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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
11

Efeitos da restrição alimentar materna sobre a prole de ratas Wistar. Avaliações teratogênicas clássicas e de imunoteratologia / Effects of maternal feed restriction in Wistar rats offspring: Evaluations by classical and immunoteratology protocols

Vânius Vinícius Dipe 11 August 2009 (has links)
A Organização Mundial da Saúde revela que mais de 20 milhões de crianças nascem com baixo peso ao nascimento em todo o mundo, sendo a má nutrição o principal fator desencadeante. Estudos realizados nas duas últimas décadas mostram que o status nutricional materno pode ser crítico no desenvolvimento de teratogenicidade; porém não há trabalhos que comprovem a associação entre restrição alimentar materna e a ocorrência de malformações. No entanto, o conceito de teratogênese não se restringe apenas às malformações estruturais logo após o nascimento, também são consideradas alterações funcionais, como aquelas comportamentais ou no sistema imune, entre outras, que podem se manifestar somente na maturação pós-natal. Assim, o presente trabalho visou verificar os efeitos da restrição alimentar materna durante a gestação, avaliando-a por meio tanto do protocolo clássico de teratogenicidade, como através de protocolos de imunoteratologia, analisando-se neste caso, as possíveis alterações no sistema imune da prole após o desmame e também na idade adulta. Foram empregadas ratas Wistar prenhes, divididas em cinco grupos iguais, um controle (CO) no qual os animais receberam ração ad libitum, e nos demais grupos, as fêmeas foram submetidas à restrição alimentar, do 6º ao 17º dia de gestação, diminuindo-se em 15 (E15), 40 (E40), 55 (E55) e 70% (E70) da quantidade de ração consumida pelos animais do grupo CO. Por meio do protocolo clássico de teratogenicidade, verificaram-se as possíveis alterações ósseas e viscerais sobre a prole. Empregou-se ainda o protocolo de imunoteratologia, no qual foram realizados testes nas proles tanto ao desmame como na idade adulta, e aferiu-se os seguintes parâmetros: hemograma, peso relativo do timo e do baço, celularidade do baço e da medula óssea; a imunidade inata: atividade de macrófagos peritoneais por meio da fagocitose, produção de peróxido de hidrogênio e óxido nítrico; a imunidade humoral: produção de anticorpos pelo ensaio do plaque forming cell e a titulação de anticorpos anti-eritrócitos de carneiro; e a imunidade celular: avaliação da hipersensibilidade tardia. Em relação às avaliações teratogênicas clássicas, estas mostraram haver, naqueles filhotes provenientes das ratas submetidas às restrições alimentares (E40, E55 e E70), diminuição no peso ao nascimento, aumento da proporção de fetos mortos até uma hora após o nascimento e aumento do número de fetos com ureter sinuoso; no entanto, não foi constatada a ocorrência de malformações graves, que pudessem colocar em risco a vida do concepto. Já as avaliações pós-natais revelaram diminuição no ganho de peso, do nascimento até a idade adulta, das proles provenientes das ratas do grupo E70. Em relação às alterações imunoteratogênicas, houve aumento no peso relativo do timo e da resposta imune celular nas proles destas mães submetidas à maior restrição alimentar, quando estes animais foram avaliados aos 21 dias de idade. Quando realizou-se este estudo nas proles com 70 dias (idade adulta), os filhotes provenientes de mães das diferentes restrições alimentares apresentaram aumento da resposta imune humoral; além disto aqueles filhotes de mães E70, mostraram aumento da resposta imune celular. Os dados apresentados na presente pesquisa permitem sugerir que a restrição alimentar em ratas Wistar durante a organogênese fetal, embora não promova malformações estruturais, produz prole de menor peso ao nascimento e é capaz de gerar alterações significantes no sistema imune dos filhotes. / The World Health Organization has reported that more than 20 million children worldwide are born with low birth weight, with malnutrition the main triggering factor. Studies in the past two decades have shown that maternal nutritional status may be critical in the development of teratogenicity, but there are no studies that directly relate maternal feed restriction and malformation. However, teratogenecity is not restricted only to structural abnormalities at birth, but may also include functional changes, such as behavioral or immune system alterations, among others, which may manifest themselves only in the postnatal period of maturation. Thus, this work aimed to assess the effects of maternal food restriction in pregnant rats using classical and immunoteratogenic protocols to evaluate the offspring. Thus, possible immune system changes were evaluated in the offspring after weaning and after maturation. Pregnant females were divided into five groups, a control group (CO) in which the animals received feed ad libitum, and four other groups, in which females were fed a restricted amount based on the total ingested by controls: 15% (E15), 40% (E40), 55% (E55) and 70% (E70) during days 6 to 17 of gestation. Rats were humanely euthanized and teratogenicity was evaluated using skeletal and visceral measurements. Immunoteratogenic effects were determined in weaned and mature offspring (10 weeks) using blood, thymus and spleen relative weights and spleen and bone marrow cellularity. In addition, innate immunity was determined using activity of peritoneal macrophages through phagocytosis, and production of hydrogen peroxide and nitric oxide. Humoral immunity was determined using production of antibodies by the plaque-forming cell assay and titers of anti-sheep red blood cells. Cellular immunity was determined by evaluating delayed type hypersensitivity. Traditional teratogenic indices showed that pups from females subjected to feed restriction (E40, E55 and E70) had a decrease in birth weight, an increased proportion of dead fetuses up to one hour after birth, and an increase in the number of fetuses with kinked ureter. No major malformations serious enough to threaten the life of the conceptus were observed. There was a postnatal decrease in weight gain in offspring from mothers of group E70 from birth to adulthood. There was also immune system changes, with an increase in the thymus relative weight (E40, E55, E70) and cellular immune response in offspring (21 days of age). When offspring were evaluated after maturation, those pups from mothers with feed restriction had increased humoral immune responses; in addition offspring from the E70 group showed an increase in cellular immune response. The data presented in this study suggest that feed restriction in Wistar rats during organogenesis does not promote structural malformations, but instead results in offspring with lower birth weights, and also promoted significant changes in the immune system of rat pups.
12

