The transcription factor, Nuclear factor, erythroid 2 (Nfe2), is a regulator of the oxidative stress response during Danio rerio development

Williams, Larissa M.; Lago, Briony A.; McArthur, Andrew G.; Raphenya, Amogelang R.; Pray, Nicholas; Saleem, Nabil; Salas, Sophia; Paulson, Katherine; Mangar, Roshni S.; Liu, Yang; Vo, Andy H.; Shavit, Jordan A.

doi:10.1016/j.aquatox.2016.09.019

Cited by 15 publications

(16 citation statements)

References 122 publications

(153 reference statements)

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“…As shown in the study by Zhang et al of erythroblast-specific FPN1 KO mice, the labile iron pool in erythroblasts is increased, leading to increased hemolysis ( 47 ). This observation illustrates the degradation of heme in hemoglobin to ferrous iron in erythroblasts and even in erythrocytes ( 48 ).…”

Section: Revisiting the Roles Of Nf-e2p45 And Nrf2 In Rbcsmentioning

confidence: 64%

“…NF-E2 KO zebrafish exhibit hypochromia in an early developmental stage (i.e., less hemoglobin staining is observed in the embryo) compared to wild-type animals, and a total loss of hemoglobin was observed in response to tert -butylhydroperoxide and diquat exposure, while wild-type fish shows only mild hypochromia. The authors argued that hypochromia in NF-E2 KO embryos may be related to decreased ALAS2 expression ( 48 ).…”

Section: Revisiting the Roles Of Nf-e2p45 And Nrf2 In Rbcsmentioning

confidence: 99%

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Emerging Regulatory Role of Nrf2 in Iron, Heme, and Hemoglobin Metabolism in Physiology and Disease

et al. 2018

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Iron has played an important role in energy production since the beginning of life, as iron-catalyzed redox reactions are required for energy production. Oxygen, a highly efficient electron acceptor with high reduction potential, facilitates highly efficient energy production in eukaryotic cells. However, the increasing atmospheric oxygen concentration produces new threats to the organism, as oxygen reacts with iron and produces reactive oxygen species unless its levels are strictly regulated. As the size of multicellular organisms increases, these organisms must transport oxygen to the peripheral tissues and begin to employ red blood cells containing hemoglobin. This system is potentially a double-edged sword, as hemoglobin autoxidation occurs at a certain speed and releases free iron into the cytoplasm. Nrf2 belongs to the CNC transcription factor family, in which NF-E2p45 is the founding member. NF-E2p45 was first identified as a transcription factor that binds to the erythroid gene regulatory element NF-E2 located in the promoter region of the heme biosynthetic porphobilinogen deaminase gene. Human Nrf2 was also identified as a transcription factor that binds to the regulatory region of the β-globin gene. Despite these original findings, NF-E2p45 and Nrf2 knockout mice exhibit few erythroid phenotypes. Nrf2 regulates the expression of a wide range of antioxidant and detoxification enzymes. In this review article, we describe and discuss the roles of Nrf2 in various iron-mediated bioreactions and its possible coevolution with iron and oxygen.

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Section: Revisiting the Roles Of Nf-e2p45 And Nrf2 In Rbcsmentioning

confidence: 64%

Section: Revisiting the Roles Of Nf-e2p45 And Nrf2 In Rbcsmentioning

confidence: 99%

Emerging Regulatory Role of Nrf2 in Iron, Heme, and Hemoglobin Metabolism in Physiology and Disease

et al. 2018

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“…LiCl treatment alone has been shown to cause both decreased heart rate and inhibition of motility in zebrafish embryos, 24,42 which coupled with transcriptional analysis demonstrate an important role of Wnt signaling in these physiological processes. 38 We provide preliminary evidence for DD's interference with both canonical and noncanonical Wnt signaling pathways which may be partially or completely remediated by treatment with LiCl. The observed effects on development, motility, and heart rate may be caused by DD directly inhibiting the protein Disheveled (dsh) which activates downstream G-proteins following the binding of Wnt ligands to the Frizzled receptor (Fz), which is known to coordinate all three known Wnt pathways: canonical or Wnt/-catenin, Wnt/Ca 2þ , and Wnt/PCP pathways.…”

Section: Dd and Wnt Signalingmentioning

confidence: 83%

Cellular effects of diquat dibromide exposure: Interference with Wnt signaling and cytoskeletal development

