title: Nrf2-mediated resistance to oxidant-induced redox disruption in embryos.
abstract: Events that control developmental changes occur during specific windows of gestation and if disrupted, can lead to dysmorphogenesis or embryolethality. One largely understudied aspect of developmental control is redox regulation, where the untimely disruption of intracellular redox potentials (E(h) ) may alter development, suggesting that tight control of developmental-stage-specific redox states is necessary to support normal development. In this study, mouse gestational day 8.5 embryos in whole embryo culture were treated with 10 μM dithiole-3-thione (D3T), an inducer of nuclear factor (erythroid-derived 2)-like 2 (Nrf2). After 14 hr, D3T-treated and -untreated conceptuses were challenged with 200 μM hydrogen peroxide (H₂O₂) to induce oxidant-induced change to intracellular E(h) s. Redox potentials of glutathione (GSH), thioredoxin-1 (Trx1), and mitochondrial thioredoxin-2 (Trx2) were then measured over a 2-hr rebounding period following H₂O₂ treatment. D3T treatment increased embryonic expression of known Nrf2-regulated genes, including those responsible for redox regulation of major intracellular redox couples. Exposure to H₂O₂ without prior D3T treatment produced significant oxidation of GSH, Trx1, and Trx2, based on E(h) values, where GSH and Trx2 E(h) recovered, reaching to pre-H₂O₂ E(h) ranges, but Trx1 E(h) remained oxidized. Following H₂O₂ addition in culture to embryos that received D3T pretreatments, GSH, Trx1, and Trx2 were insulated from significant oxidation. These data show that Nrf2 activation may serve as a means to protect the embryo from chemically induced oxidative stress through the preservation of intracellular redox states during development, allowing normal morphogenesis to ensue.
authors.affiliation: Developmental Toxicology Laboratory, Department of Environmental Health Sciences, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Craig
authors.initials: C
authors.lastname: Harris
authors.forename: Jason M
authors.initials: JM
authors.lastname: Hansen
mesh_terms: D000818:Animals; D004622:Embryo, Mammalian / Q000187:drug effects* / Q000378:metabolism*; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000633:toxicity; D051379:Mice; D008813:Mice, Inbred ICR; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D016877:Oxidants / Q000633:toxicity*; D010084:Oxidation-Reduction / Q000187:drug effects; D013871:Thiones / Q000633:toxicity; D013876:Thiophenes / Q000633:toxicity; D013879:Thioredoxins / Q000378:metabolism
chemical_list: D051267:NF-E2-Related Factor 2; D016877:Oxidants; D013871:Thiones; D013876:Thiophenes; D013879:Thioredoxins; D006861:Hydrogen Peroxide; D005978:Glutathione; C049325:1,2-dithiol-3-thione