Teratogenicity as a consequence of drug-induced embryonic cardiac arrhythmia : Common mechanism for almokalant, sotalol, cisapride, and phenytoin via inhibition of IKr

Sköld, Anna-Carin January 2000 (has links)
<p>During the last years, drugs that prolong the repolarisation phase of the myocardial action potential, due to inhibition of the rapid component of the delayed-rectifying potassium channel (I<sub>Kr</sub>) have been in focus. In addition to arrhythmogenic potential, selective Ikr-blockers have also been shown to be embryotoxic and teratogenic in animal studies. The aim of this thesis was to investigate a theory that these developmental toxic results from pharmacologically induced episodes of embryonic cardiac arrhythmias leading to hypoxia related damage in the embryo. Almokalant (ALM) was used as a model compound for selective Ikr-blockers. ALM induced embryonic cardiac arrhythmia, and in similarity with results obtained by maternal hypoxia, ALM induced embryonic death and growth retardation in both rats, and mice. </p><p>The theory of a hypoxia-related mechanism was strengthened by the results that ALM induce phase specific external and visceral defects (e.g. cleft lip/palate, distal digital, cardiovascular, and urogenital defects), and that the skeletal defects (not shown before) showed a clear trend; the later the treatment the more caudal was the site of the defect, which is in accordance with results from maternal hypoxia induced by e.g. lowering of the O<sub>2</sub> content in the air. The spin trapping agent PBN decreased almokalant induced malformations, suggesting that the defects mainly are caused by reoxygenation damage after episodes of severe embryonic dysrhythmia, rather than "pure hypoxia".</p><p>Sotalol was tested in a third species, the rabbit who expresses functional I<sub>Kr</sub> channels both in the embryo and in the adult, where it induced developmental toxicity, and indicating that the embryo is more sensitive than the adult towards arrhythmia caused by I<sub>Kr</sub>-blockers. </p>
13

