. One year of binge drinking did not alter L1 gene and protein expression in extracts from whole cerebellum. Thus, ethanol does not alter L1 expression in the developing or adult cerebellum; more likely, ethanol disrupts L1 function by modifying its conformation and signaling. Likewise, NAP antagonizes the actions of ethanol without altering L1 expression.

  20. A exposição pré-natal ao álcool como fator de risco para comportamentos disfuncionais: o papel do pediatra Prenatal alcohol exposure as a risk factor for dysfunctional behaviors: the role of the pediatrician

    Directory of Open Access Journals (Sweden)

    Wakana Momino

    2008-08-01

    Full Text Available OBJETIVO: Ainda que as características clássicas da síndrome fetal alcoólica tenham sido descritas desde 1968, a pesquisa sobre a teratogênese do álcool apenas recentemente demonstrou que o cérebro é o órgão do corpo mais vulnerável aos efeitos da exposição pré-natal ao álcool. No presente artigo, fazemos uma revisão da literatura focalizando principalmente os distúrbios comportamentais relacionados à exposição pré-natal ao álcool. FONTES DOS DADOS: Foi realizada uma pesquisa com base no PubMed sobre a literatura publicada entre 1968 e 2006, com as palavras-chave etanol, gestação e comportamento. Foram estabelecidos limites a estudos em humanos. SÍNTESE DOS DADOS: Os dados apresentados nesta revisão sugerem que jovens com efeitos do espectro do álcool fetal estão sob risco maior de terem comportamento social disruptivo, entre outros problemas neurocomportamentais. CONCLUSÕES: Ainda que seja impossível separar completamente a teratogênese sobre o cérebro decorrente da exposição ao álcool de influências ambientais pós-natais como a causa definitiva desses resultados, o pediatra deve ser estimulado ao diagnóstico precoce de crianças afetadas pela síndrome fetal alcoólica e efeitos do espectro do álcool fetal. Isso permite iniciar o manejo e cuidados apropriados para evitar as conseqüências em longo prazo no comportamento e assegurar uma adaptação social e escolar melhor e mais produtiva.OBJECTIVE: Although the classic features of fetal alcohol syndrome have been recognized since 1968, research on alcohol teratogenesis has only recently demonstrated that the brain is the organ in the body most vulnerable to the effects of prenatal alcohol exposure. In this present article, we reviewed the literature focusing mainly on behavioral disturbances related to prenatal ethanol exposure. SOURCES: We performed a PubMed search on the literature published between 1968 and 2006 using the terms ethanol, pregnancy and

  1. The Mouse House: a brief history of the ORNL mouse-genetics program, 1947-2009.

    Science.gov (United States)

    Russell, Liane B

    2013-01-01

    The large mouse genetics program at the Oak Ridge National Laboratory (ORNL) is often remembered chiefly for the germ-cell mutation-rate data it generated and their uses in estimating the risk of heritable radiation damage. In fact, it soon became a multi-faceted research effort that, over a period of almost 60 years, generated a wealth of information in the areas of mammalian mutagenesis, basic genetics (later enriched by molecular techniques), cytogenetics, reproductive biology, biochemistry of germ cells, and teratology. Research in the area of germ-cell mutagenesis explored the important physical and biological factors that affect the frequency and nature of induced mutations and made several unexpected discoveries, such as the major importance of the perigametic interval (the zygote stage) for the origin of spontaneous mutations and for the sensitivity to induced genetic change. Of practical value was the discovery that ethylnitrosourea was a supermutagen for point mutations, making high-efficiency mutagenesis in the mouse feasible worldwide. Teratogenesis findings resulted in recommendations still generally accepted in radiological practice. Studies supporting the mutagenesis research added whole bodies of information about mammalian germ-cell development and about molecular targets in germ cells. The early decision to not merely count but propagate genetic variants of all sorts made possible further discoveries, such as the Y-chromosome's importance in mammalian sex determination and the identification of rare X-autosome translocations, which, in turn, led to the formulation of the single-active-X hypothesis and provided tools for studies of functional mosaicism for autosomal genes, male sterility, and chromosome-pairing mechanism. Extensive genetic and then molecular analyses of large numbers of induced specific-locus mutants resulted in fine-structure physical and correlated functional mapping of significant portions of the mouse genome and constituted a

  2. Developmental toxicity of L-selenomethionine in Macaca fascicularis.

    Science.gov (United States)

    Tarantal, A F; Willhite, C C; Lasley, B L; Murphy, C J; Miller, C J; Cukierski, M J; Book, S A; Hendrickx, A G

    1991-01-01

    Forty pregnant long-tailed macaques were dosed via nasogastric intubation with 0, 25, 150, or 300 micrograms/kg of L-selenomethionine (Se) daily during organogenesis [Gestational Day (GD) 20-50]. Clinical examination of the dams, maternal body weights, sonographic evaluations, clinical chemistry screens, and measures of serum progesterone and urinary estrone conjugates were used as indicators of maternal and fetal status in all animals. The pregnancies of two to three dams from each dose group were followed until term (approximately GD 165); the remainder (N = 7/dose group) were scheduled for hysterotomy on GD 100 +/- 2. A standard teratologic evaluation was performed including visceral and skeletal examinations. Fetal liver, kidney, skin, and smooth, cardiac, and skeletal muscles were examined by light microscopy; heart muscle was also evaluated by transmission electron microscopy. Neonates delivered at term remained with the dams and were removed periodically for morphometric, neurologic, behavioral, and ophthalmologic assessments on Days 1, 8, 15, 22, and 30 of age. Dose-dependent maternal toxicity as evidenced by anorexia, vomiting, and a significant reduction in body weight increased with increasing duration of Se exposure. One growth-retarded fetus was recovered on GD 131 from a compromised dam exposed to 25 micrograms/kg-day; one early embryonic death (GD 35) and two fetal deaths [GD 68 (followed by maternal death) and GD 123] occurred among animals dosed with 300 micrograms/kg-day. Pregnancy loss among treated animals was not significantly different from concurrent or historical controls. No statistically significant treatment-related effects were observed at necropsy on GD 100 +/- 2. One infant exposed to 150 micrograms/kg-day prenatally exhibited a unilateral cortical cataract, which may have been a spontaneous occurrence. The limited developmental effects observed and reported teratogenesis in nonmammalian species suggest that comparative pharmacokinetic

  3. Polystyrene nanoparticles affect Xenopus laevis development

    Energy Technology Data Exchange (ETDEWEB)

    Tussellino, Margherita; Ronca, Raffaele [University of Naples Federico II, Department of Biology (Italy); Formiggini, Fabio [Italian Institute of Technology, Center for Advanced Biomaterials for Health Care IIT@CRIB (Italy); Marco, Nadia De [University of Naples Federico II, Department of Biology (Italy); Fusco, Sabato; Netti, Paolo Antonio [Italian Institute of Technology, Center for Advanced Biomaterials for Health Care IIT@CRIB (Italy); Carotenuto, Rosa, E-mail: rosa.carotenuto@unina.it [University of Naples Federico II, Department of Biology (Italy)

    2015-02-15

    Exposing living organisms to nanoparticulates is potentially hazardous, in particular when it takes place during embryogenesis. In this investigation, we have studied the effects of 50-nm-uncoated polystyrene nanoparticles (PSNPs) as a model to investigate the suitability of their possible future employments. We have used the standardized Frog Embryo Teratogenesis Assay-Xenopus test during the early stages of larval development of Xenopus laevis, and we have employed either contact exposure or microinjections. We found that the embryos mortality rate is dose dependent and that the survived embryos showed high percentage of malformations. They display disorders in pigmentation distribution, malformations of the head, gut and tail, edema in the anterior ventral region, and a shorter body length compared with sibling untreated embryos. Moreover, these embryos grow more slowly than the untreated embryos. Expressions of the mesoderm markers, bra (T-box Brachyury gene), myod1 (myogenic differentiation1), and of neural crest marker sox9 (sex SRY (determining region Y-box 9) transcription factor sox9), are modified. Confocal microscopy showed that the nanoparticles are localized in the cytoplasm, in the nucleus, and in the periphery of the digestive gut cells. Our data suggest that PSNPs are toxic and show a potential teratogenic effect for Xenopus larvae. We hypothesize that these effects may be due either to the amount of NPs that penetrate into the cells and/or to the “corona” effect caused by the interaction of PSNPs with cytoplasm components. The three endpoints of our study, i.e., mortality, malformations, and growth inhibition, suggest that the tests we used may be a powerful and flexible bioassay in evaluating pollutants in aquatic embryos.

  4. Pdgfra protects against ethanol-induced craniofacial defects in a zebrafish model of FASD

    Science.gov (United States)

    McCarthy, Neil; Wetherill, Leah; Lovely, C. Ben; Swartz, Mary E.; Foroud, Tatiana M.; Eberhart, Johann K.

