The Experts below are selected from a list of 237 Experts worldwide ranked by ideXlab platform
Thomas E Johnson - One of the best experts on this subject based on the ideXlab platform.
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quantitative trait locus mapping for ethanol Teratogenesis in bxd recombinant inbred mice
Alcoholism: Clinical and Experimental Research, 2012Co-Authors: Chris Downing, Jami Biers, Alexi Kimball, Hali Wright, David Gilliam, Christina Balderramadurbin, Thomas E JohnsonAbstract:Background Individual differences in susceptibility to the detrimental effects of prenatal ethanol (EtOH) exposure have been demonstrated. Many factors, including genetics, play a role in susceptibility and resistance. We have previously shown that C57BL/6J (B6) mice display a number of morphological malformations following an acute dose of EtOH in utero, while DBA/2J (D2) mice are relatively resistant. Here, we present the results of quantitative trait locus (QTL) mapping for EtOH Teratogenesis in recombinant inbred strains derived from a cross between B6 and D2 (BXD RIs). Methods Pregnant dams were intubated with either maltose-dextrin or 5.8 g/kg EtOH on day 9 of gestation (GD9). On GD 18, dams were sacrificed and fetuses and placentae were removed. Placentae and fetuses were weighed; fetuses were sexed and examined for gross morphological malformations. Fetuses were then either placed in Bouin's fixative for subsequent soft-tissue analyses or eviscerated and placed in EtOH for subsequent skeletal examinations. QTL mapping for maternal weight gain (MWG), prenatal mortality, fetal weight (FW) at c-section, placental weight (PW), and several morphological malformations was performed using WebQTL. Results Heritability for our traits ranged from 0.06 for PW to 0.39 for MWG. We found suggestive QTLs mediating all phenotypes and significant QTLs for FW and digit and rib malformations. While most QTL regions are large, several intriguing candidate genes emerged based on polymorphisms between B6 and D2 and gene function. Conclusions In this first mapping study for EtOH Teratogenesis, several QTLs were identified. Future studies will further characterize these regions. Identification of genes and epigenetic modifications mediating susceptibility to the teratogenic effects of alcohol in mice will provide targets to examine in human populations.
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subtle decreases in dna methylation and gene expression at the mouse igf2 locus following prenatal alcohol exposure effects of a methyl supplemented diet
Alcohol, 2011Co-Authors: Chris Downing, Colin Larson, Thomas E Johnson, Tatiana I Leakey, Rachel N Siegfried, Tonya M Rafferty, Craig A CooneyAbstract:Abstract C57BL/6J (B6) mice are susceptible to in utero growth retardation and a number of morphological malformations following prenatal alcohol exposure, while DBA/2J (D2) mice are relatively resistant. We have previously shown that genomic imprinting may play a role in differential sensitivity between B6 and D2. The best-characterized mechanism mediating genomic imprinting is differential DNA methylation. In the present study we examined DNA methylation and gene expression, in both embryonic and placental tissue, at the mouse Igf2 locus following in utero ethanol exposure. We also examined the effects of a methyl-supplemented diet on methylation and ethanol Teratogenesis. In embryos from susceptible B6 mice, we found small decreases in DNA methylation at four CpG sites in one of the differentially methylated regions of the Igf2 locus; only one of the four sites showed a statistically significant decrease. We observed no significant decreases in methylation in placentae. All Igf2 transcripts showed approximately 1.5-fold decreases following intrauterine alcohol exposure. Placing dams on a methyl-supplemented diet before pregnancy and throughout gestation brought methylation back up to control levels. Methyl supplementation also resulted in lower prenatal mortality, greater prenatal growth, and decreased digit malformations; it dramatically reduced vertebral malformations. Thus, although prenatal alcohol had only small effects on DNA methylation at the Igf2 locus, placing dams on a methyl-supplemented diet partially ameliorated ethanol Teratogenesis.