Teratogenicity as a consequence of drug-induced embryonic cardiac arrhythmia : Common mechanism for almokalant, sotalol, cisapride, and phenytoin via inhibition of IKr

Sköld, Anna-Carin January 2000 (has links)
During the last years, drugs that prolong the repolarisation phase of the myocardial action potential, due to inhibition of the rapid component of the delayed-rectifying potassium channel (IKr) have been in focus. In addition to arrhythmogenic potential, selective Ikr-blockers have also been shown to be embryotoxic and teratogenic in animal studies. The aim of this thesis was to investigate a theory that these developmental toxic results from pharmacologically induced episodes of embryonic cardiac arrhythmias leading to hypoxia related damage in the embryo. Almokalant (ALM) was used as a model compound for selective Ikr-blockers. ALM induced embryonic cardiac arrhythmia, and in similarity with results obtained by maternal hypoxia, ALM induced embryonic death and growth retardation in both rats, and mice. The theory of a hypoxia-related mechanism was strengthened by the results that ALM induce phase specific external and visceral defects (e.g. cleft lip/palate, distal digital, cardiovascular, and urogenital defects), and that the skeletal defects (not shown before) showed a clear trend; the later the treatment the more caudal was the site of the defect, which is in accordance with results from maternal hypoxia induced by e.g. lowering of the O2 content in the air. The spin trapping agent PBN decreased almokalant induced malformations, suggesting that the defects mainly are caused by reoxygenation damage after episodes of severe embryonic dysrhythmia, rather than "pure hypoxia". Sotalol was tested in a third species, the rabbit who expresses functional IKr channels both in the embryo and in the adult, where it induced developmental toxicity, and indicating that the embryo is more sensitive than the adult towards arrhythmia caused by IKr-blockers.
14