    2013-01-01

    Human birth defects are highly variable and this phenotypic variability can be influenced by both the environment and genetics. However, the synergistic interactions between these two variables are not well understood. Fetal alcohol spectrum disorders (FASD) is the umbrella term used to describe the wide range of deleterious outcomes following prenatal alcohol exposure. Although FASD are caused by prenatal ethanol exposure, FASD are thought to be genetically modulated, although the genes regulating sensitivity to ethanol teratogenesis are largely unknown. To identify potential ethanol-sensitive genes, we tested five known craniofacial mutants for ethanol sensitivity: cyp26b1, gata3, pdgfra, smad5 and smoothened. We found that only platelet-derived growth factor receptor alpha (pdgfra) interacted with ethanol during zebrafish craniofacial development. Analysis of the PDGF family in a human FASD genome-wide dataset links PDGFRA to craniofacial phenotypes in FASD, prompting a mechanistic understanding of this interaction. In zebrafish, untreated pdgfra mutants have cleft palate due to defective neural crest cell migration, whereas pdgfra heterozygotes develop normally. Ethanol-exposed pdgfra mutants have profound craniofacial defects that include the loss of the palatal skeleton and hypoplasia of the pharyngeal skeleton. Furthermore, ethanol treatment revealed latent haploinsufficiency, causing palatal defects in ∼62% of pdgfra heterozygotes. Neural crest apoptosis partially underlies these ethanol-induced defects in pdgfra mutants, demonstrating a protective role for Pdgfra. This protective role is mediated by the PI3K/mTOR pathway. Collectively, our results suggest a model where combined genetic and environmental inhibition of PI3K/mTOR signaling leads to variability within FASD. PMID:23861062

  5. Quantification of risk from fetal exposure to diagnostic ultrasound.

    Science.gov (United States)

    Church, Charles C; Miller, Morton W

    2007-01-01

    Biomedical ultrasound may induce adverse effects in patients by either thermal or non-thermal means. Temperatures above normal can adversely affect biological systems, but effects also may be produced without significant heating. Thermally induced teratogenesis has been demonstrated in many animal species as well as in a few controlled studies in humans. Various maximum 'safe' temperature elevations have been proposed, although the suggested values range from 0.0 to 2.5 degrees C. Factors relevant to thermal effects are considered, including the nature of the acoustic field in situ, the state of perfusion of the embryo/fetus, and the variation of sensitivity to thermal insult with gestational stage of development. Non-thermal mechanisms of action considered include acoustic cavitation, radiation force, and acoustic streaming. While cavitation can be quite destructive, it is extremely unlikely in the absence of stabilized gas bodies, and although the remaining mechanisms may occur in utero, they have not been shown to induce adverse effects. For example, pulsed, diagnostic ultrasound can increase fetal activity during exposure, apparently due to stimulation of auditory perception by radiation forces on the fetal head or auditory structures. In contrast, pulsed ultrasound also produces vascular damage near developing bone in the late-gestation mouse, but by a unknown mechanism and at levels above current US FDA output limits. It is concluded that: (1) thermal rather than nonthermal mechanisms are more likely to induce adverse effects in utero, and (2) while the probability of an adverse thermal event is usually small, under some conditions it can be disturbingly high.

  6. Caudate volume predicts neurocognitive performance in youth with heavy prenatal alcohol exposure.

    Science.gov (United States)

    Fryer, Susanna L; Mattson, Sarah N; Jernigan, Terry L; Archibald, Sarah L; Jones, Kenneth Lyons; Riley, Edward P

    2012-11-01

    Fetal alcohol spectrum disorders result from heavy prenatal alcohol exposure and are characterized, in some cases, by central nervous system anomalies and cognitive impairment. Regional patterns of neuroanatomical abnormalities suggest that alcohol exerts selective damage on the developing fetal brain. This study assessed brain-behavior relationships in a sample of youth with histories of heavy prenatal alcohol exposure. The aim was to characterize how structural brain alterations observed in our previous studies relate to cognitive deficits commonly reported in individuals with histories of heavy prenatal alcohol exposure. Twenty-one youth (mean age 13 years) with histories of heavy prenatal alcohol exposure and 7 nonexposed healthy comparison subjects underwent structural magnetic resonance imaging and neurobehavioral testing. Regional brain volumes within the alcohol-exposed group were correlated with neuropsychological measures of cognitive control and verbal learning/recall, as these aspects of cognition have previously been shown to be vulnerable to alcohol teratogenesis. Between-group effect sizes revealed moderate to large cognitive performance and brain volume decrements in alcohol-exposed subjects, compared with typically developing peers. Within the alcohol-exposed group, volume of the caudate nuclei was the most consistent predictor of neuropsychological performance, after controlling for potentially confounding variables including total brain volume, IQ, and age. These data are consistent with previous research associating gestational alcohol exposure with structural and functional changes of the caudate nucleus. Our findings extend this previous work by demonstrating that volume reductions of the caudate have behavioral relevance for this population, in relation to cognitive control and verbal learning and recall abilities. Copyright © 2012 by the Research Society on Alcoholism.

  7. Impact of retinoic acid exposure on midfacial shape variation and manifestation of holoprosencephaly in Twsg1 mutant mice

    Directory of Open Access Journals (Sweden)

    Charles J. Billington

    2015-02-01

    Full Text Available Holoprosencephaly (HPE is a developmental anomaly characterized by inadequate or absent midline division of the embryonic forebrain and midline facial defects. It is believed that interactions between genes and the environment play a role in the widely variable penetrance and expressivity of HPE, although direct investigation of such effects has been limited. The goal of this study was to examine whether mice carrying a mutation in a gene encoding the bone morphogenetic protein (BMP antagonist twisted gastrulation (Twsg1, which is associated with a low penetrance of HPE, are sensitized to retinoic acid (RA teratogenesis. Pregnant Twsg1+/− dams were treated by gavage with a low dose of all-trans RA (3.75 mg/kg of body weight. Embryos were analyzed between embryonic day (E9.5 and E11.5 by microscopy and geometric morphometric analysis by micro-computed tomography. P19 embryonal carcinoma cells were used to examine potential mechanisms mediating the combined effects of increased BMP and retinoid signaling. Although only 7% of wild-type embryos exposed to RA showed overt HPE or neural tube defects (NTDs, 100% of Twsg1−/− mutants exposed to RA manifested severe HPE compared to 17% without RA. Remarkably, up to 30% of Twsg1+/− mutants also showed HPE (23% or NTDs (7%. The majority of shape variation among Twsg1+/− mutants was associated with narrowing of the midface. In P19 cells, RA induced the expression of Bmp2, acted in concert with BMP2 to increase p53 expression, caspase activation and oxidative stress. This study provides direct evidence for modifying effects of the environment in a genetic mouse model carrying a predisposing mutation for HPE in the Twsg1 gene. Further study of the mechanisms underlying these gene-environment interactions in vivo will contribute to better understanding of the pathogenesis of birth defects and present an opportunity to explore potential preventive interventions.

  8. CD24 expression identifies teratogen-sensitive fetal neural stem cell subpopulations: evidence from developmental ethanol exposure and orthotopic cell transfer models.

    Science.gov (United States)

    Tingling, Joseph D; Bake, Shameena; Holgate, Rhonda; Rawlings, Jeremy; Nagsuk, Phillips P; Chandrasekharan, Jayashree; Schneider, Sarah L; Miranda, Rajesh C

    2013-01-01

    Ethanol is a potent teratogen. Its adverse neural effects are partly mediated by disrupting fetal neurogenesis. The teratogenic process is poorly understood, and vulnerable neurogenic stages have not been identified. Identifying these is a prerequisite for therapeutic interventions to mitigate effects of teratogen exposures. We used flow cytometry and qRT-PCR to screen fetal mouse-derived neurosphere cultures for ethanol-sensitive neural stem cell (NSC) subpopulations, to study NSC renewal and differentiation. The identity of vulnerable NSC populations was validated in vivo, using a maternal ethanol exposure model. Finally, the effect of ethanol exposure on the ability of vulnerable NSC subpopulations to integrate into the fetal neurogenic environment was assessed following ultrasound guided, adoptive transfer. Ethanol decreased NSC mRNAs for c-kit, Musashi-1and GFAP. The CD24(+) NSC population, specifically the CD24(+)CD15(+) double-positive subpopulation, was selectively decreased by ethanol. Maternal ethanol exposure also resulted in decreased fetal forebrain CD24 expression. Ethanol pre-exposed CD24(+) cells exhibited increased proliferation, and deficits in cell-autonomous and cue-directed neuronal differentiation, and following orthotopic transplantation into naïve fetuses, were unable to integrate into neurogenic niches. CD24(depleted) cells retained neurosphere regeneration capacity, but following ethanol exposure, generated increased numbers of CD24(+) cells relative to controls. Neuronal lineage committed CD24(+) cells exhibit specific vulnerability, and ethanol exposure persistently impairs this population's cell-autonomous differentiation capacity. CD24(+) cells may additionally serve as quorum sensors within neurogenic niches; their loss, leading to compensatory NSC activation, perhaps depleting renewal capacity. These data collectively advance a mechanistic hypothesis for teratogenesis leading to microencephaly.

  9. Detection of retinoic acid receptor antagonist contamination in the aquatic environment of the Kinki region of Japan.

    Science.gov (United States)

    Inoue, Daisuke; Sawada, Kazuko; Sei, Kazunari; Ike, Michihiko

    2016-10-15

    Retinoic acid receptor (RAR) antagonists are potential toxic compounds that can cause teratogenesis in vertebrates. This study was conducted to evaluate the occurrence of RAR antagonist contamination in aquatic environments and identify its potential sources in detail. To accomplish this, the RAR antagonistic activities of surface waters of two rivers (the Yodo River and the Ina River) and influents and effluents of municipal wastewater treatment plants (WWTPs) in the Kinki region of Japan were investigated using a yeast two-hybrid assay. In the investigated rivers, remarkable RAR antagonistic activities were detected relatively consistently in specific regions, although the levels varied with time, and tended to increase downstream of municipal WWTPs. Investigations of WWTPs also revealed that RAR antagonists were present at remarkably high levels in municipal wastewater, and that RAR antagonist contamination remained in effluent after activated sludge treatments. Comparison of the concentration factors that reduced 50% of the RAR agonistic activity of 10(-7) M all-trans retinoic acid (IC50) for selected river water and WWTP effluent samples revealed that the contamination levels were greater in effluent (IC50: concentration factors of 92-313) than river water (IC50: concentration factors of 10.2-68.9). These results indicate that municipal WWTPs could be an important source of RAR antagonist contamination in the receiving rivers. Fractionations with high-performance liquid chromatography directed by the bioassay indicated that there were multiple RAR antagonists in municipal wastewater. Although a trial to identify the causative compounds in municipal wastewater was not completed, multiple bioactive peaks that should be studied further were isolated. This study clarified the occurrence of novel endocrine disrupting chemicals (i.e., RAR antagonists) in the aquatic environment at the watershed level and identified their possible source for the first time, which

  10. Estudo anatômico comparativo entre formas normais e estruturas teratogênicas provocadas por 2,4 -D em cana-de-açúcar Comparative anatomy of the normal and abnormal forms produced by 2,4-D in sugar cane

    Directory of Open Access Journals (Sweden)

    G.M. Corso

    1980-06-01

    Full Text Available A aplicação do herbicida 2,4-D amina, para controlar plantas daninhas em cultura de cana-de-açúcar, produziu estruturas anormais e afetou a própria cultura da cana. Foram estuda das as alterações anatômicas e organográfícas dessas formas teratogénicas e comparadas com as estruturas normais. Foram observadas deformações no colmo que apresentou curvatur as e entrenós mais finos e curtos; o sistema radicular apresentou-se pouco desenvolvido. Na região do anel meristemático e saída das raízes adventícias, observou-se um intumescimento com tumoração e posterior necrose. Anatomicamente, na região do anel meristemático, a epiderme e o parênquima cortical apresentaram células hipertrofíadas e crescimento desordenado; houve malformação de feixes fibrovasculares. Na região das raízes adventícias foi observada tumoração com acentuada hiperplasia e necrose na periferia.The application of 2,4-D amine herbicide for control of weeds infesting sugar cane fields, produced teratogenesis and affected the sugar cane plants. The anatomic and organografic alterations of the teratogenic forms were studied and compared with normal structures. Stalk malformation was observed, resulting in bending and thinner stalks; root system had little development. The growth ring and root band showed severe hypertrophy, callus formation and necrosis. The growth ring, the epidermis and cortical parenchyma showed hypertrophied cells and disturbed growth. Malformation of phloem and xylem also ocurred.

