Abstract
Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that is important in protection against oxidative stress. This study was designed to determine the role of Nrf2 signaling in transcriptional activation of detoxifying and antioxidant genes in an in vivo mouse fetal alcohol syndrome model. Maternal ethanol treatment was found to increase both Nrf2 protein levels and Nrf2-ARE binding in mouse embryos. It also resulted in a moderate increase in the mRNA expression of Nrf2 downstream target detoxifying and antioxidant genes as well as an increase in the expression of antioxidant proteins. Pretreatment with the Nrf2 inducer, 3H-1,2 dithiole-3-thione (D3T), significantly increased Nrf2 protein levels and Nrf2-ARE binding, and strongly induced the mRNA expression of Nrf2 downstream target genes. It also increased the expression of antioxidant proteins and the activities of the antioxidant enzymes. Additionally, D3T pretreatment resulted in a significant decrease in ethanol-induced reactive oxygen species generation and apoptosis in mouse embryos. These results demonstrate that Nrf2 signaling is involved in the induction of antioxidant response in ethanol-exposed embryos. In addition, the potency of D3T in inducing antioxidants as well as in diminishing ethanol-induced apoptosis suggests that further exploration of the antiteratogenic effect of this compound will be fruitful.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Apoptosis / drug effects
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Blotting, Western
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Caspase 3 / genetics
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Caspase 3 / metabolism
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Catalase / genetics
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Catalase / metabolism
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Embryo, Mammalian / drug effects*
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Embryo, Mammalian / metabolism
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Ethanol / administration & dosage
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Ethanol / pharmacology*
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Female
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Fetal Alcohol Spectrum Disorders / etiology
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Fetal Alcohol Spectrum Disorders / prevention & control
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Gene Expression Regulation, Developmental / drug effects*
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Glutathione Peroxidase / genetics
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Glutathione Peroxidase / metabolism
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Glutathione Reductase / genetics
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Glutathione Reductase / metabolism
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Glutathione Transferase / genetics
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Glutathione Transferase / metabolism
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Mice
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Mice, Inbred C57BL
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NAD(P)H Dehydrogenase (Quinone)
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NADPH Dehydrogenase / genetics
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NADPH Dehydrogenase / metabolism
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NF-E2-Related Factor 2 / genetics
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NF-E2-Related Factor 2 / metabolism
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NF-E2-Related Factor 2 / physiology*
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Oxidative Stress / drug effects
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Pregnancy
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Reactive Oxygen Species / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Superoxide Dismutase / genetics
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Superoxide Dismutase / metabolism
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Thiones / administration & dosage
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Thiones / pharmacology
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Thiophenes / administration & dosage
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Thiophenes / pharmacology
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Thioredoxins / genetics
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Thioredoxins / metabolism
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Up-Regulation / drug effects
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Up-Regulation / genetics
Substances
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NF-E2-Related Factor 2
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Nfe2l2 protein, mouse
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Reactive Oxygen Species
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Thiones
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Thiophenes
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Ethanol
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Thioredoxins
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Catalase
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Glutathione Peroxidase
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Superoxide Dismutase
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NAD(P)H Dehydrogenase (Quinone)
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Nqo1 protein, mouse
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NADPH Dehydrogenase
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Glutathione Reductase
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Glutathione Transferase
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Casp3 protein, mouse
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Caspase 3
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1,2-dithiol-3-thione