Untersuchungen zur Embryotoxizität von Ozon nach einer in ovo-Begasung beim Huhn

Thiele, Margrit 21 November 2011 (has links) (PDF)
Die derzeit angewendete Formalinbegasung von Bruteiern zur Keimreduktion stellt ein wichtiges Mittel zum Schutz des Verbrauchers vor dem Eintrag der Salmonellose aus der Geflügelindustrie in die Lebensmittelkette dar. Jedoch verlangt sein kanzerogenes Potenzial die Suche nach einer ebenso effektiven und einfach zu praktizierenden, aber weniger gesundheitlich bedenklichen alternativen Methode. In dieser Arbeit wurde die Eignung einer in ovo-Ozonbegasung zur Bruteidesinfektion hinsichtlich ihrer Auswirkung auf die Embryonalentwicklung untersucht. Dafür wurden befruchtete Eier vor ihrem Einsatz in den Brüter mit unterschiedlichen Ozonkonzentrationen zwischen 0,5% bis >5,0% (wt/ wt O3 in O2) bei einer relativen Luftfeuchte von 70% in einer Laborkammer begast. Die verwendeten Ozonkonzentrationen wurden dabei in drei Konzentrationsgruppen eingeteilt: hoch (2,8% bis 5,0%), mittel (1,1% bis 2,5%) und niedrig (0,5% bis 1,0%). Nach Erreichen der Zielkonzentration blieben die Eier für eine definierte Einwirkzeit (EWZ) zwischen 0 bis 24 h in der Kammer. Am Bruttag (BT) 18, 19 oder 20 wurden die Überlebensrate (ÜLR), Gewicht und Länge erhoben sowie histologische Untersuchungen der Organe Herz, Leber, Milz und Niere vorgenommen. Bei vier Versuchen erfolgte zusätzlich die Untersuchung am BT 6 und BT 12. Insgesamt wurden 13 Versuchsreihen mit Begasungen in der Laborkammer in den drei genannten Konzentrationsgruppen durchgeführt. Des Weiteren sollte die Übertragbarkeit der ermittelten Ergebnisse auf eine großtechnische Lösung, durch die Anwendung in einer projektintern entwickelten Prototyp-Kammer überprüft werden. Die Konzipierung dieses Prototyps folgte den technischen Gegebenheiten unter Einbeziehung der ermittelten Ergebnisse zur Embryotoxizität, zur Effektivität der Keimreduktion sowie der Veränderung der Eiinhaltsstoffe. Im Prototyp wurde daher die Begasungskonzentration von 0,7% Ozon bei einer EWZ von 2 h angewendet und in 2 Versuchsreihen hinsichtlich ihrer Auswirkungen auf die Lebensfähigkeit und die morphologische Entwicklung getestet. Um zusätzlich eine Aussage treffen zu können, welche Wirkung eine hohe Ozonkonzentration bei der Applikation während der Bebrütung zur Folge hat, wurde in zwei weiteren Versuchsreihen jeweils am BT 3, 4 und 5 eine Ozondosis von 5,0% in Kombination mit 1 h EWZ appliziert. Nach der Entnahme der Embryonen am BT 6 bzw. BT 8 erfolgte die morphologische Untersuchung. Aus der vorliegenden Arbeit wird zusammenfassend geschlussfolgert:  Ozon besitzt einen dosisabhängigen Effekt auf die ÜLR: je höher die Dosis, desto geringer die Überlebensrate. Bei niedrigen Ozonkonzentrationen zwischen 0,5% und 1,0% kommt es zu ÜLR von 90% und 100%.  Die Einwirkzeit stellt einen wichtigen Einflussfaktor auf die Überlebensrate dar. Eine Kombination einer hohen Ozondosis mit langer EWZ hat eine höhere Embryomortalität zur Folge, als eine hohe Ozondosis ohne EWZ. Eine erhöhte Mortalitätsrate zeigt sich auch bei der Kombination einer mittleren Ozondosis mit einer langen EWZ. Keinen Einfluss zeigt sie bei der Kombination mit einer niedrigen Ozonkonzentration.  Ozonierte Embryonen zeigen dosisabhängig eine geringere Längen- oder Gewichtsentwicklung im Vergleich zur Kontrollgruppe. Signifikante Gewichts- und Längenunterschiede lagen nur vereinzelt bei der Begasung mit hoher Ozonkonzentration vor.  Pathohistologische Befunde an Organen, die mit einer Ozonbegasung in Zusammenhang gebracht werden können, konnten nicht erhoben werden.  Die Versuche zur Begasung während der Organogenese wiesen nicht auf ein teratogenes Potenzial von Ozon hin. Korrespondierend mit den Ergebnissen der Begasung am BT 0 zeigte sich ebenfalls eine deutliche Embryotoxizität.  Die Wirkung von Ozon folgt einem Alles-oder-Nichts-Prinzip: entweder die Schädigung ist so stark, dass es zu keiner Entwicklung mehr kommt, oder aber der überlebende Embryo bzw. Fetus zeigt ein phänotypisch normales Aussehen.  Mit den vorgestellten Untersuchungen konnte bewiesen werden, dass bei einer in ovo-Begasung von befruchteten Hühnereiern am Bruttag 0 mit einer niedrigen Ozonkonzentration von 0,5% bis 1,0% in Kombination mit einer mittleren und geringen EWZ keine teratogenen oder embryotoxischen Veränderungen zu erwarten sind.  Aus diesen Befunden ergibt sich ein unbedenklicher Einsatze von Ozon als alternative Methode zur Bruteidesinfektion. Die Voraussetzung dafür ist, dass die großtechnische Lösung die Anwendung von 1,0% Ozonkonzentration in Kombination mit 2 h EWZ ermöglicht, um eine sehr gute ÜLR, Entwicklung und eine 100%ige Inaktivierung des in Legehennenbeständen vorherrschenden Serovars Salmonella Enteritidis zu gewährleisten.
15

Feed comparison for dietary standardization of the sea urchin Lytechinus variegatus and assessment of parental dietary copper toxicity by fertilization and embryological tests

Garris, Heath W. January 2008 (has links) (PDF)
Thesis (M.S.)--University of Alabama at Birmingham, 2008. / Additional advisors: Marion Nipper, Robert A. Angus, Addison L. Lawrence. Description based on contents viewed May 30, 2008; title from title screen. Includes bibliographical references.
16

Efeito do extrato  de Mikania glomerata Sprengel (guaco) sobre a implantação e o desenvolvimento embrinário e placentário em camundongos. / Effect of Mikania glomerata Sprengel (guaco) extract on implantation and placental and embryonic development in mice.