  11. Hydrocephalus and arthrogryposis in an immunocompetent mouse model of ZIKA teratogeny: A developmental study

    Science.gov (United States)

    Xavier-Neto, Jose; Carvalho, Murilo; Pascoalino, Bruno dos Santos; Cardoso, Alisson Campos; Costa, Ângela Maria Sousa; Pereira, Ana Helena Macedo; Santos, Luana Nunes; Saito, Ângela; Marques, Rafael Elias; Smetana, Juliana Helena Costa; Consonni, Silvio Roberto; Bandeira, Carla; Costa, Vivian Vasconcelos; Bajgelman, Marcio Chaim; de Oliveira, Paulo Sérgio Lopes; Cordeiro, Marli Tenorio; Gonzales Gil, Laura Helena Vega; Pauletti, Bianca Alves; Granato, Daniela Campos; Paes Leme, Adriana Franco; Freitas-Junior, Lucio; Holanda de Freitas, Carolina Borsoi Moraes; Teixeira, Mauro Martins; Bevilacqua, Estela; Franchini, Kleber

    2017-01-01

    The teratogenic mechanisms triggered by ZIKV are still obscure due to the lack of a suitable animal model. Here we present a mouse model of developmental disruption induced by ZIKV hematogenic infection. The model utilizes immunocompetent animals from wild-type FVB/NJ and C57BL/6J strains, providing a better analogy to the human condition than approaches involving immunodeficient, genetically modified animals, or direct ZIKV injection into the brain. When injected via the jugular vein into the blood of pregnant females harboring conceptuses from early gastrulation to organogenesis stages, akin to the human second and fifth week of pregnancy, ZIKV infects maternal tissues, placentas and embryos/fetuses. Early exposure to ZIKV at developmental day 5 (second week in humans) produced complex manifestations of anterior and posterior dysraphia and hydrocephalus, as well as severe malformations and delayed development in 10.5 days post-coitum (dpc) embryos. Exposure to the virus at 7.5–9.5 dpc induces intra-amniotic hemorrhage, widespread edema, and vascular rarefaction, often prominent in the cephalic region. At these stages, most affected embryos/fetuses displayed gross malformations and/or intrauterine growth restriction (IUGR), rather than isolated microcephaly. Disrupted conceptuses failed to achieve normal developmental landmarks and died in utero. Importantly, this is the only model so far to display dysraphia and hydrocephalus, the harbinger of microcephaly in humans, as well as arthrogryposis, a set of abnormal joint postures observed in the human setting. Late exposure to ZIKV at 12.5 dpc failed to produce noticeable malformations. We have thus characterized a developmental window of opportunity for ZIKV-induced teratogenesis encompassing early gastrulation, neurulation and early organogenesis stages. This should not, however, be interpreted as evidence for any safe developmental windows for ZIKV exposure. Late developmental abnormalities correlated with

  12. A comparison of electronic and traditional cigarette butt leachate on the development of Xenopus laevis embryos

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    Tatiana Tatum Parker

    Full Text Available Potential developmental toxicities of three different cigarette butt leachates were evaluated using the frog embryo teratogenesis assay–Xenopus (FETAX. Xenopus laevis embryos were exposed to regular cigarette butt (RCB, menthol (MCB and electronic (ECB in concentrations ranging from 0 to 4 butts/l for RCB and MCB and 0–10 butts/l for ECB. The embryos were from stage 8 to 11 and were exposed for a 96-h period in static renewal test conditions. Median lethal concentration (LC50, malformation (EC50, non-observed adverse effect concentration (NOAEC, and lowest observed adverse effect concentration (LOAEC were calculated. Results from these studies suggest that each tested leachate is teratogenic for X. laevis embryos. The lowest LC50 was determined for ECB exposure at 17.9 cigarette butts/L. The LC50 value was the highest with RCB and MCB having LC50 s of approximately 1 cigarette butt/L. There were notable EC50 differences with RCB having the highest and ECB the lowest. The NOAEC and LOAEC levels for RCB and MCB were below 1 cigarette butt/L for both mortality and malformations; over 8 butts/L for ECB mortality and over 4 butts/L for malformations. From these results, we conclude that RCB leachate is the most toxic compound, while MCB leachate has the higher teratogenicity. ECB leachate has the lowest toxic and teratogenic effects on embryos but there were still noticeable effects. The results confirmed that the FETAX assay can be useful in an integrated biological hazard assessment for the preliminary screening for ecological risks of cigarette butts, and electronic cigarettes, in aquatic environment. Keywords: Cigarette butt leachate, Xenopus laevis, Development

  13. Potential uses of sea urchin embryos for identifying toxic chemicals: description of a bioassay incorporating cytologic, cytogenetic and embryologic endpoints.

    Science.gov (United States)

    Hose, J E

    1985-08-01

    A method for evaluating pollutant genotoxicity, embryotoxicity and teratogenicity using sea urchin embryos has been developed and was tested using benzo(a)pyrene (BP). Initial results suggested that the bioassay may be a sensitive indicator of pollutant toxicity and mutagenicity since several endpoints can be simultaneously assessed. The bioassay is rapid, inexpensive and appears applicable to a variety of toxicants and delivery methods. The test is based upon the standard 48 h sea urchin development assay and incorporates cytologic-cytogenetic analysis of embryos. Following toxic exposure of gametes, fertilization success is assessed. Embryos then develop for 48 h at which time survival and teratogenesis are evaluated. A subsample of embryos is stained and dissociated into monolayers and mitotic configurations are examined using light microscopy. Embryo mitotic rates are used as an indicator of overall embryonic health. Cytotoxic effects are concomitantly evaluated. Genotoxicity is measured using two methods: (1) anaphase aberration analysis, a technique which assesses abnormalities in the chromosome configurations (such as bridges and fragments) as the groups of chromosomes move to opposite poles and (2) micronucleus formation, a procedure examining the incidence of smaller, secondary nuclei composed of whole chromosomes or chromatid fragments. These two measurements preclude the need to examine individual chromosomes for deletions and exchanges, a laborious process in most aquatic organisms which possess numerous relatively small chromosomes. This genotoxicity-teratogenicity test appears promising for laboratory evaluations of individual substances or of complex chemical mixtures as well as for environmental monitoring of nearshore areas. The standard development assay has been used to screen pharmaceuticals and environmental contaminants and some recent investigations have included mitotic aberration analysis. Experiments in our laboratory suggest that the

  14. Inhibition of fumonisin B1 cytotoxicity by nanosilicate platelets during mouse embryo development.

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    Yu-Jing Liao

    Full Text Available Nanosilicate platelets (NSP, the form of natural silicate clay that was exfoliated from montmorillonite (MMT, is widely used as a feed additive for its high non-specific binding capacity with mycotoxins such as fumonisin B1 (FB1, and has been evaluated its safety for biomedical use including cytotoxicity, genotoxicity, and lethal dosage (LD. In the study, we further examined its toxicity on the development of CD1 mouse embryos and its capacity to prevent teratogenesis-induced by FB1. In vitro cultures, NSP did not disturb the development and the quality of intact pre-implantation mouse embryos. Further, newborn mice from females consumed with NSP showed no abnormalities. NSP had an unexpected high adsorption capacity in vitro. In contrast to female mice consumed with FB1 only, a very low residual level of FB1 in the circulation, reduced incidence of neutral tube defects and significantly increased fetal weight were observed in the females consumed with FB1 and NSP, suggesting a high alleviation effect of NSP on FB1 in vivo. Furthermore, FB1 treatment disturbed the gene expression of sphingolipid metabolism enzymes (longevity assurance homolog 5, LASS 5; sphingosine kinase 1, Sphk1; sphingosine kinase 2, Sphk2; sphingosine 1- phosphate lyase, Sgpl1; sphingosine 1-phosphate phosphatase, Sgpp1 in the maternal liver, uterus, fetus, and placenta, but NSP administration reversed the perturbations. Based on these findings, we conclude that NSP is a feasible and effective agent for supplementary use in reducing the toxicity of FB1 to animals.

  15. A comparison of electronic and traditional cigarette butt leachate on the development of Xenopus laevis embryos.

    Science.gov (United States)

    Parker, Tatiana Tatum; Rayburn, James

    2017-01-01

    Potential developmental toxicities of three different cigarette butt leachates were evaluated using the frog embryo teratogenesis assay-Xenopus (FETAX). Xenopus laevis embryos were exposed to regular cigarette butt (RCB), menthol (MCB) and electronic (ECB) in concentrations ranging from 0 to 4 butts/l for RCB and MCB and 0-10 butts/l for ECB. The embryos were from stage 8 to 11 and were exposed for a 96-h period in static renewal test conditions. Median lethal concentration (LC50), malformation (EC50), non-observed adverse effect concentration (NOAEC), and lowest observed adverse effect concentration (LOAEC) were calculated. Results from these studies suggest that each tested leachate is teratogenic for X. laevis embryos. The lowest LC50 was determined for ECB exposure at 17.9 cigarette butts/L. The LC50 value was the highest with RCB and MCB having LC50 s of approximately 1 cigarette butt/L. There were notable EC50 differences with RCB having the highest and ECB the lowest. The NOAEC and LOAEC levels for RCB and MCB were below 1 cigarette butt/L for both mortality and malformations; over 8 butts/L for ECB mortality and over 4 butts/L for malformations. From these results, we conclude that RCB leachate is the most toxic compound, while MCB leachate has the higher teratogenicity. ECB leachate has the lowest toxic and teratogenic effects on embryos but there were still noticeable effects. The results confirmed that the FETAX assay can be useful in an integrated biological hazard assessment for the preliminary screening for ecological risks of cigarette butts, and electronic cigarettes, in aquatic environment.