Jalil

Reddy

Plautz

2019

Toxicology Research and Application

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The herbicidal action of diquat dibromide (DD) on plant cells is due primarily to the initiation of reactive oxygen species (ROS) formation, lipoperoxidation, and apoptotic cell death. It has been demonstrated that oxidative stress also occurs in animal cells exposed to high concentrations of DD; however, observations of DD’s effects on animal cells at concentrations below the reported ROS-initiation threshold suggest that some of these effects may not be attributable to ROS-induced cell death. Our results suggest that DD causes disruption of the Wnt pathway, calcium dysregulation, and cytoskeletal damage during development. Using embryos of the pond snail Lymnaea palustris as our model organism, we observed increased mortality, developmental delay and abnormality, altered motility, calcium dysregulation, decreased heart rate, and arrhythmia in embryos exposed to DD. Sperm extracted from adult snails that were exposed to DD exhibit altered motility, increased abundance, and high mortality. Effects were quantified via real-time imaging, heart rate assessment, flow cytometry, and mortality scoring. We propose that there are two models for the mechanism of DD’s action in animal cells: at low concentrations (≤28 µg/L), apoptotic cell death does not occur, but cytoskeletal elements, calcium regulation, and Wnt signaling are compromised, causing irreversible damage in L. palustris embryos; such damage is partially remediated with antioxidants or lithium chloride. At high concentrations of DD (≥44.4 µg/L), calcium dysregulation may be triggered, leading to the establishment of an intracellular positive feedback loop of ROS formation in the mitochondria, calcium release from the endoplasmic reticulum, calcium efflux, and apoptotic cell death. Permanent cellular damage occurring from exposure to sublethal concentrations of this widespread herbicide underscores the importance of research that elucidates the mechanism of DD on nontarget organisms.

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“…The transcription factor Nfe2 (nfe2), like Nrf2, is a member of the CNC b-ZIP transcription factor family and also mediates the antioxidant response in the embryo. 50,51 Enzymes cytochrome P450 2E1 (cyp2e1) and histone deacetylase (hdac) are involved in a myriad of cellular processes including chromatin structure and the hepatic xenobiotic response, and both enzymes have been shown to have interactions with Nrf2 signaling. 52 Gene expression of gstp was significantly attenuated by approximately 60% in Nrf2a mutant larvae, regardless of exposure (p < 0.05).…”

Section: Gene Expressionantioxidant Response and Nrf2 Interactionmentioning

confidence: 99%

Embryonic exposures to mono-2-ethylhexyl phthalate induce larval steatosis in zebrafish independent of Nrf2a signaling

Sant

Moreau

Williams

et al. 2020

J Dev Orig Health Dis

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Mono-2-ethylhexyl phthalate (MEHP) is the primary metabolite of the ubiquitous plasticizer and toxicant, di-2-ethylhexyl phthalate. MEHP exposure has been linked to abnormal development, increased oxidative stress, and metabolic syndrome in vertebrates. Nuclear factor, Erythroid 2 Like 2 (Nrf2), is a transcription factor that regulates gene expression in response to oxidative stress. We investigated the role of Nrf2a in larval steatosis following embryonic exposure to MEHP. Wild-type and nrf2a mutant (m) zebrafish embryos were exposed to 0 or 200 μg/l MEHP from 6 to either 96 (histology) or 120 hours post fertilization (hpf). At 120 hpf, exposures were ceased and fish were maintained in clean conditions until 15 days post fertilization (dpf). At 15 dpf, fish lengths and lipid content were examined, and the expression of genes involved in the antioxidant response and lipid processing was quantified. At 96 hpf, a subset of animals treated with MEHP had vacuolization in the liver. At 15 dpf, deficient Nrf2a signaling attenuated fish length by 7.7%. MEHP exposure increased hepatic steatosis and increased expression of peroxisome proliferator-activated receptor alpha target fabp1a1. Cumulatively, these data indicate that developmental exposure alone to MEHP may increase risk for hepatic steatosis and that Nrf2a does not play a major role in this phenotype.

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The transcription factor, Nuclear factor, erythroid 2 (Nfe2), is a regulator of the oxidative stress response during Danio rerio development

Cited by 15 publications

References 122 publications

Emerging Regulatory Role of Nrf2 in Iron, Heme, and Hemoglobin Metabolism in Physiology and Disease

Emerging Regulatory Role of Nrf2 in Iron, Heme, and Hemoglobin Metabolism in Physiology and Disease

Cellular effects of diquat dibromide exposure: Interference with Wnt signaling and cytoskeletal development

Embryonic exposures to mono-2-ethylhexyl phthalate induce larval steatosis in zebrafish independent of Nrf2a signaling

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