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genetic and maternal effects on valproic acid Teratogenesis in c57bl 6j and dba 2j mice
Toxicological Sciences, 2010Co-Authors: Chris Downing, Jami Biers, Colin Larson, Alexi Kimball, Hali Wright, Takamasa Ishii, David Gilliam, Thomas E JohnsonAbstract:Valproic acid (VPA) is used worldwide to treat epilepsy, migraine headaches, and bipolar disorder. However, VPA is teratogenic and in utero exposure can lead to congenital malformations. Using inbred C57BL/6J (B6) and DBA/2J (D2) mice, we asked whether genetic variation could play a role in susceptibility to VPA Teratogenesis. Whereas B6 fetuses were more susceptible than D2 fetuses to digit and vertebral malformations, D2 fetuses were more susceptible to rib malformations. In a reciprocal cross between B6 and D2, genetically identical F1 mice carried in a B6 mother had a greater percentage of vertebral malformations following prenatal VPA exposure than F1 mice carried in a D2 mother. This reciprocal F1 difference is known as a maternal effect and shows that maternal genotype/uterine environment is an important mediator of VPA teratogenecity. VPA is a histone deacetylase inhibitor, and it is possible that the differential Teratogenesis in B6 and D2 is because of strain differences in histone acetylation. We observed strain differences in acetylation of histones H3 and H4 in both embryo and placenta following in utero VPA exposure, but additional studies are needed to determine the significance of these changes in mediating Teratogenesis. Our results provide additional support that genetic factors, both maternal and fetal, play a role in VPA Teratogenesis. Lines of mice derived from B6 and D2 will be a useful model for elucidating the genetic architecture underlying susceptibility to VPA Teratogenesis.
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Genetic and Maternal Effects on Valproic Acid Teratogenesis in C57BL/6J and DBA/2J Mice
Toxicological Sciences, 2010Co-Authors: Chris Downing, Jami Biers, Colin Larson, Alexi Kimball, Hali Wright, Takamasa Ishii, David Gilliam, Thomas E JohnsonAbstract:Valproic acid (VPA) is used worldwide to treat epilepsy, migraine headaches, and bipolar disorder. However, VPA is teratogenic and in utero exposure can lead to congenital malformations. Using inbred C57BL/6J (B6) and DBA/2J (D2) mice, we asked whether genetic variation could play a role in susceptibility to VPA Teratogenesis. Whereas B6 fetuses were more susceptible than D2 fetuses to digit and vertebral malformations, D2 fetuses were more susceptible to rib malformations. In a reciprocal cross between B6 and D2, genetically identical F1 mice carried in a B6 mother had a greater percentage of vertebral malformations following prenatal VPA exposure than F1 mice carried in a D2 mother. This reciprocal F1 difference is known as a maternal effect and shows that maternal genotype/uterine environment is an important mediator of VPA teratogenecity. VPA is a histone deacetylase inhibitor, and it is possible that the differential Teratogenesis in B6 and D2 is because of strain differences in histone acetylation. We observed strain differences in acetylation of histones H3 and H4 in both embryo and placenta following in utero VPA exposure, but additional studies are needed to determine the significance of these changes in mediating Teratogenesis. Our results provide additional support that genetic factors, both maternal and fetal, play a role in VPA Teratogenesis. Lines of mice derived from B6 and D2 will be a useful model for elucidating the genetic architecture underlying susceptibility to VPA Teratogenesis.
Louise M Winn - One of the best experts on this subject based on the ideXlab platform.
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epigenetic modifications in valproic acid induced Teratogenesis
Toxicology and Applied Pharmacology, 2010Co-Authors: Emily W Y Tung, Louise M WinnAbstract:Abstract Exposure to the anticonvulsant drug valproic acid (VPA) in utero is associated with a 1–2% increase in neural tube defects (NTDs), however the molecular mechanisms by which VPA induces Teratogenesis are unknown. Previous studies demonstrated that VPA, a direct inhibitor of histone deacetylase, can induce histone hyperacetylation and other epigenetic changes such as histone methylation and DNA demethylation. The objective of this study was to determine if maternal exposure to VPA in mice has the ability to cause these epigenetic alterations in the embryo and thus contribute to its mechanism of Teratogenesis. Pregnant CD-1 mice (GD 9.0) were administered a teratogenic dose of VPA (400 mg/kg, s.c.) and embryos extracted 1, 3, 6, and 24 h after injection. To assess embryonic histone acetylation and histone methylation, Western blotting was performed on whole embryo homogenates, as well as immunohistochemical staining on embryonic sections. To measure DNA methylation changes, the cytosine extension assay was performed. Results demonstrated that a significant increase in histone acetylation that peaked 3 h after VPA exposure was accompanied by an increase in histone methylation at histone H3 lysine 4 (H3K4) and a decrease in histone methylation at histone H3 lysine 9 (H3K9). Immunohistochemical staining revealed increased histone acetylation in the neuroepithelium, heart, and somites. A decrease in methylated histone H3K9 staining was observed in the neuroepithelium and somites, METHYLATED histone H3K4 staining was observed in the neuroepithelium. No significant differences in global or CpG island DNA methylation were observed in embryo homogenates. These results support the possibility that epigenetic modifications caused by VPA during early mouse organogenesis results in congenital malformations.