  16. Toxic effects of {sup 56}Fe ion radiation on the zebrafish (Danio rerio) embryonic development

    Energy Technology Data Exchange (ETDEWEB)

    Si, Jing; Zhou, Rong [Department of Radiation Medicine, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000 (China); Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Lanzhou 730000 (China); Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Gansu Province, Lanzhou 730000 (China); Song, Jing’e [Hospital of Stomatology, Lanzhou University, Lanzhou 730000 (China); Gan, Lu; Zhou, Xin; Di, Cuixia; Liu, Yang; Mao, Aihong; Zhao, Qiuyue; Wang, Yupei [Department of Radiation Medicine, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000 (China); Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Lanzhou 730000 (China); Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Gansu Province, Lanzhou 730000 (China); Zhang, Hong, E-mail: zhangh@impcas.ac.cn [Department of Radiation Medicine, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000 (China); Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Lanzhou 730000 (China); Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Gansu Province, Lanzhou 730000 (China); Gansu Wuwei Institute of Medical Sciences, Wuwei 733000 (China)

    2017-05-15

    Highlights: • Iron ion radiation induced developmental toxicity and apoptosis in zebrafish embryos. • The mRNA expression levels of apoptosis-related genes displayed more sensitivity than the developmental toxicity. • Iron ion radiation induced apoptosis in zebrafish embryos potentially due to DNA damage and mitochondrial dysfunction. - Abstract: All living organisms and ecosystems are permanently exposed to ionizing radiation. Of all the types of ionizing radiation, heavy ions such as {sup 56}Fe have the potential to cause the most severe biological effects. We therefore examined the effects and potential mechanisms of iron ion irradiation on the induction of developmental toxicity and apoptosis in zebrafish embryos. Zebrafish embryos at 4 h post-fertilization (hpf) were divided into five groups: a control group; and four groups irradiated with 0.5, 1, 2, and 4 Gy radiation, respectively. Mortality and teratogenesis were significantly increased, and spontaneous movement, heart rate, and swimming distance were decreased in the irradiated groups, accompanied by increased apoptosis. mRNA levels of genes involved in the apoptotic pathway, including p53, bax, bcl-2, and caspase-3, were significantly affected by radiation exposure. Moreover, protein expression levels of P53 and Bcl-2 changed in accordance with the corresponding mRNA expression levels. In addition, we detected the protein expression levels of γ-H2AX, which is a biomarker for radiation-induced DNA double-strand breaks, and found that γ-H2AX protein levels were significantly increased in the irradiated groups. Overall, the results of this study improve our understanding of the mechanisms of iron ion radiation-induced developmental toxicity and apoptosis, potentially involving the induction of DNA damage and mitochondrial dysfunction. The findings of this study may aid future impact assessment of environmental radioactivity in fish.

  17. Metal-on-metal bearings total hip arthroplasty: the cobalt and chromium ions release concern.

    Science.gov (United States)

    Delaunay, C; Petit, I; Learmonth, I D; Oger, P; Vendittoli, P A

    2010-12-01

    With certain concerns recently reported on metal-on-metal bearing couples in total hip arthroplasty, this study's objective is to review the current knowledge concerning release of metal ions and its potential consequences. Each metal-on-metal implant presents different tribological properties. The analytical techniques for metals are accurate and the Co ion rates seem acceptable up to 2 μg/L. A delayed type IV hypersensitivity reaction (atypical lymphocytic vasculitis-associated lesion [ALVAL]) may be the source of arthroplasty failure. Idiosyncratic, it remains unpredictable even using cutaneous tests and apparently is rare (0.3%). Today, there are no scientific or epidemiologic data supporting a risk of carcinogenesis or teratogenesis related to the use of a metal-on-metal bearings couple. Solid pseudotumors nearly exclusively are observed with resurfacing procedures, carrying a high annual revision rate in women under 40 years of age, occurring particularly in cases of acetabular malposition and with use of cast molded Cr-Co alloys. Osteolysis manifests through complete and progressive radiolucent lines or through cavitary lesions stemming from ALVAL-type alterations or impingement problems or implant incompatibility. The formation of wear debris exceeding the biological tolerance is possible with implant malposition, subluxation, and jamming of the femoral head in cases of cup deformity. Moreover, each implant presents different metal ion production; assessment of their performance and safety is required before their clinical use. With the knowledge available today, metal-on-metal bearing couples are contraindicated in cases of metal allergies or end stage renal dysfunction and small size resurfacing should cautiously be used. Copyright © 2010. Published by Elsevier Masson SAS.

  18. Biological effect of radiation on human

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Yun Sil; Cho, Chul Koo; Lee, Su Jae [and others

    2000-04-01

    1. Adaptive response when 0.01 Gy was preirradiated before high challenging dose is induced in normal cell types such normal lymphocytes, primary keratinocytes, and L929 fibroblast cells but not in neoplastic cells such as L5178Y lymphoma cells, EL-4 lymphoma cells and 308 papilloma cells. 2. Heat shock protein (HSP) 25 and inducible HSP70 is responsible for the induction of adaptive response and radioresistance - cell cycle regulation, antiapoptotic molecule and PKC activation were involved. 3. Apoptosis was induced at most 5. hrs after irradiation in primary keratinocytes, in v-rasHa transformed keratinocytes, the maximum interval was 16 hrs, and in 308 papilloma cells, the maximum was 48 hrs. 4. PKC response by radiation is correlated with induction of apoptosis. 5. Rapid induction PKCdelta in primary keratinocytes and no response of PKC epsilon may involved in radiation induced apoptosis. 6. The rate of resorption was increased when radiation was given at 2.5 days after gestation. Early death including foetal death were highly expressed when radiation was given at 7.5 days after gestation. There are no difference in incidence of late death including embryonic death. 7. 2 Gy is the most effective dose in radiation induced teratogenesis in mouse model. 8. Growth retardation and small head was present when radiation was given at 5.5, 7.5, 11.5 and 15.5 days after gestation and small head showed high incidence at 11.5 days after gestation. 9. External malformation, internal malformation and skeletal malformation was induced when radiation was given at 7.5 days after gestation. 10. OGG1-mutated cells induced radiosensitive by G2/M cell cycle arrest. 11. Radiation induced G2/M phase cell cycle and correlated with radiosensitivity. 12. PKCalpha induced differentiation. 13. Radiation exposed cells showed carcinogenic effect. 14. Organ specific radiosensitivity was shown and protein expression was involved.

  19. Potential novel uses of thalidomide: focus on palliative care.

    Science.gov (United States)

    Peuckmann, V; Fisch, M; Bruera, E

    2000-08-01

    Thalidomide, after being banned from the market in the early 1960s because of the worldwide teratogenesis disaster, is currently being rediscovered because of its multiple therapeutic effects in various serious diseases and symptoms. Original studies examined the anxiolytic, mild hypnotic, anti-emetic and adjuvant analgesic properties of this drug. Subsequently, thalidomide was found to be highly effective in managing the cutaneous manifestations of leprosy (erythema nodosum leprosum) and even to be superior to aspirin (acetylsalicylic acid) in controlling leprosy-associated fever. Recent research shows promising results with thalidomide in patients with progressive bodyweight loss related to advanced cancer and HIV infection. Thalidomide therapy of diseases such as tuberculosis, sarcoidosis, aphthous ulcers in HIV syndrome and Behcet's disease, rheumatoid arthritis, multiple myeloma, graft-versus-host disease, pyoderma gangrenosum, inflammatory bowel disease, Sjögren's syndrome, lupus erythematosus and a variety of solid tumours is currently being explored. Furthermore, in preliminary studies, thalidomide has been found to be effective in several syndromes related to advanced cancer, such as the cancer cachexia syndrome, chronic nausea, insomnia, profuse sweating and pain. Whether thalidomide has a therapeutic effect on neoplastic fever has yet to be elucidated. These intriguing features make the use of the drug potentially attractive for palliative care. In addition, by a distinct mechanism of action compared with most other drugs, thalidomide offers the possibility of combined treatment with other agents with non-overlapping toxicities. The mechanism of action of thalidomide is probably based on the suppression of tumour necrosis factor-alpha and the modulation of interleukins. However, it is not possible to identify a single dominant mechanism, since the action of cytokines and the effect of thalidomide appear to be complex. This review article discusses the

  20. Tratamiento de las neoplasias hematológicas en el embarazo Treatment of hematologic neoplasms during pregnancy

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    Norma E Tartas

    2007-12-01

    Full Text Available La neoplasia hematológica más frecuente en la mujer gestante es el linfoma de Hodgkin. Con menor frecuencia se han comunicado leucemias agudas o linfomas no Hodgkin (LNH. En los últimos años se han introducido nuevos fármacos que han cambiado el pronóstico de neoplasias como la leucemia promielocítica aguda, los linfomas no Hodgkin y la leucemia mieloide crónica. Se presenta aquí información actualizada sobre drogas y tratamientos, desarrollo de nuevos fármacos, mecanismo de acción, aplicación clínica, experiencias y resultados del tratamiento, efectos secundarios y teratogénicos, a fin de orientar a hematólogos, oncólogos y pediatras. El equipo médico debe ofrecer el tratamiento más eficaz disponible para alcanzar la curación o remisión de la enfermedad, e informar acerca de sus posibles riesgos para la madre y el feto, así como los derivados por la demora de su aplicación.The most common hematological malignancy in pregnant patients is Hodgkin's lymphoma, but other diseases such as chronic and acute leukemia or non Hodgkin's lymphoma have also been reported. In the last decade, new drugs have changed the prognostic of acute promyelocytic leukemia, chronic myeloid leukemia and non Hodgkin's lymphoma. Herein we present updated information on drugs and treatments, new developments, mechanism of action, clinical application, experience on treatment outcomes, adverse effects and teratogenesis, with the objective of orienting hematologists, oncologists and pediatricians. The medical team should offer the most efficient treatment available in order to achieve cure or remission of the disease, and also inform on possible risks for the mother and the fetus, as well as those derived from the delay in treatment application.

