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.

Keywords: Development; Embryo; NFE2L2; Nrf2; Oxidative stress; Zebrafish.

Fig. 1. Comparative genomics of NFE2-related genes in zebrafish

Location and shared synteny involving NFE2-related genes and HOX genes in the human genome (top) and zebrafish genome (bottom). This research was originally published in The Journal of Biological Chemistry. Timme-Laragy et al., Nrf2b, Novel Zebrafish Paralog of Oxidant-responsive Transcription Factor NF-E2-related Factor 2 (NRF2). The Journal of Biological Chemistry. 2012; Vol. 287: 4609-4627. [234] © the American Society for Biochemistry and Molecular Biology.

Fig. 2. Concentrations of GSH_T and E_h during the first 120 hours of zebrafish development

Four “windows” of dynamic glutathione conditions during embryonic development are observed. A) reduced E_h and low GSH_T, observed in mature oocytes; B) oxidized E_h and low GSH_T, observed in embryos from the mid-blastula transition through somitogenesis (3-24 hpf); C) oxidized E_h and high GSH_T, observed in embryos undergoing organ differentiation (30-48 hpf), and D) reduced E_h and high GSH_T, observed in post-hatch eleutheroembryos. Reproduced, with permission, from Timme-Laragy et al. [263].