Camila Figueira Mendes 19 March 2012 (has links)
Nos dias atuais, a utilização de fitoterápicos tem crescido acentuadamente. No Brasil, um país cuja flora nativa é riquíssima, tem-se investido substancialmente em pesquisas nesta área. Isto se deve, em parte, à necessidade de novos medicamentos, ao interesse na comercialização destes produtos, ao interesse na preservação da cultura popular e da reserva da flora nacional. Paralelamente a este cenário, está a crença de que medicamentos fitoterápicos são inofensivos em circunstâncias especiais tais como: gravidez, hipertensão, diabetes, etc. É como se os fitoterápicos atuassem especificamente sobre uma determinada patologia não sobre o metabolismo como um todo. A Mikania glomerata Sprengel, conhecida popularmente como guaco e originária da América do Sul, é uma planta subarbustiva, que nasce nas matas e cerrados e, que se adapta muito bem ao cultivo doméstico. Ela é vastamente utilizada pela população no tratamento de doenças como a asma, bronquite, e reumatismo, além de possuir efeito antifúngico, antimicrobiano, antialérgico, antiinflamatório e antiofídico, na grande maioria das vezes administrada sem supervisão de profissionais da área da saúde. Neste estudo, nosso objetivo é estudar a possível ação do extrato vegetal de Mikania glomerata Sprengel (guaco) no perfil reprodutivo e gestacional de camundongos (Mus musculus domesticus) e determinar se a administração desta droga pode comprometer o embrião/feto e placenta durante a prenhez. Este estudo mostrou que a utilização do extrato de Mikania glomerata em doses supra-terapêuticas pode atuar sobre processos morfofuncionais orgânicos, interferindo no crescimento placentário e fetal e podendo levar ao insucesso gestacional e ao aparecimento de defeitos congênitos. Além disto, a diminuição do crescimento fetal observado nas doses consideradas terapêuticas também é um alerta para o uso inadvertido do extrato de guaco sem acompanhamento médico devido, em qualquer período gestacional. / Nowadays, the use of medicinal plants has grown dramatically. In Brazil, a country whose native flora is rich, has invested substantially in research in this area. This is due in part to the need for new drugs, the interest in marketing these products, the interest in the preservation of popular culture and the reserve of national flora. In parallel with this scenario is the belief that phitotherapeutics are harmless in special circumstances such as pregnancy, hypertension, diabetes, etc. It is as if the herbal acted specifically in a determinate disease not on the metabolism as a whole. The Mikania glomerata Sprengel, popularly known as guaco and originating from South America, is a plant undergrowth, which rises in the forests and savannahs, and that lends itself very well to domestic cultivation. It is widely used by local people in the treatment of diseases such as asthma, bronchitis, and rheumatism, as well as having antifungal effect, antimicrobial, antiallergic, anti-inflammatory and anti-snakebite, in most cases administered without the supervision of health professionals. In this study, our goal is to study the possible action of plant extract of Mikania glomerata Sprengel (guaco) in pregnancy and reproductive profile of mice (Mus musculus domesticus) and determine whether the administration of this drug may affect the embryo / fetus and placenta during pregnancy . This study showed that the use of extract of Mikania glomerata at supratherapeutic doses can act on morphofunctional organic processes, interfering with fetal and placental growth and could lead to pregnancy failure as well as contribute to the appearance of birth defects. Furthermore, the decrease in fetal growth observed in therapeutic doses is also considered a warning to the inadvertent use of the extract guaco without medical supervision because, at any gestational period.
17

