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Peter G Wells - One of the best experts on this subject based on the ideXlab platform.
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Embryopathic effects of thalidomide and its hydrolysis products in rabbit Embryo Culture evidence for a prostaglandin h synthase phs dependent reactive oxygen species ros mediated mechanism
The FASEB Journal, 2011Co-Authors: Luísa L. Gonçalves, Peter G WellsAbstract:Thalidomide (TD) causes birth defects in humans and rabbits via several potential mecha- nisms, including bioactivation by Embryonic prostaglan- din H synthase (PHS) enzymes to a reactive intermedi- ate that enhances reactive oxygen species (ROS) formation. We show herein that TD in rabbit Embryo Culture produces relevant Embryopathies, including decreases in head/brain development by 28% and limb bud growth by 71% (P<0.05). Two TD hydrolysis products, 2-phthalimidoglutaramic acid (PGMA) and 2-phthalimidoglutaric acid (PGA), were similarly em- bryopathic, attenuating otic vesicle (ear) and limb bud formation by up to 36 and 77%, respectively (P<0.05). TD, PGMA, and PGA all increased Embryonic DNA oxidation measured as 8-oxoguanine (8-oxoG) by up to 2-fold (P<0.05). Co- or pretreatment with the PHS inhibitors eicosatetraynoic acid (ETYA) or acetylsali- cylic acid (ASA), or the free-radical spin trap phenyl- butylnitrone (PBN), completely blocked Embryonic 8-oxoG formation and/or Embryopathies initiated by TD, PGMA, and PGA. This is the first demonstration of limb bud Embryopathies initiated by TD, as well as its hydrolysis products, in a mammalian Embryo Culture model of a species susceptible to TD in vivo, indicating that all likely contribute to TD teratogenicity in vivo ,i n part through PHS-dependent, ROS-mediated mecha- nisms.—Lee, C. J. J., Goncalves, L. L., Wells, P. G. Embryopathic effects of thalidomide and its hydrolysis products in rabbit Embryo Culture: evidence for a prostaglandin H synthase (PHS)-dependent, reactive oxygen species (ROS)-mediated mechanism. FASEB J. 25, 000 - 000 (2011). www.fasebj.org
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Embryopathic effects of thalidomide and its hydrolysis products in rabbit Embryo Culture evidence for a prostaglandin h synthase phs dependent reactive oxygen species ros mediated mechanism
The FASEB Journal, 2011Co-Authors: Luísa L. Gonçalves, Peter G WellsAbstract:Thalidomide (TD) causes birth defects in humans and rabbits via several potential mecha- nisms, including bioactivation by Embryonic prostaglan- din H synthase (PHS) enzymes to a reactive intermedi- ate that enhances reactive oxygen species (ROS) formation. We show herein that TD in rabbit Embryo Culture produces relevant Embryopathies, including decreases in head/brain development by 28% and limb bud growth by 71% (P<0.05). Two TD hydrolysis products, 2-phthalimidoglutaramic acid (PGMA) and 2-phthalimidoglutaric acid (PGA), were similarly em- bryopathic, attenuating otic vesicle (ear) and limb bud formation by up to 36 and 77%, respectively (P<0.05). TD, PGMA, and PGA all increased Embryonic DNA oxidation measured as 8-oxoguanine (8-oxoG) by up to 2-fold (P<0.05). Co- or pretreatment with the PHS inhibitors eicosatetraynoic acid (ETYA) or acetylsali- cylic acid (ASA), or the free-radical spin trap phenyl- butylnitrone (PBN), completely blocked Embryonic 8-oxoG formation and/or Embryopathies initiated by TD, PGMA, and PGA. This is the first demonstration of limb bud Embryopathies initiated by TD, as well as its hydrolysis products, in a mammalian Embryo Culture model of a species susceptible to TD in vivo, indicating that all likely contribute to TD teratogenicity in vivo ,i n part through PHS-dependent, ROS-mediated mecha- nisms.—Lee, C. J. J., Goncalves, L. L., Wells, P. G. Embryopathic effects of thalidomide and its hydrolysis products in rabbit Embryo Culture: evidence for a prostaglandin H synthase (PHS)-dependent, reactive oxygen species (ROS)-mediated mechanism. FASEB J. 25, 000 - 000 (2011). www.fasebj.org
Luísa L. Gonçalves - One of the best experts on this subject based on the ideXlab platform.