  1. Effects of {sup 12}C{sup 6+} ion radiation and ferulic acid on the zebrafish (Danio rerio) embryonic oxidative stress response and gene expression

    Energy Technology Data Exchange (ETDEWEB)

    Si, Jing [Department of Heavy Ion Radiation Medicine, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000 (China); Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Lanzhou 730000 (China); Key Laboratory of Heavy Ion Radiation Medicine of Gansu Province, Lanzhou 730000 (China); Zhang, Hong, E-mail: zhangh@impcas.ac.cn [Department of Heavy Ion Radiation Medicine, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000 (China); Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Lanzhou 730000 (China); Key Laboratory of Heavy Ion Radiation Medicine of Gansu Province, Lanzhou 730000 (China); Wang, Zhenhua; Wu, Zhenhua [Department of Heavy Ion Radiation Medicine, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000 (China); Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Lanzhou 730000 (China); Key Laboratory of Heavy Ion Radiation Medicine of Gansu Province, Lanzhou 730000 (China); Lu, Jiang [Key Laboratory of Xinjiang Phytomedicine Resources, College of Pharmacy, Shihezi University, Shihezi 832002 (China); Di, Cuixia; Zhou, Xin [Department of Heavy Ion Radiation Medicine, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000 (China); Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Lanzhou 730000 (China); Key Laboratory of Heavy Ion Radiation Medicine of Gansu Province, Lanzhou 730000 (China); Wang, Xiaowei [Key Laboratory of Xinjiang Phytomedicine Resources, College of Pharmacy, Shihezi University, Shihezi 832002 (China)

    2013-05-15

    Highlights: • Carbon ion radiation increased the oxidative stress in zebrafish embryos. • Carbon ion radiation induced transcriptional level effects. • The transcriptional level displayed more sensitivity to low dose radiation than the antioxidant enzyme activities. • FA induced radioprotective effects by the inhibition of oxidative stress. - Abstract: The effects of carbon ion irradiation and ferulic acid (FA) on the induction of oxidative stress and alteration of gene expression were studied in zebrafish (Danio rerio) embryos. Zebrafish embryos at 8 hpf were divided into seven groups: the control group; the 1 Gy, 3 Gy and 7 Gy irradiation groups; and three FA-pre-treated irradiation groups. In the irradiated groups, a significant increase in the teratogenesis of the zebrafish embryos and oxidative stress was accompanied by increased malondialdehyde (MDA) content, decreased glutathione (GSH) content and alterations in antioxidant enzyme activities (such as catalase [CAT] and superoxide dismutase [SOD]). Moreover, the mRNA levels for Cu/Zn–sod, Mn–sod, cat and gpx, the genes encoding these antioxidant proteins, were altered significantly. However, the mRNA expression patterns were not in accordance with those of the antioxidant enzymes and were more sensitive under low-dose irradiation. In addition, we detected the mRNA expression of ucp-2 and bcl-2, which are located at the mitochondrial inner membrane and related to reactive oxidative species (ROS) production. In the irradiated groups, the mRNA level of ucp-2 was significantly increased, whereas the mRNA level of bcl-2 was significantly decreased. Supplementation with FA, an antioxidant, was better able to reduce the irradiation-induced oxidative damage marked by changes in mortality, morphology, antioxidant enzyme activities and the MDA and GSH content, as well as in the mRNA expression levels. Overall, this study provided helpful information about the transcriptional effects of irradiation to better

  2. Retinoic acid is a potential dorsalising signal in the late embryonic chick hindbrain

    Directory of Open Access Journals (Sweden)

    Maden Malcolm

    2007-12-01

    Full Text Available Abstract Background Human retinoic acid teratogenesis results in malformations of dorsally derived hindbrain structures such as the cerebellum, noradrenergic hindbrain neurons and the precerebellar system. These structures originate from the rhombic lip and adjacent dorsal precursor pools that border the fourth ventricle roofplate. While retinoic acid synthesis is known to occur in the meninges that blanket the hindbrain, the particular sensitivity of only dorsal structures to disruptions in retinoid signalling is puzzling. We therefore looked for evidence within the neural tube for more spatiotemporally specific signalling pathways using an in situ hybridisation screen of known retinoic acid pathway transcripts. Results We find that there are highly restricted domains of retinoic acid synthesis and breakdown within specific hindbrain nuclei as well as the ventricular layer and roofplate. Intriguingly, transcripts of cellular retinoic acid binding protein 1 are always found at the interface between dividing and post-mitotic cells. By contrast to earlier stages of development, domains of synthesis and breakdown in post-mitotic neurons are co-localised. At the rhombic lip, expression of the mRNA for retinoic acid synthesising and catabolising enzymes is spatially highly organised with respect to the Cath1-positive precursors of migratory precerebellar neurons. Conclusion The late developing hindbrain shows patterns of retinoic acid synthesis and use that are distinct from the well characterised phase of rostrocaudal patterning. Selected post-mitotic populations, such as the locus coeruleus, appear to both make and break down retinoic acid suggesting that a requirement for an autocrine, or at least a highly localised paracrine signalling network, might explain its acute sensitivity to retinoic acid disruption. At the rhombic lip, retinoic acid is likely to act as a dorsalising factor in parallel with other roofplate signalling pathways. While its

  3. Pregnancy prevention among women taking isotretinoin

    Science.gov (United States)

    Boucher, Nina; Beaulac-Baillargeon, Louise

    2006-01-01

    OBJECTIVE To assess whether prescribing physicians advised female patients taking isotretinoin according to pregnancy prevention recommendations, whether women understood those recommendations, and whether women complied with recommendations to prevent pregnancy. DESIGN Cross-sectional study designed to collect patients’ self-reported information. Women were interviewed by telephone with a standardized questionnaire. SETTING Quebec. PARTICIPANTS Participants were recruited through pharmacies, medical clinics, and newspapers in Quebec. All subjects (45 women 14 years and older) were treated with isotretinoin at the time of the interview or in the preceding 6 months. MAIN OUTCOME MEASURES Women’s self-report of their physician’s behaviour regarding prevention of pregnancy, women’s comprehension of the information, and their level of compliance with recommendations. RESULTS Prescribing physicians discussed the risks of teratogenesis with 93% of the women but gave written information to only 36% of them. Seventy-eight percent of the women admitted not using 2 contraceptive methods all the time during the treatment, and 3 women reported having had sexual intercourse without any contraception. Physicians prescribed a pregnancy test before treatment for 44% of the women. Only 18% of the women waited for their next menstrual period to begin isotretinoin treatment, and this advice was given by 20% of physicians. A statistically significant relationship between counseling and recommendations given by physicians and women’s use of double contraception was highlighted. CONCLUSION Female patients reported physicians did not always advise them according to recommendations concerning pregnancy prevention. Women understood the information received but did not fully comply. The extent of pregnancy prevention measures taken by physicians was linked to women’s compliance. Further study exploring underlying reasons for women’s noncompliance could provide information on

  4. The Mouse House: A brief history of the ORNL mouse-genetics program, 1947–2009

    Energy Technology Data Exchange (ETDEWEB)

    Russell, Liane B.

    2013-10-01

    The large mouse genetics program at the Oak Ridge National Lab is often re-membered chiefly for the germ-cell mutation-rate data it generated and their uses in estimating the risk of heritable radiation damage. In fact, it soon became a multi-faceted research effort that, over a period of almost 60 years, generated a wealth of information in the areas of mammalian mutagenesis, basic genetics (later enriched by molecular techniques), cytogenetics, reproductive biology, biochemistry of germ cells, and teratology. Research in the area of germ-cell mutagenesis explored the important physical and biological factors that affect the frequency and nature of induced mutations and made several unexpected discoveries, such as the major importance of the perigametic interval (the zygote stage) for the origin of spontaneous mutations and for the sensitivity to induced genetic change. Of practical value was the discovery that ethylnitrosourea was a supermutagen for point mutations, making high-efficiency mutagenesis in the mouse feasible worldwide. Teratogenesis findings resulted in recommendations still generally accepted in radiological practice. Studies supporting the mutagenesis research added whole bodies of information about mammalian germ-cell development and about molecular targets in germ cells. The early decision to not merely count but propagate genetic variants of all sorts made possible further discoveries, such as the Y-Chromosome s importance in mammalian sex determination and the identification of rare X-autosome translocations, which, in turn, led to the formulation of the single-active-X hypothesis and provided tools for studies of functional mosaicism for autosomal genes, male sterility, and chromosome-pairing mechanism. Extensive genetic and then molecular analyses of large numbers of induced specific-locus mutants resulted in fine-structure physical and correlated functional mapping of significant portions of the mouse genome and constituted a valuable

  5. ULTRASTRUCTURAL MODIFICATIONS INDUCED BY DIRECT ACTION OF CU2+ UPON EARLY CHICK EMBRYO

    Directory of Open Access Journals (Sweden)

    Delia Checiu

    2003-01-01

    experimental approach to a possible cellular and molecular mechanism of Cu2+ in teratogenesis. Also, by electron microscopically investigations we tried to show the target cellular organite for Cu2+

  6. [Secondary cystathioninuria due to vitamin B 6 deficiency in familial neuroblastoma].

    Science.gov (United States)

    Plöchl, E

    1976-01-01

    nonhereditary cases may be caused by vitamin-B6-deficiency. Since in this family the excretion of catecholamines was examined in a prior investigation a comparison of these two studies does not support the suggestion of a direct connection between the excretion of catecholamines and cystathioninuria, as it has been assumed to occur in sporadic neuroblastoma. The vitamin-B6-deficiency as seen in this family can also be considered in relation to tumor development. In the discussion about this possibility also the appearance of cystathioninuria in other tumors of early childhood is mentioned. Furthermore the relation of vitamin B6 to teratogenesis is commented on.

  7. Potentiation of the teratogenic effects induced by coadministration of retinoic acid or phytanic acid/phytol with synthetic retinoid receptor ligands.