Mouse Limb Bud Development in Submerged Culture: Quantitative Assessment of the Effects of in Vivo Exposure to Retinoic Acid

Kwasigroch, Thomas E., Skalko, R. G., Church, J. K. 01 January 1984 (has links)
Retinoic acid, suspended in cottonseed oil, was administered via gavage to pregnant mice (ICR strain) on day 11 (E 11) of gestation at doses of either 20, 40, or 80 mg/kg. Fetuses were examined for external malformations on day 17 (E 17). Retinoic acid treatment induced micromelia (with the elimination of several long bones at higher doses) and digital defects (ectrodactyly and syndactyly) in a dose‐dependent manner in fetuses examined on day 17. Hindlimbs were affected more than forelimbs. In another group of experiments, limbs exposed to retinoic acid treatment in utero on E 11 were cultured on E 12 and maintained for 3 days in submerged culture. Cultured limbs were examined qualitatively for digital and long bone defects, and image analysis of the area and form of bone anlagen of cultured limbs was used to quantitatively evaluate the teratogenic potential of retinoic acid. The qualitative evaluation indicated that the retinoic acid‐induced effects obtained in vivo and with pretreated, cultured limbs were essentially the same, except that the severity of regional effects changed as a result of culture. The incidence of ectrodactyly was higher with cultured limbs than with E 17 fetal limbs, but fewer cultured limbs were missing long bones. These results suggest that culturing limbs, after they have been pretreated in utero, modifies their response to a teratogen and demonstrates that the paw skeleton is extremely sensitive to teratogen treatment under these experimental conditions. Therefore, care must be exercised when attempting to compare in vivo and in vitro teratogenic data. This study also clearly demonstrates the power and usefulness of image analysis for quantitative evaluation of both the area and form of a cultured specimen such as the developing limb bud. Quantitative, image analysis of cultured limbs showed a dose‐dependent decrease in area of both fore‐ and hindlimbs. The effect was most severe in hindlimbs. In the forelimb, the paw was affected more than the long bones; as the dose increased, this disparity of effect also increased. With the hindlimb, a greater effect on the paw occurred only at 80 mg/kg. Computing the soft tissue/bone ratio illustrated that retinoic acid had a greater effect on chondrogenic tissue than on soft tissue.
18

Entwicklung und Erprobung eines Teratogenitäts-Screening Testes mit Embryonen des Zebrabärblings Danio rerio

Bachmann, Jean 14 September 2002 (has links) (PDF)
Obwohl fetale Mißbildungen seit langem bekannt sind, wird eine intensive Prüfung von Arzneimitteln und anderen Substanzen erst seit den 1960er Jahren durchgeführt. Dem Tierschutzbericht von 2001 ist zu entnehmen, daß im Jahr 1999 insgesamt etwa 1,6 Millionen Wirbeltiere zu Versuchszwecken benötigt wurden. Als mögliche Alternative zu Untersuchungen mit Säugetieren wurde ein Testmodell mit Embryonen des Zebrabärblings (D. rerio) entwickelt. Ziel der vorliegenden Arbeit ist es zu klären, ob sich mit den Embryonen von Danio rerio ein teratogenes Potential von Substanzen erkennen und quantifizieren läßt. Dazu wurde DarT (?Danio rerio Teratogenicity Assay?) als Teratogenitäts-Screening Test entwickelt. Es können anhand von toxikologischen Endpunkten sowohl die letalen als auch die subletalen Wirkungen von Substanzen bestimmt werden. Darüber hinaus werden anhand von teratogenen Endpunkten speziell Malformationen erfaßt. Der Vergleich der beobachteten Effekte und der daraus berechneten Wirkkonzentrationen gestattet eine Einschätzung des teratogenen Potentials von Substanzen. Die im DarT erzielten Ergebnisse werden mit der bekannten Zuordnungen des ?säugerteratogenen? Potentials verglichen. Für 88 % der getesteten Substanzen gibt DarT die aus säugertoxikologischen Untersuchungen bekannten Einordnungen hinsichtlich des teratogenen Potentials wieder. Für 10 % der Testsubstanzen wurde das teratogene Potential zu hoch, für 2 % zu niedrig eingeschätzt. Mit dem Testsystem ?Danio rerio Teratogenicity Assay ? DarT? ist ein Vergleich von Substanzen hinsichtlich ihres teratogenen und allgemein toxischen Potentials möglich. In einem Modell können Wirkkonzentrationen und Konzentrations-Wirkungs-Beziehung ermittelt und direkt verglichen werden. Mit DarT kann eine große Anzahl von Substanzen zeit- und kostengünstig untersucht werden. Die aus Untersuchungen mit Säugetieren bekannten Zuordnungen der teratogenen Potentiale von Substanzen wird gut wiedergegeben.
19