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Embryopathic effects of thalidomide and its hydrolysis products in rabbit Embryo Culture evidence for a prostaglandin h synthase phs dependent reactive oxygen species ros mediated mechanism
The FASEB Journal, 2011Co-Authors: Luísa L. Gonçalves, Peter G WellsAbstract:Thalidomide (TD) causes birth defects in humans and rabbits via several potential mecha- nisms, including bioactivation by Embryonic prostaglan- din H synthase (PHS) enzymes to a reactive intermedi- ate that enhances reactive oxygen species (ROS) formation. We show herein that TD in rabbit Embryo Culture produces relevant Embryopathies, including decreases in head/brain development by 28% and limb bud growth by 71% (P<0.05). Two TD hydrolysis products, 2-phthalimidoglutaramic acid (PGMA) and 2-phthalimidoglutaric acid (PGA), were similarly em- bryopathic, attenuating otic vesicle (ear) and limb bud formation by up to 36 and 77%, respectively (P<0.05). TD, PGMA, and PGA all increased Embryonic DNA oxidation measured as 8-oxoguanine (8-oxoG) by up to 2-fold (P<0.05). Co- or pretreatment with the PHS inhibitors eicosatetraynoic acid (ETYA) or acetylsali- cylic acid (ASA), or the free-radical spin trap phenyl- butylnitrone (PBN), completely blocked Embryonic 8-oxoG formation and/or Embryopathies initiated by TD, PGMA, and PGA. This is the first demonstration of limb bud Embryopathies initiated by TD, as well as its hydrolysis products, in a mammalian Embryo Culture model of a species susceptible to TD in vivo, indicating that all likely contribute to TD teratogenicity in vivo ,i n part through PHS-dependent, ROS-mediated mecha- nisms.—Lee, C. J. J., Goncalves, L. L., Wells, P. G. Embryopathic effects of thalidomide and its hydrolysis products in rabbit Embryo Culture: evidence for a prostaglandin H synthase (PHS)-dependent, reactive oxygen species (ROS)-mediated mechanism. FASEB J. 25, 000 - 000 (2011). www.fasebj.org
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Embryopathic effects of thalidomide and its hydrolysis products in rabbit Embryo Culture evidence for a prostaglandin h synthase phs dependent reactive oxygen species ros mediated mechanism
The FASEB Journal, 2011Co-Authors: Luísa L. Gonçalves, Peter G WellsAbstract:Thalidomide (TD) causes birth defects in humans and rabbits via several potential mecha- nisms, including bioactivation by Embryonic prostaglan- din H synthase (PHS) enzymes to a reactive intermedi- ate that enhances reactive oxygen species (ROS) formation. We show herein that TD in rabbit Embryo Culture produces relevant Embryopathies, including decreases in head/brain development by 28% and limb bud growth by 71% (P<0.05). Two TD hydrolysis products, 2-phthalimidoglutaramic acid (PGMA) and 2-phthalimidoglutaric acid (PGA), were similarly em- bryopathic, attenuating otic vesicle (ear) and limb bud formation by up to 36 and 77%, respectively (P<0.05). TD, PGMA, and PGA all increased Embryonic DNA oxidation measured as 8-oxoguanine (8-oxoG) by up to 2-fold (P<0.05). Co- or pretreatment with the PHS inhibitors eicosatetraynoic acid (ETYA) or acetylsali- cylic acid (ASA), or the free-radical spin trap phenyl- butylnitrone (PBN), completely blocked Embryonic 8-oxoG formation and/or Embryopathies initiated by TD, PGMA, and PGA. This is the first demonstration of limb bud Embryopathies initiated by TD, as well as its hydrolysis products, in a mammalian Embryo Culture model of a species susceptible to TD in vivo, indicating that all likely contribute to TD teratogenicity in vivo ,i n part through PHS-dependent, ROS-mediated mecha- nisms.—Lee, C. J. J., Goncalves, L. L., Wells, P. G. Embryopathic effects of thalidomide and its hydrolysis products in rabbit Embryo Culture: evidence for a prostaglandin H synthase (PHS)-dependent, reactive oxygen species (ROS)-mediated mechanism. FASEB J. 25, 000 - 000 (2011). www.fasebj.org
Aldert H Piersma - One of the best experts on this subject based on the ideXlab platform.
