Nrf2 and Nrf2-related proteins in development and developmental toxicity: Insights from studies in zebrafish (Danio rerio)

doi:10.1016/j.freeradbiomed.2015.06.022

Free Radical Biology and Medicine

Volume 88, Part B, November 2015, Pages 275-289

https://doi.org/10.1016/j.freeradbiomed.2015.06.022 Get rights and content

Highlights

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The zebrafish is a valuable model for studying developmental roles of Nrf proteins.
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Zebrafish and mammals share a core set of oxidative stress response genes.
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Zebrafish and mammals share four types of NRF family transcription factors.
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Zebrafish nrf gene duplicates can help elucidate pleotropic roles of Nrf proteins.
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Loss-of-function approaches can reveal Nrf target genes in embryos.

Abstract

Oxidative stress is an important mechanism of chemical toxicity, contributing to developmental toxicity and teratogenesis as well as to cardiovascular and neurodegenerative diseases and diabetic embryopathy. Developing animals are especially sensitive to effects of chemicals that disrupt the balance of processes generating reactive species and oxidative stress, and those anti-oxidant defenses that protect against oxidative stress. The expression and inducibility of anti-oxidant defenses through activation of NFE2-related factor 2 (Nrf2) and related proteins is an essential process affecting the susceptibility to oxidants, but the complex interactions of Nrf2 in determining embryonic response to oxidants and oxidative stress are only beginning to be understood. The zebrafish (Danio rerio) is an established model in developmental biology and now also in developmental toxicology and redox signaling. Here we review the regulation of genes involved in protection against oxidative stress in developing vertebrates, with a focus on Nrf2 and related cap′n′collar (CNC)-basic-leucine zipper (bZIP) transcription factors. Vertebrate animals including zebrafish share Nfe2, Nrf1, Nrf2, and Nrf3 as well as a core set of genes that respond to oxidative stress, contributing to the value of zebrafish as a model system with which to investigate the mechanisms involved in regulation of redox signaling and the response to oxidative stress during embryolarval development. Moreover, studies in zebrafish have revealed nrf and keap1 gene duplications that provide an opportunity to dissect multiple functions of vertebrate NRF genes, including multiple sensing mechanisms involved in chemical-specific effects.

Introduction

Oxidative stress occurs when the cellular redox balance is altered, disrupting redox signaling and regulation [1], [2], [3]. It can occur through the generation and action of reactive species such as superoxide anion, hydrogen peroxide, peroxynitrite, and other reactive products that can alter thiol redox circuits [4], [5], [6]. Oxidative stress is increasingly recognized as a significant mechanism of chemical toxicity and as a contributing factor in a wide range of pathological conditions and diseases in adults, and in developing animals. The roles of reactive species and redox status in normal physiology, and the mechanisms underlying adverse effects of oxidative stress, have been studied extensively in adult animals and cells. However, less is known about the role of these processes in developmental disorders and chemical toxicity during embryonic and fetal development.

Developing animals are uniquely sensitive to oxidative stress because of the rapid changes in cell proliferation and differentiation that occur at this time, and because enzymatic systems that protect against or repair toxic damage may not be fully mature early in development. The expression and inducibility of anti-oxidant defenses are critical factors affecting susceptibility to oxidative stress, but the ontogenic development of antioxidant defenses and their regulation at early life stages are only beginning to be understood. The zebrafish (Danio rerio), an established model in developmental biology, has emerged recently as a valuable system for studying the expression and regulation of antioxidant defenses during development, and in particular the role of Nfe2-related transcription factors. Here we provide a review of the development and regulation of genes involved in protection against oxidative stress, with a focus on insights obtained from studies in zebrafish early life stages (embryos and larvae). For an additional perspective on the use of zebrafish as a model to study oxidative mechanisms, please see a recent review [7].

Section snippets

Importance of redox status and oxidant signaling during development

Embryonic development involves precisely orchestrated processes--including proliferation, differentiation, apoptosis, establishment of left-right asymmetry, gene expression, and epigenetic modifications--that increasingly are found to depend on redox signaling and intracellular redox potentials (E_h) [8], [9], [10], [11], [12], [13], [14], [15], [16]. Because endogenous oxidants and cellular redox potential play such important and fundamental roles in normal embryonic development, tight

Zebrafish as a model for studying developmental roles of Nrf2 and related proteins

The zebrafish has emerged as a powerful system in which to examine mechanisms involved in the regulation of the oxidative stress response by Nrf2 and related proteins in developing animals. The zebrafish embryo is an important vertebrate model (or “tool” [142]) in embryology and developmental biology [143], [144], [145], [146], [147], [148], [149], [150], [151], [152], [153]. Because zebrafish are vertebrates, results obtained in this system have more direct relevance for humans as compared to

Diversity of CNC-bZip transcription factors and related genes in zebrafish

Studies over the past 15 years have begun to establish the molecular mechanisms underlying the regulation of the oxidative stress response in fish and their similarity to those in mammals. Early studies [225], [226] demonstrated that reporter gene constructs containing a luciferase gene under control of mammalian ARE sequences, when transfected into fish cells, could be induced by exposure to tert-butylhydroquinone (tBHQ), suggesting that fish oxidant-responsive transcription factors are able

Ontogeny of glutathione redox dynamics and constitutive antioxidant defenses in developing embryos