Pluripotent Stem Cells of Embryonic Origin : Applications in Developmental Toxicology

Jergil, Måns January 2009 (has links)
General toxicity evaluation and risk assessment for human exposure is essential when developing new pharmaceuticals and chemicals. Developmental toxicology is an important part of this risk assessment which consumes large resources and many laboratory animals. The prediction of developmental toxicity could potentially be assessed in vitro using embryo-derived pluripotent stem cells for lead characterization and optimization. This thesis explored the potential of short-time assays with pluripotent stem cells of embryonic origin using toxicogenomics. Three established pluripotent stem cell lines; P19 mouse embryonal carcinoma (EC) cells, R1 mouse embryonic stem (mES) cells, and SA002 human embryonic stem (hES) cells were used in the studies. Valproic acid (VPA), an antiepileptic drug which can cause the neural tube defects spina bifida in human and exencephaly in mouse, was used together with microarrays to investigate the global transcriptional response in pluripotent stem cells using short-time exposures (1.5 - 24 h). In addition to VPA, three closely related VPA analogs were tested, one of which was not teratogenic in mice. These analogs also differed in their ability to inhibit histone deacetylase (HDAC) allowing this potential mechanism of VPA teratogenicity to be investigated. The results in EC cells indicated a large number of genes to be putative VPA targets, many of which are known to be involved in neural tube morphogenesis. When compared with data generated in mouse embryos, a number of genes emerged as candidate in vitro markers of VPA-induced teratogenicity. VPA and its teratogenic HDAC inhibiting analog induced major and often overlapping deregulation of genes in mES cells and hES cells. On the other hand, the two non-HDAC inhibiting analogs (one teratogenic and one not) had only minor effects on gene expression. This indicated that HDAC inhibition is likely to be the major mechanism of gene deregulation induced by VPA. In addition, a comparison between human and mouse ES cells revealed an overlap of deregulated genes as well as species specific deregulated genes.
20

Efeitos tóxicos da \"Ipomoea carnea\" em caprinos. II - estudos de teratogenicidade / Toxic effects of the Ipomoea carnea in goats. 11- studies of teratogenicity

