title: Nrf2 and Nrf2-related proteins in development and developmental toxicity: Insights from studies in zebrafish (Danio rerio).
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.
authors.affiliation: Biology Department, Woods Hole Oceanographic Institution, Woods Hole, Massachusetts, United States of America. Electronic address: mhahn@whoi.edu.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Hahn
authors.affiliation: Biology Department, Woods Hole Oceanographic Institution, Woods Hole, Massachusetts, United States of America; Department of Environmental Health Sciences, School of Public Health and Health Sciences, University of Massachusetts, Amherst, Massachusetts, United States of America.
authors.forename: Alicia R
authors.initials: AR
authors.lastname: Timme-Laragy
authors.affiliation: Biology Department, Woods Hole Oceanographic Institution, Woods Hole, Massachusetts, United States of America.
authors.forename: Sibel I
authors.initials: SI
authors.lastname: Karchner
authors.affiliation: Biology Department, Woods Hole Oceanographic Institution, Woods Hole, Massachusetts, United States of America.
authors.forename: John J
authors.initials: JJ
authors.lastname: Stegeman
mesh_terms: D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors / Q000378:metabolism; D004625:Embryo, Nonmammalian; D047108:Embryonic Development / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology*; D015027:Zebrafish / Q000196:embryology*; D029961:Zebrafish Proteins / Q000378:metabolism*
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; D051267:NF-E2-Related Factor 2; D029961:Zebrafish Proteins; C495638:nfe2l2a protein, zebrafish
keywords: Development; Embryo; NFE2L2; Nrf2; Oxidative stress; Zebrafish