    Science.gov (United States)

    Elmazar, M M A; Nau, H

    2004-11-01

    teratogenesis can be induced by coadministration of a natural RXR ligand (phytanic acid) with a synthetic RAR agonist (Am580). Thus, certain potentially useful therapeutic agents or nutritional factors such as phytanic acid should be tested for teratogenic risk by coadministration with other retinoid receptor agonists.

  8. The role of Nrf1 and Nrf2 in the regulation of glutathione and redox dynamics in the developing zebrafish embryo

    Directory of Open Access Journals (Sweden)

    Karilyn E. Sant

    2017-10-01

    Full Text Available Redox signaling is important for embryogenesis, guiding pathways that govern processes crucial for embryo patterning, including cell polarization, proliferation, and apoptosis. Exposure to pro-oxidants during this period can be deleterious, resulting in altered physiology, teratogenesis, later-life diseases, or lethality. We previously reported that the glutathione antioxidant defense system becomes increasingly robust, including a doubling of total glutathione and dynamic shifts in the glutathione redox potential at specific stages during embryonic development in the zebrafish, Danio rerio. However, the mechanisms underlying these changes are unclear, as is the effectiveness of the glutathione system in ameliorating oxidative insults to the embryo at different stages. Here, we examine how the glutathione system responds to the model pro-oxidants tert-butylhydroperoxide and tert-butylhydroquinone at different developmental stages, and the role of Nuclear factor erythroid 2-related factor (Nrf proteins in regulating developmental glutathione redox status. Embryos became increasingly sensitive to pro-oxidants after 72 h post-fertilization (hpf, after which the duration of the recovery period for the glutathione redox potential was increased. To determine whether the doubling of glutathione or the dynamic changes in glutathione redox potential are mediated by zebrafish paralogs of Nrf transcription factors, morpholino oligonucleotides were used to knock down translation of Nrf1 and Nrf2 (nrf1a, nrf1b, nrf2a, nrf2b. Knockdown of Nrf1a or Nrf1b perturbed glutathione redox state until 72 hpf. Knockdown of Nrf2 paralogs also perturbed glutathione redox state but did not significantly affect the response of glutathione to pro-oxidants. Nrf1b morphants had decreased gene expression of glutathione synthesis enzymes, while hsp70 increased in Nrf2b morphants. This work demonstrates that despite having a more robust glutathione system, embryos become more

  9. Gochnatia polymorpha ssp. floccosa: bioprospecting of an anti-inflammatory phytotherapy for use during pregnancy.

    Science.gov (United States)

    David, Natan de; Mauro, Mariana de Oliveira; Gonçalves, Caroline Amélia; Pesarini, João Renato; Strapasson, Regiane Lauriano Batista; Kassuya, Cândida Aparecida Leite; Stefanello, Maria Élida Alves; Cunha-Laura, Andréa Luiza; Monreal, Antônio Carlos Duenhas; Oliveira, Rodrigo Juliano

    2014-06-11

    Gochnatia polymorpha ssp. floccosa is used in folk medicine to treat inflammation and infections. Non-steroidal anti-inflammatory drugs (NSAIDs) are the most commonly consumed medications during pregnancy in women with inflammatory diseases. However, the relationship between the use of NSAIDs and the risk of miscarriage and birth defects and/or benefits is not fully understood. Thus, an investigation regarding the use of Gochnatia polymorpha during gestation is of relevance for developing safe anti-inflammatory drugs for use during pregnancy. The pregnant females were randomly divided into 5 groups. Control group received a hydroalcoholic solution (1.2%), via gavage, for at least 15 days prior to mating and throughout the gestational period. The pre-treatment group received Gochnatia polymorpha ethanol extract (GPEE), via gavage, at a dose of 100mg/kg body weight (b.w.) for at least 15 days prior to mating and up to the appearance of the vaginal plug. The organogenesis group received GPEE at a dose of 100mg/kg (b.w.), via gavage, on the 5-15th gestacional day. The pregnancy group received GPEE at a dose of 100mg/kg (b.w.), via gavage, throughout the gestational period (from the 1st to the 18th day of pregnancy). The pre+pregnancy group received GPEE at a dose of 100mg/kg (b.w.), via gavage, for at least 15 days prior to mating and throughout the entire gestational period. The clinical signals of maternal toxicity and teratogenesis were evaluated. Additional assays to evaluate chronic inflammation, antigenotoxicity and immunomodolatory activity were performed. The results indicated that GPEE does not interfere with reproductive performance or embryo-fetal development but does correlate with reduced weight and fetal length. The extract was not teratogenic or mutagenic or an immunomodulator. However, GPEE did exhibit effective anti-inflammatory activity. Based on this study, it can be inferred that GPEE is an important, safe anti-inflammatory agent for use during

  10. Gordon Research Conference on Genetic Toxicology

    Energy Technology Data Exchange (ETDEWEB)

    Project Director Penelope Jeggo

    2003-02-15

    Genetic toxicology represents a study of the genetic damage that a cell can incur, the agents that induce such damage, the damage response mechanisms available to cells and organisms, and the potential consequences of such damage. Genotoxic agents are abundant in the environment and are also induced endogenously. The consequences of such damage can include carcinogenesis and teratogenesis. An understanding of genetic toxicology is essential to carry out risk evaluations of the impact of genotoxic agents and to assess how individual genetic differences influence the response to genotoxic damage. In recent years, the importance of maintaining genomic stability has become increasingly recognized, in part by the realization that failure of the damage response mechanisms underlies many, if not all, cancer incidence. The importance of these mechanisms is also underscored by their remarkable conservation between species, allowing the study of simple organisms to provide significant input into our understanding of the underlying mechanisms. It has also become clear that the damage response mechanisms interface closely with other aspects of cellular metabolism including replication, transcription and cell cycle regulation. Moreover, defects in many of these mechanisms, as observed for example in ataxia telangiectasia patients, confer disorders with associated developmental abnormalities demonstrating their essential roles during growth and development. In short, while a decade ago, a study of the impact of DNA damage was seen as a compartmentalized area of cellular research, it is now appreciated to lie at the centre of an array of cellular responses of crucial importance to human health. Consequently, this has become a dynamic and rapidly advancing area of research. The Genetic Toxicology Gordon Research Conference is biannual with an evolving change in the emphasis of the meetings. From evaluating the nature of genotoxic chemicals, which lay at the centre of the early

  11. Alcohol-induced epigenetic alterations to developmentally crucial genes regulating neural stemness and differentiation.

    Science.gov (United States)

    Veazey, Kylee J; Carnahan, Mindy N; Muller, Daria; Miranda, Rajesh C; Golding, Michael C

    2013-07-01

    program. These observations indicate that alterations to chromatin structure may represent a crucial component of alcohol teratogenesis and progress toward a better understanding of the developmental origins of fetal alcohol spectrum disorders. Copyright © 2013 by the Research Society on Alcoholism.

  12. Selective Serotonin Reuptake Inhibitor (SSRI Antidepressants in Pregnancy and Congenital Anomalies: Analysis of Linked Databases in Wales, Norway and Funen, Denmark.

    Directory of Open Access Journals (Sweden)

    Sue Jordan

    dose-response relationship between severe CHD and SSRI dose (meta-regression OR 1.49, 1.12-1.97 was consistent with SSRI-exposure related risk. Analyses in Wales suggested no associations between anomalies and diagnosed depression.The additional absolute risk of teratogenesis associated with SSRIs, if causal, is small. However, the high prevalence of SSRI use augments its public health importance, justifying modifications to preconception care.

  13. DNA oxidation as a potential molecular mechanism mediating drug-induced birth defects: phenytoin and structurally related teratogens initiate the formation of 8-hydroxy-2'-deoxyguanosine in vitro and in vivo in murine maternal hepatic and embryonic tissues.

    Science.gov (United States)

    Liu, L; Wells, P G

    1995-11-01

    A considerable number of teratogens, including the anticonvulsant drug phenytoin and structurally related drugs and environmental chemicals, may be bioactivated by peroxidases, such as prostaglandin H synthase (PHS) and lipoxygenases (LPOs), to a reactive free radical intermediate that initiates birth defects. However, the molecular targets of the reactive free radical intermediates mediating chemical teratogenesis, and hence the fundamental determinants of susceptibility, are poorly understood. In these studies, a teratogenic dose of phenytoin (65 mg/kg), when injected into pregnant CD-1 mice during organogenesis on gestational day 12, initiated the oxidation of DNA in maternal hepatic and embryonic nuclei, forming 8-hydroxy-2'-deoxyguanosine. Significant maternal and embryonic DNA oxidation occurred at 6 and 3 h, respectively, suggesting relative embryonic deficiencies in free radical-related cytoprotective enzymes, although the rates appeared similar. Maximal DNA oxidation in both maternal and embryonic tissues occurred at 6 h, presumably reflecting the balance of DNA oxidation and repair, the latter of which appeared similar in both tissues. Inhibition of phenytoin-initiated embryonic DNA oxidation by the free radical spin trapping agent alpha-phenyl-N-t-butylnitrone (41.5 mg/kg), and by acetylsalicylic acid (10 mg/kg), an inhibitor of the cyclooxygenase component of PHS, was consistent with the previously reported reduction by these inhibitors of phenytoin-initiated murine birth defects. In vitro studies using a horseradish peroxidase (0.5 mg/ml)-H2O2 (5.45 micrograms/ml) bioactivating system for drug-initiated oxidation of 2'-deoxyguanosine (3.74 mM), indicated that the potency of xenobiotic-initiated formation of 8-hydroxy-2'-deoxyguanosine for the structurally related drugs and metabolites phenytoin, 5-(p-hydroxyphenyl)-5-phenylhydantoin, trimethadione, dimethadione, l-mephenytoin, l-nirvanol, d-nirvanol (80 microM each), or thalidomide (64 micro

  14. Phenytoin-initiated hydroxyl radical formation: characterization by enhanced salicylate hydroxylation.

    Science.gov (United States)

    Kim, P M; Wells, P G

    1996-01-01

    interfere. The substantial, dose-dependent initiation of 2,3-DHBA formation by phenytoin, and its inhibition by ASA, provide the first in vivo evidence that PHS-dependent .OH formation could contribute to the molecular mechanism of phenytoin teratogenesis.

