Role of nuclear factor, erythroid 2 (Nfe2) in the oxidative stress response during development

The Williams Lab studies chemical sensitivity during development and the role of transcription factors (called the “Nrf” family) in that response.  We are particularly interested in how low levels of environmental chemicals can disrupt developmental process and lead to disease. We use the zebrafish (Danio rerio) model because they rapidly develop as transparent embryos and share upwards of 80% of their genome with humans.  The evolutionary conservation between humans and zebrafish helps facilitate the extrapolation of results in our lab to human health.

Project Summary

Sensitivity to toxicants is often enhanced during embryonic development, when exposure to low levels of chemicals can disrupt developmental processes and lead to abnormalities, disease, or death. Many chemicals elicit embryotoxic effects by perturbing the cellular redox state through the generation of reactive oxygen species (ROS). Embryo sensitivity to oxidative stress may involve lower levels of basal and inducible antioxidant defenses as compared to adults, although the mechanism is not well understood. In adult vertebrates, the response to oxidative stress is mediated through a family of CNC-bZIP transcription factors, referred to as the NRFs. Inducible by pro-oxidants, NRFs transcriptionally regulate the expression of genes whose protein products (and byproducts) quench excess ROS and mediate the detoxification of the cell. Much attention has been paid to two members of the NRF family, NRF1 and NRF2, as regulators of the response. However, recent discoveries revolving around a third member, NFE2, have identified a novel role for this protein in the response. This proposal seeks to build on these findings, using a multi-disciplinary approach, to elucidate windows of susceptibility to pro-oxidants during development and identify the role of Nfe2 in mediating the oxidative stress response. Zebrafish are an ideal model to study these interactions because of their rapid and external development as transparent embryos, the availability of extensive genomic and molecular tools, and the conservation of developmental signaling pathways with humans, which can facilitate the extrapolation of results. Through two aims, and a multidisciplinary approach, this research seeks to understand differential sensitivity of embryos to structurally diverse pro-oxidants and the molecular mechanism of action. This research will provide a novel detailed and mechanistic understanding of the role of Nfe2 in the oxidative stress response. It will determine the importance of this response during the most sensitive life stage, the embryo, and provide a better understanding of how molecular signaling can protect embryos from potentially embryotoxic events and later life consequences following toxicant exposure.

Relevance of Research

Many common environmental chemicals can pose a risk to human health and are associated with later reproductive problems, cancer, asthma, and metabolic disorders, especially if exposures occur during the prenatal and perinatal periods. Many of these problems arise due to the generation of oxidative stress. The goal of this research is to use zebrafish embryos to identify stages of early development that are susceptible to chemical exposure and determine the molecular mechanisms underlying these phenotypic outcomes.