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valproic acid induced gene expression responses in rat whole Embryo Culture and comparison across in vitro developmental and non developmental models
Reproductive Toxicology, 2013Co-Authors: Jeroen L A Pennings, Joshua F Robinson, Aart Verhoef, Aldert H Piersma, Elisa C M Tonk, Peter T TheunissenAbstract:Transcriptomic evaluations may improve toxicity prediction of in vitro-based developmental models. In this study, transcriptomics was used to identify VPA-induced gene expression changes in rat whole Embryo Culture (WEC). Furthermore, VPA-induced responses were compared across in vitro-based developmental models, such as the cardiac and neural Embryonic stem cells (ESTc and ESTn, respectively) and the zebrafish Embryotoxicity model. VPA-induced gene regulation in WEC corresponded with observed morphological effects and previously suggested mechanisms of toxicity. Gene Ontology term-directed analysis showed conservation of VPA-induced gene expression changes across in vitro-based developmental models, with ESTc and ESTn exhibiting complementary responses. Furthermore, comparison of in vitro-based developmental and non-developmental models revealed that more generalized VPA-induced effects can be detected using non-developmental models whereas developmental models provide added value when assessing developmental-specific effects. These analyses can be used to optimize test batteries for the detection of developmental toxicants in vitro.
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dose response analysis of phthalate effects on gene expression in rat whole Embryo Culture
Toxicology and Applied Pharmacology, 2012Co-Authors: Joshua F Robinson, Jeroen L A Pennings, Vincent A Van Beelen, Aart Verhoef, Aldert H PiersmaAbstract:The rat postimplantation whole Embryo Culture (WEC) model serves as a potential screening tool for developmental toxicity. In this model, Cultured rat Embryos are exposed during early Embryogenesis and evaluated for morphological effects. The integration of molecular-based markers may lead to improved objectivity, sensitivity and predictability of WEC in assessing developmental toxic properties of compounds. In this study, we investigated the concentration-dependent effects of two phthalates differing in potency, mono(2-ethylhexyl) phthalate (MEHP) and monomethyl phthalate (MMP, less toxic), on the transcriptome in WEC to examine gene expression in relation with dysmorphogenesis. MEHP was more potent than MMP in inducing gene expression changes as well as changes on morphology. MEHP induced significant enrichment of cholesterol/lipid/steroid (CLS) metabolism and apoptosis pathways which was associated with developmental toxicity. Regulation of genes within CLS metabolism pathways represented the most sensitive markers of MEHP exposure, more sensitive than classical morphological endpoints. As shown in direct comparisons with toxicogenomic in vivo studies, alterations in the regulation of CLS metabolism pathways has been previously identified to be associated with developmental toxicity due to phthalate exposure in utero. Our results support the application of WEC as a model to examine relative phthalate potency through gene expression and morphological responses. Additionally, our results further define the applicability domain of the WEC model for developmental toxicological investigations.
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Embryotoxicant specific transcriptomic responses in rat postimplantation whole Embryo Culture
Toxicological Sciences, 2010Co-Authors: Mirjam Luijten, Jeroen L A Pennings, Joshua F Robinson, Vincent A Van Beelen, Aart Verhoef, Marc F J Renkens, Marcel H M Van Herwijnen, Anja Westerman, Aldert H PiersmaAbstract:Rat postimplantation whole-Embryo Culture (WEC) is a promising alternative test for the assessment of developmental toxicity. Toxicogenomic-based approaches may improve the predictive ability of the WEC model by providing a means to identify compound-specific mechanistic responses associated with Embryotoxicity in vivo. Furthermore, alterations in gene expression may serve as a sensitive, objective, and robust marker, which precedes the observation of classical developmental toxicity endpoints in time. In this study, in combination with morphological developmental assessments, we studied transcriptomic responses associated with four distinct teratogens (caffeine [CAF], methylmercury [MM], monobutyl phthalate, and methoxyacetic acid) after 4 h of exposure, well before apparent Embryotoxicity in WEC. We evaluated gene expression changes associated with similar levels of induced morphological Embryotoxicity for each teratogen (as determined by total morphological score), evaluating for functional enrichment and quantitative changes in response. Concentrations selected for each of the four teratogens used induced a number of common effects on Embryonic development (neural tube closure and optic/otic system). Despite inducing common morphological effects, our analysis suggests limited overlap in terms of toxicogenomic response at the gene expression level and at the level of biological processes across all four test chemicals. Many unique responses associated with each chemical correlated with previously hypothesized modes of developmental toxicity. For example, alterations in developmental signaling and cholesterol metabolism were observed with MM and CAF, respectively. This initial study suggests that distinct chemically induced toxicogenomic responses precede morphological effects in WEC and that these responses are relevant with mechanisms of toxicity previously observed in vivo.