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oxidative damage in chemical Teratogenesis
Mutation Research, 1997Co-Authors: Peter G Wells, Rebecca R Laposa, Christopher J Nicol, Toufan Parmana, Louise M WinnAbstract:The teratogenicity of many xenobiotics is thought to depend at least in part upon their bioactivation by embryonic cytochromes P450, prostaglandin H synthase (PHS) and lipoxygenases (LPOs) to electrophilic and/or free radical reactive intermediates that covalently bind to or oxidize cellular macromolecules such as DNA, protein and lipid, resulting in in utero death or Teratogenesis. Using as models the tobacco carcinogens benzo[a]pyrene (B[a]P) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), the anticonvulsant drug phenytoin, structurally related anticonvulsants (e.g. mephenytoin, nirvanol, trimethadione, dimethadione) and the sedative drug thalidomide, we have examined the potential teratologic relevance of free radical-initiated, reactive oxygen species (ROS)-mediated oxidative molecular target damage, genotoxicity (micronucleus formation) and DNA repair in mouse and rabbit models in vivo and in embryo culture, and in vitro using purified enzymes or cultured rat skin fibroblasts. These teratogens were bioactivated by PHS and LPOs to free radical reactive intermediary metabolites, characterized by electron spin resonance spectrometry, that initiated ROS formation, including hydroxyl radicals, which were characterized by salicylate hydroxylation. ROS-initiated oxidation of DNA (8-hydroxy-2′-deoxyguanosine formation), protein (carbonyl formation), glutathione (GSH) and lipid (peroxidation), and embryotoxicity were shown for phenytoin, its major hydroxylated metabolite p-(hydroxyphenyl)-5-phenylhydantoin (HPPH), thalidomide, B[a]P and NNK in vivo and/or in embryo culture, the latter indicating a teratologically critical role for embryonic, as distinct from maternal, processes. DNA oxidation and teratogenicity of phenytoin and thalidomide were reduced by PHS inhibitors. Oxidative macromolecular lesions and teratogenicity also were reduced by the free radical trapping agent phenylbutylnitrone (PBN), and the antioxidants caffeic acid and vitamin E. In embryo culture, addition of superoxide dismutase (SOD) to the medium enhanced embryonic SOD activity, and SOD or catalase blocked the oxidative lesions and embryotoxicity initiated by phenytoin and B[a]P, suggesting a major contribution of ROS, as distinct from covalent binding, to the teratologic mechanism. In in vivo studies, other antioxidative enzymes like GSH peroxidase, GSH reductase and glucose-6-phosphate dehydrogenase (G6PD) were similarly protective. Even untreated G6PD-deficient mice had enhanced embryopathies, indicating a teratological role for endogenous oxidative stress. In cultured fibroblasts, B[a]P, NNK, phenytoin and HPPH initiated DNA oxidation and micronucleus formation, which were inhibited by SOD. Oxidation of DNA may be particularly critical, since transgenic mice with +/− or −/− deficiencies in the p53 tumor suppressor gene, which facilitates DNA repair, are more susceptible to phenytoin and B[a]P teratogenicity. Even p53-deficient mice treated only with normal saline showed enhanced embryopathies, suggesting the teratological importance of endogenous oxidative stress, as observed with G6PD deficiency. These results suggest that oxidative macromolecular damage may play a role in the teratologic mechanism of xenobiotics that are bioactivated to a reactive intermediate, as well in the mechanism of embryopathies occurring in the absence of xenobiotic exposure.
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biochemical toxicology of chemical Teratogenesis
Critical Reviews in Biochemistry and Molecular Biology, 1996Co-Authors: Peter G Wells, Louise M WinnAbstract:Although exposure during pregnancy to many drugs and environmental chemicals is known to cause in utero death of the embryo or fetus, or initiate birth defects (Teratogenesis) in the surviving offspring, surprisingly little is known about the underlying biochemical and molecular mechanisms, or the determinants of teratological susceptibility, particularly in hu- mans. In vim and in vivo studies based primarily on rodent models suggest that many potential embryotoxic xenobiotics are actually proteratogens that must be bioactivated by enzymes such as the cytochromes P450 and peroxidases such as prostaglandin H synthase to teratogenic reactive intermediary metabolites. These reactive intermediates generally are electrophiles or free radicals that bind covalently (irreversibly) to, or directly or indirectly oxidize, embryonic cellular macromolecules such as DNA, protein, and lipid, irreversibly altering cellular function. Target oxidation, known as oxidative stress, often appears to be mediated by reactive oxygen species (ROS) such as hydroxyl radicals. The precise nature of the teratologically relevant molecular targets remains to be established, as do the relative contributions of the various types of macromolecular lesions. Teratological susceptibility appears to be determined in part by a balance among pathways of maternal xenobiotic elimination, embryonic xenobiotic bioactivation and detoxification of the xenobiotic reactive intermediate, direct and indirect pathways for the detoxification of ROS (cytoprotection), and repair of macromolecular lesions. Due largely to immature or otherwise compromised embryonic pathways for detoxification, cytoprotection, and repair, the embryo is relatively susceptible to reactive intermediates, and Teratogenesis via this mechanism can occur from exposure to therapeutic concentrations of drugs, or supposedly safe concentrations of environmental chemicals. Greater insight into the mechanisms involved in human reactive intermediate-mediated teratogenicity, and the determinants of individual terato- logical susceptibility, will be necessary to reduce the unwarranted embryonic attrition from xenobiotic exposure.
