Molecular and biochemical mechanisms in teratogenesis involving reactive oxygen species

Wells, Peter G.; Bhuller, Yadvinder; Chen, Connie S.; Jeng, Winnie; Kasapinovic, Sonja; Kennedy, J. S.; Kim, Perry M.; Laposa, Rebecca R.; McCallum, Gordon P.; Nicol, Christopher J.B.; Parman, Toufan; Wiley, Michael J.; Wong, Aol

doi:10.1016/j.taap.2005.01.061

Cited by 202 publications

(152 citation statements)

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“…This is supported by our earlier observation that embryos treated with GTN ex ovo and examined 18 h later showed the presence of nitrated proteins (Bardai et al, 2011). This post-translational modification of proteins is a consequence of the formation of radical nitrating species such as NO, a free radical that is generated as a consequence of GTN metabolism and is capable of causing developmental pathologies (Wells et al, 2005). We analyzed the cytosolic fraction to which GTN had been added for the presence of NO but were unable to detect NO in these assays (data not shown).…”

Section: Discussionsupporting

confidence: 72%

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Glyceryl trinitrate metabolism in the quail embryo by the glutathione S-transferases leads to a perturbation in redox status and embryotoxicity

Bardai

Hales

Sunahara

2013

Comparative Biochemistry and Physiology Part B: Biochemistry an

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/npsi/ctrl?lang=en http://nparc.cisti-icist.nrc-cnrc.gc.ca/npsi/ctrl?lang=fr Access and use of this website and the material on it are subject to the Terms and Conditions set forth at http://nparc.cisti-icist.nrc-cnrc.gc.ca/npsi/jsp/nparc_cp.jsp?lang=en NRC Publications Archive Archives des publications du CNRCThis publication could be one of several versions: author's original, accepted manuscript or the publisher's version. / La version de cette publication peut être l'une des suivantes : la version prépublication de l'auteur, la version acceptée du manuscrit ou la version de l'éditeur. For the publisher's version, please access the DOI link below./ Pour consulter la version de l'éditeur, utilisez le lien DOI ci-dessous.http://dx.doi.org/10. 1016/j.cbpb.2013.04.001 Comparative Biochemistry and Physiology Part B: Biochemistry and Molecular Biology, 165, 3, pp. 153-164, 2013-04-12 Glyceryl trinitrate metabolism in the quail embryo by the glutathione Stransferases leads to a perturbation in redox status and embryotoxicity Bardai, Ghalib K.; Hales, Barbara F.; Sunahara, Geoffrey I. induces malformations that were associated in previous studies with an increase in protein nitration.Increased nitration suggests metabolism of GTN by the embryo. The goals of this study were to characterize the enzymes and co-factors required for GTN metabolism by quail embryos, and to determine the effects of in ovo treatment with N-acetyl cysteine (NAC), a precursor of glutathione (GSH), on GTN embryotoxicity. GTN treatment of quail embryo resulted in an increase in nitrite, a 2 decrease in total GSH, and an increase in the ratio of NADP+/NADPH, indicating that redox balance may be compromised in exposed embryos. Glutathione S-transferases (GSTs; EC 2.5.1.18) purified from the whole embryo (K m 0.84 mM; V max 36 µM/min) and the embryonic eye (K m 0.20 mM; V max 30 µM/min) had GTN-metabolizing activity (1436 and 34 nmol/min/mg, respectively); the addition of ethacrynic acid, an inhibitor of GST activity, decreased GTN metabolism. Peptide sequencing of the GST isozymes indicated that alpha-or mu-type GSTs in the embryo and embryonic eye had GTN metabolizing activity. NAC co-treatment partially protected against the effects of GTN exposure. Thus, GTN denitration by quail embryo GSTs may represent a key initial step in the developmental toxicity of GTN.

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Section: Discussionsupporting

confidence: 72%

“…The proper functioning of redox sensitive thiols is dependent upon a finely tuned balance between their reduced and oxidized forms. Dysregulation of the redox equilibrium can severely hamper embryo development (Wells et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Glyceryl trinitrate metabolism in the quail embryo by the glutathione S-transferases leads to a perturbation in redox status and embryotoxicity

Bardai

Hales

Sunahara

2013

Comparative Biochemistry and Physiology Part B: Biochemistry an

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“…Some critical detoxifying enzymes, such as glutathione S-transferases, are also much less in fetal than that in mother liver (Wells et al, 2009). And activities of most antioxidative enzymes in embryonic liver are only around 5% of that in maternal liver (Wells et al, 2005). In addition, fetuses are more susceptible to genetic damage than adults.…”