In addition to the oxidative stress response and developmental events regulated by the Nrf- family of transcription factors, other endogenous antioxidant defenses play important roles in embryonic development. Glutathione (GSH) is the most abundant cellular antioxidant, present in mM concentrations, and is required for successful embryonic development [254], [255]. Importantly, numerous studies have demonstrated a strong relationship between concentrations and nuclear localization of GSH and

Developmental expression of Nfe2-related genes and inducible antioxidant defenses

The constitutive expression of genes involved in antioxidant defense may help to ensure that redox conditions are appropriate for normal embryonic development, and may provide some immediate protection against challenges posed by exposure to chemicals or other stressors. In addition, embryos possess the ability to up-regulate antioxidant defenses in response to challenges, but how these inducible responses vary by cell type and developmental stage and how they are regulated during development

Loss-of-function approaches to define the roles of Nrf proteins

Measurements of gene expression—whether of nrf genes themselves or their putative target genes—provide intriguing associations but do not reveal regulatory relationships or mechanisms. In contrast, loss-of-function experiments in which the expression or function of a protein is reduced or eliminated can provide valuable mechanistic information about the role of that protein. The primary approach used so far to elucidate the functional roles of Nrf proteins in zebrafish embryos has been

Conclusions and Future Directions

Regulation of constitutive and inducible defenses against oxidative stress by Nfe2-related factors is an evolutionarily conserved feature of animals. Conservation is especially evident among vertebrate animals, which share Nfe2, Nrf1, Nrf2, and Nrf3, as well as a core set of genes that respond to oxidative stress [227], [234], [237]. This conservation contributes to the value of zebrafish as a model system with which to investigate the mechanisms involved in regulation of redox signaling and

Acknowledgments

We thank Dr. Makoto Kobayashi (University of Tsukuba, Japan) for his generosity in providing plasmids and information, and for his groundbreaking work to establish the zebrafish embryo model for studying the oxidative stress response. We thank Dr. Elwood Linney (Duke University) for inspiration and many helpful discussions on the use of the zebrafish model. This work was supported in part by National Institutes of Health grants R01ES016366 (MEH), R01ES015912 (JJS), and F32ES017585 (ART-L). The

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Nrf2 and Nrf2-related proteins in development and developmental toxicity: Insights from studies in zebrafish (Danio rerio)

Highlights

Abstract

Introduction

Section snippets

Importance of redox status and oxidant signaling during development

Zebrafish as a model for studying developmental roles of Nrf2 and related proteins

Diversity of CNC-bZip transcription factors and related genes in zebrafish

Ontogeny of glutathione redox dynamics and constitutive antioxidant defenses in developing embryos

Developmental expression of Nfe2-related genes and inducible antioxidant defenses

Loss-of-function approaches to define the roles of Nrf proteins

Conclusions and Future Directions

Acknowledgments

Redox biology

Free radical biology & medicine

Developmental biology

Developmental biology

Free radical biology & medicine

Developmental biology

Developmental biology

Free radical biology & medicine

Toxicol Appl Pharmacol

Mutation research

Reproductive toxicology (Elmsford, N.Y

Reproductive toxicology (Elmsford, N.Y

Mutation research

Toxicol Appl Pharmacol

Neurotoxicology and teratology

Toxicol Appl Pharmacol

Neuroscience letters

Free radical biology & medicine

Neurotoxicology and teratology

Toxicol Appl Pharmacol

Arch Biochem Biophys

Reproductive toxicology

Free radical biology & medicine

The Journal of biological chemistry

The Journal of biological chemistry

The Journal of biological chemistry

The Journal of biological chemistry

The Journal of biological chemistry

The Journal of biological chemistry

Trends in biochemical sciences

Developmental cell

The Journal of biological chemistry

Oxygen toxicity: a radical explanation

The Journal of experimental biology

Oxidation of biological systems: oxidative stress phenomena, antioxidants, redox reactions, and methods for their quantification

Toxicologic pathology

Nuclear and mitochondrial compartmentation of oxidative stress and redox signaling

Annual review of pharmacology and toxicology

Redefining oxidative stress

Antioxidants & redox signaling

Radical-free biology of oxidative stress

American journal of physiology. Cell physiology

Redox control in mammalian embryo development

Antioxidants & redox signaling

The Roles of Glutathione Peroxidases during Embryo Development

. Frontiers in molecular neuroscience

Role of redox in fetal development and neonatal diseases

Antioxidants & redox signaling

Effects of oxidative stress on embryonic development

Birth Defects Res C Embryo Today

Oxidative stress in developmental origins of disease: teratogenesis, neurodevelopmental deficits, and cancer

Toxicol Sci

Oxidative DNA damage: mechanisms, mutation, and disease

Faseb J

Academy of Sciences

Genetic ablation of Nrf2 enhances susceptibility to cigarette smoke-induced emphysema in mice

The Journal of clinical investigation

Oxidative stress in neurodegeneration: cause or consequence?

Nature medicine

Molecular pathways to neurodegeneration

Nature medicine

Oxidative stress as a mechanism of teratogenesis

Birth Defects Res C Embryo Today

Radiation effects on development

Birth Defects Res C Embryo Today

Maternal smoking, genetic variation of glutathione s-transferases, and risk for orofacial clefts

Epidemiology