Chris Downing - One of the best experts on this subject based on the ideXlab platform.
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quantitative trait locus mapping for ethanol Teratogenesis in bxd recombinant inbred mice
Alcoholism: Clinical and Experimental Research, 2012Co-Authors: Chris Downing, Jami Biers, Alexi Kimball, Hali Wright, David Gilliam, Christina Balderramadurbin, Thomas E JohnsonAbstract:Background Individual differences in susceptibility to the detrimental effects of prenatal ethanol (EtOH) exposure have been demonstrated. Many factors, including genetics, play a role in susceptibility and resistance. We have previously shown that C57BL/6J (B6) mice display a number of morphological malformations following an acute dose of EtOH in utero, while DBA/2J (D2) mice are relatively resistant. Here, we present the results of quantitative trait locus (QTL) mapping for EtOH Teratogenesis in recombinant inbred strains derived from a cross between B6 and D2 (BXD RIs). Methods Pregnant dams were intubated with either maltose-dextrin or 5.8 g/kg EtOH on day 9 of gestation (GD9). On GD 18, dams were sacrificed and fetuses and placentae were removed. Placentae and fetuses were weighed; fetuses were sexed and examined for gross morphological malformations. Fetuses were then either placed in Bouin's fixative for subsequent soft-tissue analyses or eviscerated and placed in EtOH for subsequent skeletal examinations. QTL mapping for maternal weight gain (MWG), prenatal mortality, fetal weight (FW) at c-section, placental weight (PW), and several morphological malformations was performed using WebQTL. Results Heritability for our traits ranged from 0.06 for PW to 0.39 for MWG. We found suggestive QTLs mediating all phenotypes and significant QTLs for FW and digit and rib malformations. While most QTL regions are large, several intriguing candidate genes emerged based on polymorphisms between B6 and D2 and gene function. Conclusions In this first mapping study for EtOH Teratogenesis, several QTLs were identified. Future studies will further characterize these regions. Identification of genes and epigenetic modifications mediating susceptibility to the teratogenic effects of alcohol in mice will provide targets to examine in human populations.
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Maternal effects on ethanol Teratogenesis in a cross between A/J and C57BL/6J mice
Alcohol, 2011Co-Authors: David Gilliam, Nate Valdez, Scott Branson, Ashley Dixon, Chris DowningAbstract:Abstract Genetic factors influence adverse pregnancy outcome in both humans and animal models. Animal research reveals that both the maternal and fetal genetic profiles are important for determining the risk of physical birth defects and prenatal mortality. Using a reciprocal-cross breeding design, we investigated whether the mother's genes may be more important than fetal genes in determining risk for ethanol Teratogenesis. Examination of possible synergistic genetic effects on ethanol Teratogenesis was made possible by using two mouse strains known to be susceptible to specific malformations. Inbred A/J (A) and C57BL/6J (B6) mice were mated to produce four fetal genotype groups: the true-bred AċA and B6ċB6 genotypes and the genetically identical AċB6 and B6ċA genotypes (the F 1 genotype). Dams were administered either 5.8g/kg ethanol or an isocaloric amount of maltose–dextrin on day 9 of pregnancy. Fetuses were removed by laparotomy on gestation day 18, weighed, and assessed for digit, vertebral, and kidney malformations. Digit malformations in the genetically identical F 1 ethanol-exposed litters showed a pattern consistent with a maternal genetic effect (AċB6 [2%] and B6ċA [30%]). In contrast, vertebral malformations were similar in all ethanol-exposed litters (AċA [26%], AċB6 [18%], B6ċA [22%], and B6ċB6 [33%]). The percentage of malformations did not differ between male and female fetuses, indicating sex-linked factors are not responsible for the maternal effect. Ethanol exposure decreased litter weights but did not affect litter mortality compared with maltose-exposed controls. This study supports the idea that genes influence malformation risk following in utero alcohol exposure. Specifically, maternal genes influence risk more than fetal genes for some teratogenic outcomes. No evidence supported synergistic genetic effects on ethanol Teratogenesis. This research supports the conclusion that uterine environment contributes to determining risk of Fetal Alcohol Spectrum Disorder.