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transcriptomics analysis of retinoic acid Embryotoxicity in rat postimplantation whole Embryo Culture
Reproductive Toxicology, 2010Co-Authors: Mirjam Luijten, Jeroen L A Pennings, Vincent A Van Beelen, Aart Verhoef, Marc F J Renkens, Marcel H M Van Herwijnen, Anja Westerman, Frederikj Van Schooten, Aldert H PiersmaAbstract:Abstract Rodent postimplantation whole Embryo Culture (WEC) is a classical alternative test to study developmental toxicants. Here, we have successfully applied transcriptomics to monitor early responses in WEC after exposure to the Embryotoxicant retinoic acid (RA). We demonstrated that RA exposures ranging from 2 to 24 h affect RA-responsive genes in individual Embryos. Furthermore, 2, 3 or 4 somite Embryos gave similar responses, allowing combining Embryos of these Embryonic stages within the same analysis. Microarray analysis of Embryonic gene expression after RA exposure revealed the regulation of many genes known to be RA responsive. Finally, use of a Culture medium based on bovine serum instead of rat serum yielded similar gene expression responses after RA exposure. These findings support the robustness of the identified gene expression patterns and show the feasibility of detecting early gene expression changes in WEC after Embryotoxic exposures. This approach may result in a more sensitive readout for detecting Embryotoxicity in WEC.
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state of the art in developmental toxicity screening methods and a way forward a meeting report addressing Embryonic stem cells whole Embryo Culture and zebrafish
Birth Defects Research Part B-developmental and Reproductive Toxicology, 2008Co-Authors: Robert E Chapin, Thomas J. Flynn, Karen Augustinerauch, Bruce K Beyer, George P Daston, Richard H Finnell, Sidney Hunter, Phillip Mirkes, Sue K Oshea, Aldert H PiersmaAbstract:A meeting was convened so that users of three models for in vitro developmental toxicity (Embryonic stem cells, whole Embryo Culture, and zebrafish) could share their experiences with each model, and explore the areas for improvement. We present a summary of this meeting and the recommendations of the group.
Pui Yu Chiu - One of the best experts on this subject based on the ideXlab platform.
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an in vitro study of ginsenoside rb1 induced teratogenicity using a whole rat Embryo Culture model
Human Reproduction, 2003Co-Authors: Louis Yiksi Chan, Pui Yu Chiu, Tze-kin LauAbstract:BACKGROUND Ginseng is a commonly used herbal medicine worldwide. However, there is limited information regarding its effects on the developing Embryo. METHODS The effect of ginsenoside on the developing Embryo during the critical period of organogenesis was investigated using a whole rat Embryo Culture model. Embryos were exposed to various concentrations of ginsenoside Rb(1) and scored for growth and differentiation at the end of the Culture period. RESULTS Median total morphological scores in Embryos exposed to 30 micro g/ml of ginsenoside Rb(1) was significantly lower (P < 0.05) than that in control Embryos (35 versus 45). Morphological scores for flexion, forelimb and hindlimb were also significantly reduced. The median total morphological scores further decreased to 28 when the concentration of ginsenoside Rb(1) was increased to 50 micro g/ml. At this concentration, the Embryonic crown-rump length and somite number were also significantly reduced compared with control Embryos (2.8 versus 3.0 mm and 16.0 versus 21.0, respectively). CONCLUSIONS Our study has demonstrated that ginsenoside exerts direct teratogenic effects on rat Embryos. Until more is known about the effects of ginsenoside in women of reproductive age, we suggest its use should be treated with caution.
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an in vitro study of ginsenoside rb1 induced teratogenicity using a whole rat Embryo Culture model
Human Reproduction, 2003Co-Authors: Louis Yiksi Chan, Pui Yu ChiuAbstract:BACKGROUND: Ginseng is a commonly used herbal medicine worldwide. However, there is limited information regarding its effects on the developing Embryo. METHODS: The effect of ginsenoside on the developing Embryo during the critical period of organogenesis was investigated using a whole rat Embryo Culture model. Embryos were exposed to various concentrations of ginsenoside Rb(1) and scored for growth and differentiation at the end of the Culture period. RESULTS: Median total morphological scores in Embryos exposed to 30 micro g/ml of ginsenoside Rb(1) was significantly lower (P < 0.05) than that in control Embryos (35 versus 45). Morphological scores for flexion, forelimb and hindlimb were also significantly reduced. The median total morphological scores further decreased to 28 when the concentration of ginsenoside Rb(1) was increased to 50 micro g/ml. At this concentration, the Embryonic crown-rump length and somite number were also significantly reduced compared with control Embryos (2.8 versus 3.0 mm and 16.0 versus 21.0, respectively). CONCLUSIONS: Our study has demonstrated that ginsenoside exerts direct teratogenic effects on rat Embryos. Until more is known about the effects of ginsenoside in women of reproductive age, we suggest its use should be treated with caution.