Section: Discussionmentioning

confidence: 99%

Maternal-Fetal Disposition and Metabolism of Retrorsine in Pregnant Rats

Yang

Xiang

et al. 2018

Drug Metab Dispos

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The number of text pages: 21The number of figures: 7 The number of references: 44 The number of words in the Abstract: 276 The number of words in the Introduction: 625 The number of words in the Discussion: 1231 Abbreviations pyrrolizidine alkaloids, PAs; cytochrome P450, CYP; retrorsine, RTS; gestation day, GD; glutathione, GSH; glyceraldehyde phosphate dehydrogenase, GAPDH; 4-dimethylaminobenzaldehyde, DABA; hematoxylin and eosin, HE; declustering potential, DP; collision energy, CE; collision cell exit potential, CXP; highperformance liquid chromatography, HPLC; multiple-reaction monitoring, MRM; ATP-binding cassette, ABC AbstractPyrrolizidine alkaloids (PAs) are extensively synthesized by plants and are commonly present in herbs and foodstuffs, which exhibit hepatotoxicity requiring metabolic activation by cytochrome P450 (CYP) 3A to form the electrophilic metabolites-pyrrolic esters. PAs also cause embryo toxicity, but the metabolic profiles of PAs in fetus and placenta have been far from clear. In this study, we determined the basal metabolic activation of retrorsine (RTS) in rat maternal liver, placenta and fetal liver in vitro, and examined the fetal toxicity and bioactivation of RTS in vivo. Detection of microsomal RTS metabolites in vitro showed that the basal metabolic activity of fetal liver and placenta to RTS was much weaker than that of maternal liver. In addition, higher rate of pyrrolic ester formation was found in normal male fetal liver, compared with that of female pups. In vivo exposure to RTS caused fetal growth retardation as well as placenta and fetal liver injury. Little difference in serum RTS was observed in dams and fetuses, but the content of pyrrole-protein adduction in fetal liver was much lower than that in mother liver, which was consistent with basal metabolic activity. Unexpectedly, compared with basal metabolism in fetal liver, exposure to RTS during middle and late pregnancy caused an opposite gender difference in RTS metabolism and CYP3A expression in fetal liver. For the first time, our study proved that RTS was capable of permeating placenta barrier and entering fetal circulation, while the intrauterine pyrrolic metabolite was mainly generated by fetal liver, but not transported from mother circulation. Induction of CYP3A by RTS was gender-dependent in fetal liver, which was probably responsible for RTS-induced fetal

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“…11,32,33 The deleterious embryonic and fetal effects of ROS, in the absence of maternal toxicity, likely reflects, in part, the low levels of most embryonic antioxidative enzymes and antioxidants. 6,9 On GD 13, among control embryos exposed in utero to the unsupplemented diet, the increased level of DNA oxidation in p53 null embryos, compared with both their þ/À and þ/þ littermates, suggests that endogenous embryonic oxidative stress in the absence of repair of oxidative DNA damage, one role of p53, may contribute to the more rapid onset of postnatal tumorigenesis in this genotype. Loss of only one p53 allele had no measurable effect on embryonic DNA oxidation, suggesting that, at least in the absence of enhanced oxidative stress, DNA repair in the heterozygous littermates is adequate to contribute, in part, to their slower development of postnatal FIGURE 6.…”

Section: Discussionmentioning

confidence: 99%

Reduced tumorigenesis in p53 knockout mice exposed in utero to low‐dose vitamin E

Chen

Squire

Wells

2009

Cancer

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BACKGROUND: The limited antioxidative capacity of the fetus renders it more susceptible to reactive oxygen species (ROS), and possibly to ROS‐mediated cancer initiation or promotion in utero. METHODS: To test this hypothesis, pregnant cancer‐prone p53 knockout mice were prenatally supplemented with a low dietary dose of the antioxidant vitamin E (VE) (0.1% all‐rac‐α‐tocopherol‐acetate), and the homozygous (−/−) and heterozygous (+/‐) p53‐deficient and wild‐type (+/+) offspring were examined for VE levels, oxidative DNA damage, chromosomal stability, cellular viability and postnatal tumorigenesis. RESULTS: In utero exposure to VE reduced spontaneous postnatal tumorigenesis in p53 +/‐ offspring, and increased VE levels and reduced fetal DNA oxidation in some but not all tissues of p53‐deficient fetuses. Survival of VE‐exposed p53 +/‐ offspring at the end of the study was double that of the +/‐ controls (45% vs 23%). In primary culture of skin fibroblasts from VE‐exposed fetuses, VE did not alter chromosomal ploidy, but reduced cell death, indicating that its protective effect did not involve chromosomal stability. CONCLUSIONS: The tissue‐selective increase in fetal VE levels and reduced DNA oxidation, together with a concomitant reduction in postnatal tumorigenesis, suggest that in utero oxidative stress contributes to some postnatal cancers, and the risk can be reduced by maternal dietary supplementation with low‐dose VE. Cancer 2009. © 2009 American Cancer Society.

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Molecular and biochemical mechanisms in teratogenesis involving reactive oxygen species

Cited by 202 publications

References 32 publications

Glyceryl trinitrate metabolism in the quail embryo by the glutathione S-transferases leads to a perturbation in redox status and embryotoxicity

Glyceryl trinitrate metabolism in the quail embryo by the glutathione S-transferases leads to a perturbation in redox status and embryotoxicity

Maternal-Fetal Disposition and Metabolism of Retrorsine in Pregnant Rats

Reduced tumorigenesis in p53 knockout mice exposed in utero to low‐dose vitamin E

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