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subtle decreases in dna methylation and gene expression at the mouse igf2 locus following prenatal alcohol exposure effects of a methyl supplemented diet
Alcohol, 2011Co-Authors: Chris Downing, Colin Larson, Thomas E Johnson, Tatiana I Leakey, Rachel N Siegfried, Tonya M Rafferty, Craig A CooneyAbstract:Abstract C57BL/6J (B6) mice are susceptible to in utero growth retardation and a number of morphological malformations following prenatal alcohol exposure, while DBA/2J (D2) mice are relatively resistant. We have previously shown that genomic imprinting may play a role in differential sensitivity between B6 and D2. The best-characterized mechanism mediating genomic imprinting is differential DNA methylation. In the present study we examined DNA methylation and gene expression, in both embryonic and placental tissue, at the mouse Igf2 locus following in utero ethanol exposure. We also examined the effects of a methyl-supplemented diet on methylation and ethanol Teratogenesis. In embryos from susceptible B6 mice, we found small decreases in DNA methylation at four CpG sites in one of the differentially methylated regions of the Igf2 locus; only one of the four sites showed a statistically significant decrease. We observed no significant decreases in methylation in placentae. All Igf2 transcripts showed approximately 1.5-fold decreases following intrauterine alcohol exposure. Placing dams on a methyl-supplemented diet before pregnancy and throughout gestation brought methylation back up to control levels. Methyl supplementation also resulted in lower prenatal mortality, greater prenatal growth, and decreased digit malformations; it dramatically reduced vertebral malformations. Thus, although prenatal alcohol had only small effects on DNA methylation at the Igf2 locus, placing dams on a methyl-supplemented diet partially ameliorated ethanol Teratogenesis.
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genetic and maternal effects on valproic acid Teratogenesis in c57bl 6j and dba 2j mice
Toxicological Sciences, 2010Co-Authors: Chris Downing, Jami Biers, Colin Larson, Alexi Kimball, Hali Wright, Takamasa Ishii, David Gilliam, Thomas E JohnsonAbstract:Valproic acid (VPA) is used worldwide to treat epilepsy, migraine headaches, and bipolar disorder. However, VPA is teratogenic and in utero exposure can lead to congenital malformations. Using inbred C57BL/6J (B6) and DBA/2J (D2) mice, we asked whether genetic variation could play a role in susceptibility to VPA Teratogenesis. Whereas B6 fetuses were more susceptible than D2 fetuses to digit and vertebral malformations, D2 fetuses were more susceptible to rib malformations. In a reciprocal cross between B6 and D2, genetically identical F1 mice carried in a B6 mother had a greater percentage of vertebral malformations following prenatal VPA exposure than F1 mice carried in a D2 mother. This reciprocal F1 difference is known as a maternal effect and shows that maternal genotype/uterine environment is an important mediator of VPA teratogenecity. VPA is a histone deacetylase inhibitor, and it is possible that the differential Teratogenesis in B6 and D2 is because of strain differences in histone acetylation. We observed strain differences in acetylation of histones H3 and H4 in both embryo and placenta following in utero VPA exposure, but additional studies are needed to determine the significance of these changes in mediating Teratogenesis. Our results provide additional support that genetic factors, both maternal and fetal, play a role in VPA Teratogenesis. Lines of mice derived from B6 and D2 will be a useful model for elucidating the genetic architecture underlying susceptibility to VPA Teratogenesis.
