The role of Nrf1 and Nrf2 in the regulation of glutathione and redox dynamics in the developing zebrafish embryo
Sant, Karilyn E.
Hansen, Jason M.
Williams, Larissa M.
Tran, Nancy L.
Goldstone, Jared V.
Stegeman, John J.
Hahn, Mark E.
Timme-Laragy, Alicia R.
MetadataShow full item record
Redox signaling is important for embryogenesis, guiding pathways that govern processes crucial for embryo patterning, including cell polarization, proliferation, and apoptosis. Exposure to pro-oxidants during this period can be deleterious, resulting in altered physiology, teratogenesis, later-life diseases, or lethality. We previously reported that the glutathione antioxidant defense system becomes increasingly robust, including a doubling of total glutathione and dynamic shifts in the glutathione redox potential at specific stages during embryonic development in the zebrafish, Danio rerio. However, the mechanisms underlying these changes are unclear, as is the effectiveness of the glutathione system in ameliorating oxidative insults to the embryo at different stages. Here, we examine how the glutathione system responds to the model pro-oxidants tert-butylhydroperoxide and tert-butylhydroquinone at different developmental stages, and the role of Nuclear factor erythroid 2-related factor (Nrf) proteins in regulating developmental glutathione redox status. Embryos became increasingly sensitive to pro-oxidants after 72 h post-fertilization (hpf), after which the duration of the recovery period for the glutathione redox potential was increased. To determine whether the doubling of glutathione or the dynamic changes in glutathione redox potential are mediated by zebrafish paralogs of Nrf transcription factors, morpholino oligonucleotides were used to knock down translation of Nrf1 and Nrf2 (nrf1a, nrf1b, nrf2a, nrf2b). Knockdown of Nrf1a or Nrf1b perturbed glutathione redox state until 72 hpf. Knockdown of Nrf2 paralogs also perturbed glutathione redox state but did not significantly affect the response of glutathione to pro-oxidants. Nrf1b morphants had decreased gene expression of glutathione synthesis enzymes, while hsp70 increased in Nrf2b morphants. This work demonstrates that despite having a more robust glutathione system, embryos become more sensitive to oxidative stress later in development, and that neither Nrf1 nor Nrf2 alone appear to be essential for the response and recovery of glutathione to oxidative insults.
© The Author(s), 2017. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Redox Biology 13 (2017): 207–218, doi:10.1016/j.redox.2017.05.023.
Suggested CitationArticle: Sant, Karilyn E., Hansen, Jason M., Williams, Larissa M., Tran, Nancy L., Goldstone, Jared V., Stegeman, John J., Hahn, Mark E., Timme-Laragy, Alicia R., "The role of Nrf1 and Nrf2 in the regulation of glutathione and redox dynamics in the developing zebrafish embryo", Redox Biology 13 (2017): 207–218, DOI:10.1016/j.redox.2017.05.023, https://hdl.handle.net/1912/9047
The following license files are associated with this item:
Except where otherwise noted, this item's license is described as Attribution-NonCommercial-NoDerivatives 4.0 International
Showing items related by title, author, creator and subject.
Timme-Laragy, Alicia R.; Goldstone, Jared V.; Imhoff, Barry R.; Stegeman, John J.; Hahn, Mark E.; Hansen, Jason M. (2013-06)Embryonic development involves dramatic changes in cell proliferation and differentiation that must be highly coordinated and tightly regulated. Cellular redox balance is critical for cell fate decisions, but it is susceptible ...
Timme-Laragy, Alicia R.; Van Tiem, Lindsey A.; Linney, Elwood A.; Di Giulio, Richard T. (2008-12)Early piscine life-stages are sensitive to polycyclic aromatic hydrocarbon (PAH) exposure, which can cause pericardial effusion and craniofacial malformations. We previously reported that certain combinations of PAHs ...
Thomason, Rebecca T.; Pettiglio, Michael A.; Herrera, Carolina; Kao, Clara; Gitlin, Jonathan D.; Bartnikas, Thomas B. (Public Library of Science, 2017-06-15)Trace metals are essential for health but toxic when present in excess. The maintenance of trace metals at physiologic levels reflects both import and export by cells and absorption and excretion by organs. The mechanism ...