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a study of diclofenac induced teratogenicity during organogenesis using a whole rat Embryo Culture model
Human Reproduction, 2001Co-Authors: Louis Yiksi Chan, Pui Yu ChiuAbstract:BACKGROUND: Diclofenac is a non-steroidal anti-inflammatory drug, commonly used by reproductive age women for the treatment of a variety of conditions. However, there is limited information regarding the teratogenic effects of this drug. METHODS: The effect of diclofenac on the developing Embryo during the critical period of organogenesis was investigated by using a whole rat Embryo Culture model. Embryos were exposed to various concentrations of diclofenac and scored for growth and differentiation at the end of the Culture period. RESULTS: Total developmental score and score for caudal neural tube, flexion and hindlimb were significantly lower in Embryos exposed to high concentrations of diclofenac (7.5 and 15.0 microg/ml), but no difference in these parameters was observed when Embryos were exposed to low concentration of diclofenac (1.5, 2.5 and 5.0 microg/ml). No significant differences in yolk sac diameter, crown-rump length and number of somites was found between Embryos in the experimental and the control group. CONCLUSIONS: Our study has demonstrated that diclofenac exerts direct teratogenic effects on rat Embryos. Until more is known about the effects of diclofenac (especially in moderate to high doses) in women of reproductive age, we suggest its use should be treated with caution.
Sarah A Robertson - One of the best experts on this subject based on the ideXlab platform.
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granulocyte macrophage colony stimulating factor alleviates adverse consequences of Embryo Culture on fetal growth trajectory and placental morphogenesis
Endocrinology, 2005Co-Authors: Cecilia Sjoblom, Claire T Roberts, Matts F Wikland, Sarah A RobertsonAbstract:Growth factors secreted by the female reproductive tract promote development of the preimplantation Embryo and potentially act as epigenetic determinants of postimplantation developmental competence and pregnancy outcome. In a comprehensive Embryo transfer study in mice, we examined the late gestational and postnatal effects of Embryo exposure to the cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF), identified as a key physiological regulator of cell number and viability in mouse and human blastocysts. Embryo development in Culture in the absence of GM-CSF restricted fetal growth, accelerated postnatal growth, and increased adult body mass and adiposity in offspring compared with in vivo-grown Embryos, especially in males. Addition of GM-CSF to Embryo Culture medium increased the proportion of transferred Embryos that generated viable progeny and alleviated the effects of in vitro Culture on fetal and postnatal growth trajectory but did not prevent programming of adult obesity. Placental morphogenesis was modified by Embryo Culture, which inhibited development of labyrinthine exchange tissue and adversely altered some structural correlates of placental transfer function. GM-CSF reversed the effect of Culture on labyrinthine growth and increased the surface area of placental trophoblast available for nutrient exchange. These findings indicate that the detrimental influence of Embryo Culture on fetal viability and growth may be largely mediated through altered placental morphogenesis and can be alleviated by GM-CSF. This demonstrates that Embryonic exposure to GM-CSF is essential for normal placental development and fetal growth.
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granulocyte macrophage colony stimulating factor alleviates adverse consequences of Embryo Culture on fetal growth trajectory and placental morphogenesis
Endocrinology, 2005Co-Authors: Cecilia Sjoblom, Claire T Roberts, Matts F Wikland, Sarah A RobertsonAbstract:Growth factors secreted by the female reproductive tract promote development of the preimplantation Embryo and potentially act as epigenetic determinants of postimplantation developmental competence and pregnancy outcome. In a comprehensive Embryo transfer study in mice, we examined the late gestational and postnatal effects of Embryo exposure to the cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF), identified as a key physiological regulator of cell number and viability in mouse and human blastocysts. Embryo development in Culture in the absence of GM-CSF restricted fetal growth, accelerated postnatal growth, and increased adult body mass and adiposity in offspring compared with in vivo-grown Embryos, especially in males. Addition of GM-CSF to Embryo Culture medium increased the proportion of transferred Embryos that generated viable progeny and alleviated the effects of in vitro Culture on fetal and postnatal growth trajectory but did not prevent programing of adult obesity. Placental ...