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Genetic and Maternal Effects on Valproic Acid Teratogenesis in C57BL/6J and DBA/2J Mice
Toxicological Sciences, 2010Co-Authors: Chris Downing, Jami Biers, Colin Larson, Alexi Kimball, Hali Wright, Takamasa Ishii, David Gilliam, Thomas E JohnsonAbstract:Valproic acid (VPA) is used worldwide to treat epilepsy, migraine headaches, and bipolar disorder. However, VPA is teratogenic and in utero exposure can lead to congenital malformations. Using inbred C57BL/6J (B6) and DBA/2J (D2) mice, we asked whether genetic variation could play a role in susceptibility to VPA Teratogenesis. Whereas B6 fetuses were more susceptible than D2 fetuses to digit and vertebral malformations, D2 fetuses were more susceptible to rib malformations. In a reciprocal cross between B6 and D2, genetically identical F1 mice carried in a B6 mother had a greater percentage of vertebral malformations following prenatal VPA exposure than F1 mice carried in a D2 mother. This reciprocal F1 difference is known as a maternal effect and shows that maternal genotype/uterine environment is an important mediator of VPA teratogenecity. VPA is a histone deacetylase inhibitor, and it is possible that the differential Teratogenesis in B6 and D2 is because of strain differences in histone acetylation. We observed strain differences in acetylation of histones H3 and H4 in both embryo and placenta following in utero VPA exposure, but additional studies are needed to determine the significance of these changes in mediating Teratogenesis. Our results provide additional support that genetic factors, both maternal and fetal, play a role in VPA Teratogenesis. Lines of mice derived from B6 and D2 will be a useful model for elucidating the genetic architecture underlying susceptibility to VPA Teratogenesis.
David Gilliam - One of the best experts on this subject based on the ideXlab platform.
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quantitative trait locus mapping for ethanol Teratogenesis in bxd recombinant inbred mice
Alcoholism: Clinical and Experimental Research, 2012Co-Authors: Chris Downing, Jami Biers, Alexi Kimball, Hali Wright, David Gilliam, Christina Balderramadurbin, Thomas E JohnsonAbstract:Background Individual differences in susceptibility to the detrimental effects of prenatal ethanol (EtOH) exposure have been demonstrated. Many factors, including genetics, play a role in susceptibility and resistance. We have previously shown that C57BL/6J (B6) mice display a number of morphological malformations following an acute dose of EtOH in utero, while DBA/2J (D2) mice are relatively resistant. Here, we present the results of quantitative trait locus (QTL) mapping for EtOH Teratogenesis in recombinant inbred strains derived from a cross between B6 and D2 (BXD RIs). Methods Pregnant dams were intubated with either maltose-dextrin or 5.8 g/kg EtOH on day 9 of gestation (GD9). On GD 18, dams were sacrificed and fetuses and placentae were removed. Placentae and fetuses were weighed; fetuses were sexed and examined for gross morphological malformations. Fetuses were then either placed in Bouin's fixative for subsequent soft-tissue analyses or eviscerated and placed in EtOH for subsequent skeletal examinations. QTL mapping for maternal weight gain (MWG), prenatal mortality, fetal weight (FW) at c-section, placental weight (PW), and several morphological malformations was performed using WebQTL. Results Heritability for our traits ranged from 0.06 for PW to 0.39 for MWG. We found suggestive QTLs mediating all phenotypes and significant QTLs for FW and digit and rib malformations. While most QTL regions are large, several intriguing candidate genes emerged based on polymorphisms between B6 and D2 and gene function. Conclusions In this first mapping study for EtOH Teratogenesis, several QTLs were identified. Future studies will further characterize these regions. Identification of genes and epigenetic modifications mediating susceptibility to the teratogenic effects of alcohol in mice will provide targets to examine in human populations.
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Maternal effects on ethanol Teratogenesis in a cross between A/J and C57BL/6J mice
Alcohol, 2011Co-Authors: David Gilliam, Nate Valdez, Scott Branson, Ashley Dixon, Chris DowningAbstract:Abstract Genetic factors influence adverse pregnancy outcome in both humans and animal models. Animal research reveals that both the maternal and fetal genetic profiles are important for determining the risk of physical birth defects and prenatal mortality. Using a reciprocal-cross breeding design, we investigated whether the mother's genes may be more important than fetal genes in determining risk for ethanol Teratogenesis. Examination of possible synergistic genetic effects on ethanol Teratogenesis was made possible by using two mouse strains known to be susceptible to specific malformations. Inbred A/J (A) and C57BL/6J (B6) mice were mated to produce four fetal genotype groups: the true-bred AċA and B6ċB6 genotypes and the genetically identical AċB6 and B6ċA genotypes (the F 1 genotype). Dams were administered either 5.8g/kg ethanol or an isocaloric amount of maltose–dextrin on day 9 of pregnancy. Fetuses were removed by laparotomy on gestation day 18, weighed, and assessed for digit, vertebral, and kidney malformations. Digit malformations in the genetically identical F 1 ethanol-exposed litters showed a pattern consistent with a maternal genetic effect (AċB6 [2%] and B6ċA [30%]). In contrast, vertebral malformations were similar in all ethanol-exposed litters (AċA [26%], AċB6 [18%], B6ċA [22%], and B6ċB6 [33%]). The percentage of malformations did not differ between male and female fetuses, indicating sex-linked factors are not responsible for the maternal effect. Ethanol exposure decreased litter weights but did not affect litter mortality compared with maltose-exposed controls. This study supports the idea that genes influence malformation risk following in utero alcohol exposure. Specifically, maternal genes influence risk more than fetal genes for some teratogenic outcomes. No evidence supported synergistic genetic effects on ethanol Teratogenesis. This research supports the conclusion that uterine environment contributes to determining risk of Fetal Alcohol Spectrum Disorder.