Henrique, Breno Schumaher 01 July 2005 (has links)
A Ipomoea carnea, pertencente à família das Convolvulaceae, é uma planta tóxica que tem ampla distribuição pelo país, tendo como principal princípio ativo a suainsonina. É uma das poucas plantas que se conserva verde durante a seca, podendo servir como fonte de matéria verde para bovinos, ovinos e caprinos, é nesse período, quando normalmente ocorrem os casos de intoxicação, sendo a espécie caprina a mais susceptível. Até o momento, não há relatos sobre efeitos tóxicos desta planta em conseqüência da possível passagem transplacentária da suainsonina. Assim, o objetivo do presente estudo foi avaliar os possíveis efeitos teratogênicos da I. carnea, em caprinos. Foram usados 20 cabras, divididas em 4 grupos iguais: 3 experimentais e 1 controle. As cabras dos grupos experimentais receberam a partir do 27° dia de prenhez até o final da gestação 1,0; 5,0 e 7,5 glkg/dia de I. carnea. Nas fêmeas gestantes foi feito o exame clínico periódico, colheita de sangue para avaliação do hemograma e bioquímica sanguínea, exames fetais ultra-sonográficos (US) e acompanhamento do parto. Ao nascimento, todos os filhotes foram avaliados para identificação de malformações, alguns foram submetidos à eutanásia, para a realização do estudo anatomopatológico e nos demais avaliou-se o ganho de peso, hemograma e bioquímica sanguínea. Os resultados obtidos mostraram que apenas as fêmeas que receberam 7,5g/kg de I.carnea apresentaram sintomatologia nervosa. No estudo US feito na 5°, 7° e 9° semana, observou-se redução significante dos movimentos fetais, de todos os animais experimentais. Alterações hematolágicas e na bioquímica sérica (como o aumento dos níveis sérico de glicose, aspartato amino transferase, uréia, fosfatase alcalina, albumina e diminuição dos níveis sé ricos de gama-glutamil transferase e colesterol) foram observadas em cabras dos grupos experimentais. No estudo histopatológico foram observadas vacuolizacões em diversos tecidos (fígado, rim e no sistema nervoso central). Na 10° semana de gestação uma cabra, tratada com a maior dose, abortou espontaneamente um feto, o qual apresentou artrogripose e ausência do fechamento da cavidade abdominal. Ao nascimento, verificou-se a ocorrência de mal formações fetais em filhotes caracterizada por retroagnatia, contratura congênita múltipla dos membros e artrogripose. Estes achados permitem concluir, que a ingestão da I. carnea durante a gestação de cabras, além de causar toxicidade materna, pode causar efeitos teratogênicos e que o US pode ser útil para acompanhar a ocorrência de efeitos nocivos desencadeados pela planta, durante a vida intra-uterina. / Ipomoea carnea (Convolvulaceae) is a toxic plant largely distributed throughout Brazil. The alkaloid swainsonine is the major active compound present in the plant. I. Carnea is resistent to drought, serving during this adverse climatic condition as a food source for cattle, sheeps and goats. It is well known that the ingestion of the plant promotes toxic effects to the animais, in particular to goats, the most susceptible specie. There are no reports about toxic effects of the plant to fetuses as a consequence of a possible placental transportation of the compound swainsonine. The objective of the present study was to evaluate the possible teratogenic effects of I. Carnea in goats. In the study 20 female goats were employed, divided into 4 groups: 3 experimental and 1 control. The experimental goats received from gestation day (GD) 27 to parturition day 1.0, 5.0 or 7.5 g/Kglday of I.carnea fresh leaves. Duringpregnancy the females were periodically accompanied by hematologic studies as hemograms and serum biochemical assays, ultrasonographic (US) fetuses assays and were accompanied during parturition. At post-natal day (PND) 01 ali the pups were evaluated for identificationof physical anormalities. Some were euthanized for histopathologic studies and the others had weight gain, hemograms and biochemical blood tests recorded during development. The obtained data showed that only the 7.5 g/Kg/day treated dams presented neurologic effects. The US study realized at the 5th,6thand th weeks of gestation, showed that ali the experimental groups presented significant reduction of the fetal intrauterine moviments. Hematologic and serum blood biochemical alterations (Iike increased levels of glucose, aspartate-amine transferase, urea, alkaline phosphatase, albumine and reduced levels of gamma-glutamyl transferase and cholesterol) were observed in goats of the experimental groups. The histopathologic study showed vacuolization in several tissues (liver,kidneys and brain). At the 10thweek of gestation one goat, treated with the increased dose, aborted a fetus. This fetus presented arthrogriposis and no closure of the abdominal cavity.At parturition(PND01) fetal malformationswere observed and characterized as retrognatia, multiple congenit contracture of the members and arthrogriposis. The present data showed that I. Carnea ingestion by pregnant goats promoted maternal toxicityand fetal teratogenic effects. In addition, the US showed to be an important tool to monitorize the toxic effects promoted by the plant ingestion during intrauterine life.

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