  15. Effects of 17α-trenbolone and melengestrol acetate on Xenopus laevis growth, development, and survival.

    Science.gov (United States)

    Finch, Bryson E; Blackwell, Brett R; Faust, Derek R; Wooten, Kimberly J; Maul, Jonathan D; Cox, Stephen B; Smith, Philip N

    2013-02-01

    The synthetic growth-promoting hormones trenbolone and melengestrol acetate have been detected in the environment near beef cattle feedlots and are reportedly transported via wind-borne particulate matter. Therefore, movement of synthetic hormones from beef cattle feedlots to water bodies via particulate matter is possible. Our objective was to evaluate potential effects of 17α-trenbolone (17α-TB), melengestrol acetate (MGA), and combinations of both on growth, development, and survival of Xenopus laevis larvae. On post-hatch day 2 (stage 33/34), X. laevis larvae were exposed to three nominal concentrations of 17α-TB (10, 100, and 500 ng/L), MGA (1, 10, and 100 ng/L), a combination of both (1/10, 10/100, and 100/500 ng/L MGA/17α-TB), frog embryo teratogenesis assay-Xenopus medium, or a solvent control. Significant increases in all X. laevis growth metrics were observed among larvae in the 1 ng/L MGA + 10 ng/L 17α-TB and 10 ng/L MGA + 100 ng/L 17α-TB treatments. Stage of development was increased among larvae in the 1 ng/L MGA + 10 ng/L 17α-TB treatment group and significantly decreased among those in the 500 ng/L 17α-TB treatment. Total body mass and snout-vent length of X. laevis larvae were significantly reduced in the 100 ng/L MGA and 100 ng/L MGA + 500 ng/L 17α-TB treatment groups. Larvae exposed to 500 ng/L 17α-TB had decreased total body mass, snout-vent length, and total length. In general, growth measurements decreased with increasing concentration of MGA, 17α-TB, or a combination of both. Survival among all treatments was not significantly different from controls. Amphibians exposed to MGA and 17α-TB in the environment may experience alterations in growth and development.

  16. Neuroprotective peptides influence cytokine and chemokine alterations in a model of fetal alcohol syndrome.

    Science.gov (United States)

    Roberson, Robin; Kuddo, Thea; Benassou, Ines; Abebe, Daniel; Spong, Catherine Y

    2012-12-01

    Fetal alcohol syndrome (FAS) is associated with intellectual disability and neurodevelopmental abnormalities. Neuroprotective peptides NAPVSIPQ (NAP) and SALLRSIPA (SAL) can prevent some of the alcohol-induced teratogenesis including fetal death, growth abnormalities, and learning impairment in part by preventing alcohol-induced alterations in N-methyl-D-aspartate receptor gene expression in a mouse model for FAS. We evaluated a panel of cytokines and chemokines to determine whether NAP plus SAL work through a cytokine/chemokine-mediated pathway in preventing these alterations. Using a well-characterized FAS model, timed, pregnant C57BL6/J mice were treated on gestational day (E) 8 with alcohol (0.03 mL/g), placebo, or alcohol plus peptides. Embryos were evaluated at 2 time points: after 6 hours and 10 days later at E18. A panel of cytokines/chemokines was measured using a microsphere-based multiplex immunoassay (Luminex xMAP; Millipore, Billerica, MA). Statistical analysis included Kruskal-Wallis, with P Alcohol treatment resulted in detectable levels and significant increases in IL-6 (median, 15.7; range, 10.1-45.9 pg/mL) and KC (median, 45.9; range, 32.5-99.1 pg/mL). Embryos exposed to alcohol plus NAP plus SAL had undetectable IL-6 and KC (both P Alcohol exposure resulted in a significant increase of granulocyte colony-stimulating factor (G-CSF) (P alcohol-induced increase. IL-13 and IL-1β were decreased 6 hours after alcohol exposure, and exposure to alcohol plus NAP plus SAL did not completely ameliorate the decrease. At E18, 10 days after exposure, these alterations were no longer present. Several analytes (regulated upon activation, normal T cell expressed, and secreted, tumor necrosis factor-α, interferon-γ, and IL-4) were not detectable at either time point in any of the groups. Prenatal alcohol exposure acutely results in a significant elevation of IL-6, G-CSF and the KC, which are known to affect N-methyl-D-aspartate receptors. NAP plus SAL treatment

  17. Nickel affects gill and muscle development in oriental fire-bellied toad (Bombina orientalis) embryos

    Energy Technology Data Exchange (ETDEWEB)

    Park, Chan Jin; Song, Sang Ha; Kim, Dae Han; Gye, Myung Chan, E-mail: mcgye@hanyang.ac.kr

    2017-01-15

    Highlights: • Nickel inhibited the development of external gill in B. orientalis embryos. • The 168 h LC{sub 50} and EC{sub 50} values of nickel were 33.8 and 5.4 μM, respectively, in embryos. • Nickel induced abnormal tail development of embryos. • NF stage 26–31 was the most sensitive window for embryos to nickel exposure. • Nickel affected the calcium-dependent myogenic gene expression in embryos. - Abstract: The developmental toxicity of nickel was examined in the embryos of Bombina orientalis, a common amphibian in Korea. Based on a standard frog embryo teratogenesis assay, the LC{sub 50} and EC{sub 50} for malformation of nickel after 168 h of treatment were 33.8 μM and 5.4 μM, respectively. At a lethal concentration (100 μM), nickel treatment decreased the space between gill filaments and caused epithelial swelling and abnormal fusion of gill filaments. These findings suggest that nickel affects the functional development of gills, leading to embryonic death. At sublethal concentrations (1–10 μM), nickel produced multiple embryonic abnormalities, including bent tail and tail dysplasia. At 10 μM, nickel significantly decreased tail length and tail muscle fiber density in tadpoles, indicating inhibition of myogenic differentiation. Before hatching, the pre-muscular response to muscular response stages (stages 26–31) were the most sensitive period to nickel with respect to tail muscle development. During these stages, MyoD mRNA was upregulated, whereas myogenic regulatory factor 4 mRNA was downregulated by 0.1 μM nickel. Calcium-dependent kinase activities in muscular response stage embryos were significantly decreased by nickel, whereas these activities were restored by exogenous calcium. In tadpoles, 10 μM nickel significantly decreased the expression of the myosin heavy chain and the 12/101 muscle marker protein in the tail. Expression was restored by exogenous calcium. Our results indicate that nickel affects muscle development by

  18. A glyphosate micro-emulsion formulation displays teratogenicity in Xenopus laevis.

    Science.gov (United States)

    Bonfanti, Patrizia; Saibene, M; Bacchetta, R; Mantecca, P; Colombo, A

    2018-02-01

    Glyphosate is the active ingredient in broad-spectrum herbicide formulations used in agriculture, domestic area and aquatic weed control worldwide. Its market is growing steadily concurrently with the cultivation of glyphosate-tolerant transgenic crops and emergence of weeds less sensitive to glyphosate. Ephemeral and lentic waters near to agricultural lands, representing favorite habitats for amphibian reproduction and early life-stage development, may thus be contaminated by glyphosate based herbicides (GBHs) residues. Previous studies on larval anuran species highlighted increased mortality and growth effects after exposure to different GBHs in comparison to glyphosate itself, mainly because of the surfactants such as polyethoxylated tallow amine present in the formulations. Nevertheless, these conclusions are not completely fulfilled when the early development, characterized by primary organogenesis events, is considered. In this study, we compare the embryotoxicity of Roundup ® Power 2.0, a new GBH formulation currently authorized in Italy, with that of technical grade glyphosate using the Frog Embryo Teratogenesis Assay-Xenopus (FETAX). Our results evidenced that glyphosate was not embryolethal and only at the highest concentration (50 mg a.e./L) caused edemas. Conversely, Roundup ® Power 2.0 exhibited a 96 h LC50 of 24.78 mg a.e./L and a 96 h EC50 of 7.8 mg a.e./L. A Teratogenic Index of 3.4 was derived, pointing out the high teratogenic potential of the Roundup ® Power 2.0. Specific concentration-dependent abnormal phenotypes, such as craniofacial alterations, microphthalmia, narrow eyes and forebrain regionalization defects were evidenced by gross malformation screening and histopathological analysis. These phenotypes are coherent with those evidenced in Xenopus laevis embryos injected with glyphosate, allowing us to hypothesize that the teratogenicity observed for Roundup ® Power 2.0 may be related to the improved efficacy in delivering

  19. [Novel potential uses of thalidomide in the management of pain? A review of the literature].

    Science.gov (United States)

    Peuckmann, V; Strumpf, M; Zenz, M; Bruera, E

    2003-06-01

    Thalidomide was introduced as a sedative and antiemetic agent to the European market in the late 1950s. However, it soon became clear that a hitherto unheard-of incidence of severe birth defects was due to the maternal use of thalidomide and the drug was withdrawn from the market. Despite its teratogenesis, thalidomide is currently being rediscovered because of its known spectrum of anticachectic, antiemetic, mildly hypnotic, anxiolytic, anti-inflammatory, antiangiogenic, and analgesic properties. The mechanism of action of thalidomide is probably based on its immunomodulatory effect, namely the suppression of production of tumor necrosis factor alpha and the modulation of interleukins. A striking but not well-known finding is the effectiveness of thalidomide as an analgesic or analgesic adjuvant. During the early era of thalidomide use, the drug was shown to enhance the analgesic efficacy of a combined treatment with acetylsalicylic acid, phenacetin, and caffeine (APC) by testing "normal volunteers, using electrical stimulation of teeth." The combination of thalidomide and APC was superior to other combinations (APC alone, APC and codeine) with respect to both the total analgesic effect and the duration of this analgesic effect. In 1965 thalidomide was found to be effective in treating the painful subcutaneous manifestations of the leprosy-associated erythema nodosum leprosum, a condition for which it eventually was approved by the United States Food and Drug Administration in 1998. In an animal model of neuropathic pain (chronic constriction injury), thalidomide was shown to reduce both mechanical allodynia and thermal hyperalgesia. Recent studies documented the analgesic efficacy of thalidomide in treating painful mucocutaneous aphthous ulcers associated with HIV syndrome and Behcet's disease.However, to date there are no recent clinical trials that are specifically designed to explore the analgesic potential of thalidomide. In view of the current basic research