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genetic and maternal effects on valproic acid Teratogenesis in c57bl 6j and dba 2j mice
Toxicological Sciences, 2010Co-Authors: Chris Downing, Jami Biers, Colin Larson, Alexi Kimball, Hali Wright, Takamasa Ishii, David Gilliam, Thomas E JohnsonAbstract:Valproic acid (VPA) is used worldwide to treat epilepsy, migraine headaches, and bipolar disorder. However, VPA is teratogenic and in utero exposure can lead to congenital malformations. Using inbred C57BL/6J (B6) and DBA/2J (D2) mice, we asked whether genetic variation could play a role in susceptibility to VPA Teratogenesis. Whereas B6 fetuses were more susceptible than D2 fetuses to digit and vertebral malformations, D2 fetuses were more susceptible to rib malformations. In a reciprocal cross between B6 and D2, genetically identical F1 mice carried in a B6 mother had a greater percentage of vertebral malformations following prenatal VPA exposure than F1 mice carried in a D2 mother. This reciprocal F1 difference is known as a maternal effect and shows that maternal genotype/uterine environment is an important mediator of VPA teratogenecity. VPA is a histone deacetylase inhibitor, and it is possible that the differential Teratogenesis in B6 and D2 is because of strain differences in histone acetylation. We observed strain differences in acetylation of histones H3 and H4 in both embryo and placenta following in utero VPA exposure, but additional studies are needed to determine the significance of these changes in mediating Teratogenesis. Our results provide additional support that genetic factors, both maternal and fetal, play a role in VPA Teratogenesis. Lines of mice derived from B6 and D2 will be a useful model for elucidating the genetic architecture underlying susceptibility to VPA Teratogenesis.
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Genetic and Maternal Effects on Valproic Acid Teratogenesis in C57BL/6J and DBA/2J Mice
Toxicological Sciences, 2010Co-Authors: Chris Downing, Jami Biers, Colin Larson, Alexi Kimball, Hali Wright, Takamasa Ishii, David Gilliam, Thomas E JohnsonAbstract:Valproic acid (VPA) is used worldwide to treat epilepsy, migraine headaches, and bipolar disorder. However, VPA is teratogenic and in utero exposure can lead to congenital malformations. Using inbred C57BL/6J (B6) and DBA/2J (D2) mice, we asked whether genetic variation could play a role in susceptibility to VPA Teratogenesis. Whereas B6 fetuses were more susceptible than D2 fetuses to digit and vertebral malformations, D2 fetuses were more susceptible to rib malformations. In a reciprocal cross between B6 and D2, genetically identical F1 mice carried in a B6 mother had a greater percentage of vertebral malformations following prenatal VPA exposure than F1 mice carried in a D2 mother. This reciprocal F1 difference is known as a maternal effect and shows that maternal genotype/uterine environment is an important mediator of VPA teratogenecity. VPA is a histone deacetylase inhibitor, and it is possible that the differential Teratogenesis in B6 and D2 is because of strain differences in histone acetylation. We observed strain differences in acetylation of histones H3 and H4 in both embryo and placenta following in utero VPA exposure, but additional studies are needed to determine the significance of these changes in mediating Teratogenesis. Our results provide additional support that genetic factors, both maternal and fetal, play a role in VPA Teratogenesis. Lines of mice derived from B6 and D2 will be a useful model for elucidating the genetic architecture underlying susceptibility to VPA Teratogenesis.
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Cytoplasmic factors do not contribute to a maternal effect on ethanol Teratogenesis.
Behavior Genetics, 1999Co-Authors: Chris Downing, David GilliamAbstract:Both maternal and fetal genetic factors influence variations in response to prenatal ethanol exposure. To assess the effect of maternal genotype on the incidence of ethanol Teratogenesis, a reciprocal cross study was conducted in an animal mode using the relatively susceptible C57BL/6J (B6) and the relatively resistant DBA/2J (D2) inbred mice. This mating pattern produced four embryonic genotypes: true-bred B6B6 and D2D2 litters and hybrid B6D2 and D2B6 litters. To examine the role of maternal egg cytoplasm as the source of variation that could account for a maternal effect, B6D2 and D2B6 F1 females were mated back to B6 males, which produced two additional embryonic genotypes: B6D2.B6 and D2B6.B6. Dams were intubated with either 5.8 g/kg of ethanol or an isocaloric amount of maltose–dextrin on day 9 of pregnancy. On day 18 of pregnancy, dams were sacrificed, fetuses were removed, weighed, sexed, and examined for gross morphological malformations. Every other fetus within a litter was prepared for either skeletal or soft tissue analysis. Results showed a higher rate of Teratogenesis in the B6D2 group compared to the genetically similar D2B6 group, which indicates an influence of maternal genotype on susceptibility to ethanol Teratogenesis. The percentage of affected male and female fetuses did not differ, which suggests that sex-linked factors are not responsible for the maternal effect. The backcross B6D2.B6 and D2B6.B6 litters did not differ significantly for any measure of Teratogenesis, suggesting that differences in maternally transmitted cytoplasmic material are not the cause of the maternal effect. Factors that could account for the maternal effect are differences in the maternal uterine environment and genomic imprinting. Separating maternal from fetal-mediated mechanisms responsible for susceptibility to ethahol Teratogenesis is needed for identifying mothers and infants at risk.
John A. Bantle - One of the best experts on this subject based on the ideXlab platform.
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Linking Teratogenesis, growth, and DNA photodamage to artificial ultraviolet B radiation in Xenopus laevis larvae
Environmental Toxicology and Chemistry, 1998Co-Authors: Douglas J. Bruggeman, John A. Bantle, Carla GoadAbstract:The frog embryo Teratogenesis assay—Xenopus (FETAX) was used to illustrate sublethal endpoints indicative of ultraviolet B (UV-B) radiation exposure in Xenopus laevis larvae. Xenopus laevis embryos were covered with plastic cutoff filters to manipulate UV dose, and irradiated under a light carriage consisting of two UV-B and three UV-A bulbs. At the end of day 2, 20% of the tadpoles from all treatments were removed, and DNA was extracted. Frequency of pyrimidine dimers was estimated by quantifying single-strand breaks after incubating DNA with an endonuclease specific for cyclobutane pyrimidine dimers. Remaining tadpoles were sacrificed on day 5, and mortality, malformations, and growth data were recorded. Teratogenesis and growth inhibition were positively correlated with increasing UV-B dose in all tests. Photodamage to DNA in experiment 1 increased with higher UV-B doses. Teratogenesis positively correlated with the frequency of pyrimidine dimers. In experiment 2, significant variation with DNA photodamage in egg clutches was observed and no treatment effect was found. Usage of these sublethal endpoints in the field or laboratory would be helpful in discerning adaptational responses of developing amphibians to UV-B radiation, and interactive effects between UV and photosensitive chemicals.
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developmental toxicology of potato alkaloids in the frog embryo Teratogenesis assay xenopus fetax
Food and Chemical Toxicology, 1991Co-Authors: Mendel Friedman, James R Rayburn, John A. BantleAbstract:Abstract Potatoes frequently contain growth inhibitors and toxic compounds including digestive enzyme inhibitors, lectins and glycoalkaloids. The literature suggests that Solanum alkaloids have the ability to induce neurological damage such as spina bifida and other malformations. As part of a programme of improvement in the safety of potatoes using molecular plant genetics and parallel food safety evaluation, we evaluated the effect of several potato glycoalkaloids and aglycones in the frog embryo Teratogenesis assay—Xenopus (FETAX) with and without metabolic activation by Aroclor 1254-induced rat liver microsomes. The data suggest that the glycoalkaloid α-chaconine is teratogenic and more embryotoxic than α-solanine, in terms of the median lethal concentration (LC 50 ) after 96 hr of exposure, the concentration inducing gross terata in 50% of the surviving frog embryos (96-hr EC 50 , malformation), and the minimum concentration needed to inhibit the growth of the embryos. Since these two compounds differ only in the nature of the carbohydrate side chain attached to the 3-OH group of solanidine, the side chain appears to be an important factor in governing teratogenicity. The aglycones demissidine, soladine and solasodine were less toxic than the glycosides α-chaconine and α-solanine. The in vitro Teratogenesis assay should be useful for: (a) predicting the teratogenic potential of Solanaceae alkaloids, glycoalkaloids and related natural products, and (b) facilitating experimental approaches to suppress plant genes and enzymes that control the biosynthesis of the most toxic compounds.