  20. Consumo de cafeína e prematuridade Caffeine intake and prematurity

    Directory of Open Access Journals (Sweden)

    Rita Adriana Gomes de Souza

    2005-10-01

    Full Text Available A cafeína (1, 3, 7-trimetilxantina é uma metilxantina que facilmente atravessa a barreira placentária, com quantidades substanciais passando para o líquido amniótico, sangue do cordão umbilical, plasma e urina dos neonatos. As maiores fontes de cafeína são café, chá, chocolate e refrigerantes do tipo cola. Além disso, cerca de mil drogas prescritas e 2 mil drogas não prescritas contêm cafeína, e 25 dessas drogas podem ser usadas na gravidez. Embora estudos em animais indiquem que a cafeína leve à diminuição no crescimento intrauterino fetal, redução do peso ao nascer, reabsorção fetal e teratogênese, nos estudos epidemiológicos os achados são, ainda, inconclusivos. Pelo fato de os alimentos com cafeína serem amplamente consumidos na gravidez, é importante avaliar se o uso dessa substância está associado com a redução da idade gestacional. Este artigo examina o conhecimento atual do consumo de cafeína durante a gravidez, abordando os estudos epidemiológicos sobre a associação entre consumo de cafeína e prematuridade, as fontes de cafeína e seu consumo na gravidez, a bioquímica, a fisiopatologia e a plausibilidade biológica da associação e as principais limitações dos estudos sobre cafeína e prematuridade.Caffeine (1, 3, 7-trimethylxanthine is a methylxanthine that easily crosses the placental barrier, substantial amounts passing into the amniotic fluid, umbilical cord blood, and the plasma and urine of the neonates. The main sources of caffeine are coffee, tea, chocolate and cola soft drinks. Moreover, about 1000 prescribed drugs and 2000 non-prescribed drugs contain caffeine, and 25 of these drugs can be used during pregnancy. Although animal studies indicate that caffeine leads to a decrease in fetal intrauterine growth, low birth weight, fetal re-absorption and teratogenesis, these findings are still inconclusive in the epidemiological studies. Since foods containing caffeine are widely consumed

  1. Relevancia de la farmacovigilancia hospitalaria en la práctica médica actual Importance of pharmacovigilance in current medical practice

    Directory of Open Access Journals (Sweden)

    Marcelo L. Ponte

    2013-02-01

    in a tertiary care hospital in Buenos Aires City. The hospital phamacovigilance database for the period June 2008- February 2012, was analyzed. The Naranjo score was applied to assess drug causality. We consider serious an ADRs when it potentially compromised life, induced hospitalization or prolonged it, caused discapacity, teratogenesis or death. In this period, a total of 2420 ADRs were detected: 469 (19.38%; CI 95%: 17.80 - 20.95 were serious, mainly because they induced hospitalization (n = 287. There were 14 ADRs-related deaths. Cardiovascular and neuropsychiatric drugs, antibiotics and corticoids were those most frequently related to toxicity. Endocrine-metabolic disorders, hepatotoxicity, nephrotoxicity and pharmacodermy were the most frequently involved. Among the ADR most frequently associated to hospitalization were Immunosuppressant-associated severe infections and upper gastrointestinal bleeding related to oral anticoagulants and non steroids anti-inflammatory drugs. The ADRs incidence in hospitalized patients and ADRs related hospital admissions were considered relatively high. Drugs involved were similar to those reported in the international bibliography except for the higher incidence of immunosuppressants related admissions here observed.

  2. ¿Por qué se está usando otra vez la talidomida? Why is thalidomide back?

    Directory of Open Access Journals (Sweden)

    Emilio Sanín Pérez

    2004-02-01

    óxica ni en la Enfermedad crónica injerto contra huésped. Background: in 1998 the FDA approved the restricted commercialization of Thalidomide for the treatment of Erithema Nodosum Leprosum. Brazil and Mexico have also regulated its use. Because of the current use of this teratogenic drug in rheumatological, dermatological, infectious and neoplasic diseases, it is necessary to instruct General Practitioners and specialists on its most relevant topics, active principle, benefic and deleterious effects. We carried out a revision by reading and analyzing controlled clinical trials, randomized or not, case series and reviews about thalidomide and its potential uses, that appeared in Medline from January 1993 to December 2003, to draw indications and contraindications in light of the evidence found in them. Results: forty six randomized controlled studies were found and 22 (with at least 50 patients described were reviewed (complete articles and/or including design and end points measured – expressed abstracts, plus 10 reviews and 22 cases series. The analysis allowed us to inform potential or restricted and not indicated uses of thalidomide in humans, its pharmacokynetic principles which explain its benefic and deleterious effects, and recommendations to prevent teratogenesis. Conclusion: thalidomide is available, with restrictions, for the treatment of Erithema Nodosum Leprosum (first line and Multiple Myeloma (refractory to multiple chemotherapy. It appears to have beneficial effects in many other serious conditions refractory to first line treatments: AIDS, esophagus and prostate cancer and some severe dermatosis, rheumatological or not.

  3. Impacto do uso do telefone celular na saúde de crianças e adolescentes Impact of mobile phone use on the health of children and adolescents

    Directory of Open Access Journals (Sweden)

    Aracy Pereira S Balbani

    2011-09-01

    pre and post-natal exposure to those fields, and the impact of mobile phones use on the central nervous system and behavior in children. DATA SOURCE: Articles written in English published from 2004 to 2009 and indexed on PubMed under the keywords: "children", "mobile phones", and "microwaves". DATA SYNTHESIS: Mobile phones emit radiofrequency in the microwave range, with possible thermal (tissue heating or non-thermal (oxidative stress and chromatin conformation alteration biological effects. Experimental research suggests that the dissipation of radiofrequency energy in tissues might be higher in children than in adults. Pre-natal exposure of rats to radiofrequency in non-thermal levels has not resulted in teratogenesis, mutagenesis, increased blood-brain barrier permeability or heat shock protein expression in the brain. There is no conclusive evidence of harmful effects of mobile phone radiation on cognitive function in children. Making voice calls or sending text messages at night increases the likelihood of day-time somnolence in adolescents. Children who use mobile phones may present memory impairment and impulsive behavior. CONCLUSIONS: There is no compelling evidence that pre- or post-natal exposure to mobile phone radiation, within the safety limits for human beings, causes damage to the central nervous system development. Nevertheless, cultural patterns related to mobile phones possession and use influence the behavior of children and adolescents and may trigger sleep disorders.

  4. Genotoxic and reprotoxic effects of tritium and external gamma irradiation on aquatic animals.

    Science.gov (United States)

    Adam-Guillermin, Christelle; Pereira, Sandrine; Della-Vedova, Claire; Hinton, Tom; Garnier-Laplace, Jacqueline

    2012-01-01

    Aquatic ecosystems are chronically exposed to natural radioactivity or to artificial radionuclides released by human activities (e.g., nuclear medicine and biology,nuclear industry, military applications). Should the nuclear industry expand in the future, radioactive environmental releases, under normal operating conditions or accidental ones, are expected to increase, which raises public concerns about possible consequences on the environment and human health. Radionuclide exposures may drive macromolecule alterations, and among macromolecules DNA is the major target for ionizing radiations. DNA damage, if not correctly repaired, may induce mutations, teratogenesis, and reproductive effects. As such, damage at the molecular level may have consequences at the population level. In this review, we present an overview of the literature dealing with the effects of radionuclides on DNA, development, and reproduction of aquatic organisms. The review focuses on the main radionuclides that are released by nuclear power plants under normal operating conditions, γ emitters and tritium. Additionally, we fitted nonlinear curves to the dose-response data provided in the reviewed publications and manuscripts, and thus obtained endpoints commonly associated with ecotoxicological studies, such as the EDR(10). These were then used as a common metric for comparing the values and data published in the literature.The effects of tritium on aquatic organisms were reviewed for dose rates that ranged from 29 nGy/day to 29 Gy/day. Although beta emission from tritium decay presents a rather special risk of damage to DNA, genotoxicity-induced by tritium has been scarcely studied. Most of the effects studied have related to reproduction and development. Species sensitivity and the form of tritium present are important factors that drive the ecotoxicity of tritium. We have concluded from this review that invertebrates are more sensitive to the effects of tritium than are vertebrates

  5. O tempo e a anestesia obstétrica: da cosmologia caótica à cronobiologia El tiempo y la anestesia obstétrica: de la cosmología caótica a la cronobiología Time and obstetric anesthesia: from chaotic cosmology to chronobiology

    Directory of Open Access Journals (Sweden)

    Nilton Bezerra do Vale

    2009-10-01

    /light; birth/death; etc., along with environmental conditions (synchronizers, influence labor physiology because of the presence of endogenous clocks (oscillators that interact with social diuturnal clues. In this review, the most important cyclic anesthetic-obstetric parameters in parturient care are listed. CONTENTS: Chronobiological analysis of the main events in the obstetric pathophysiology of Mulier sapiens: I Embryogenesis - risk of teratogenesis; II From prematurity to post-didacticism: from eutocic labor to cervical cerclage; III Night and labor: higher incidence of nocturnal labor (physiological facilitation and daylight cesarean section (choice of the obstetrician; IV The moon and labor - non-conclusive results; V The night shift in obstetric anesthesia: riskier professional contingency; VI Phases of cesarean section: removal of the fetus: UD stage (uterotomy - delivery as brief as possible; effective correction of hypotension and valorize pre-anesthetic fasting; VII circadian variation of dystocia: pain; uterine contraction; blood loss; hypertension (HTN; risk of allergy and asthma. In the nocturnal phase, the intensity of contraction and risk of hemorrhage, allergy, and asthma are greater. On the other hand, HTN in eclampsia does not show circadian variation; VIII Obstetric chronopharmacology: local anesthetics, analgesics, hypnotics, general anesthetics, and neuromuscular blockers. Chronoenergy explains the matinal peak of opioid analgesia, vespertine of local anesthetic, and nocturnal of inhalational anesthetics. CONCLUSIONS: The chronobiological approach of labor anesthesia emphasizes the obstetric importance of circadian rhythmicity in labor humanization and safety.