Mechanisms of embryo response to oxidative stress
Oxidative stress resulting from environmental exposures is associated with a variety of human diseases ranging from chemical teratogenesis to cardiovascular and neurodegenerative diseases. Developing animals appear to be especially sensitive to chemicals causing oxidative stress. The expression and inducibility of antioxidant defenses are critical factors affecting susceptibility to oxidants at these early life stages, but the ontogenic development of these responses in embryos is not well understood.
In adult animals, oxidants initiate an anti-oxidant response by activating NF-E2-related factor 2 (NRF2) and related proteins, which bind to the anti-oxidant response element and activate transcription of genes such as glutathione S-transferases, NAD(P)H-quinone oxidoreductase, glutamyl-cysteine ligase, and superoxide dismutase. The overall objective of the research proposed here is to elucidate the mechanisms by which vertebrate embryos respond to oxidative stress during development. These studies are being performed in vivo using embryos of the zebrafish (Danio rerio), a valuable model in which to examine mechanisms of toxicity in developing animals and to screen chemicals for developmental toxicity. The results of these studies will establish the composition and ontogeny of the transcriptional response to oxidative stress in vertebrate embryos, elucidate fundamental mechanisms underlying this response, generate tools for screening chemicals for activity as developmental toxicants or antioxidants, and provide insight into the role of oxidative stress in human disease.
Hahn, M.E., Timme-Laragy, A.R., Karchner, S.I., Stegeman, J.J. (2015) Nrf2 and Nrf2-Related Proteins in Development and Developmental Toxicity: Insights from studies in Zebrafish (Danio rerio). Free Radical Biology & Medicine 88:275-289. PMCID: PMC4698826.
Timme-Laragy, A. R., Karchner, S. I., Franks, D. G., Jenny, M. J., Harbeitner, R. C., Goldstone, J. V., McArthur, A. G., and Hahn, M. E.(2012). Nrf2b: a novel zebrafish paralog of the oxidant-responsive transcription factor NF-E2-related factor 2 (Nrf2). J. Biol. Chem. 287, 4609-4627.
This research has been supported by the National Institute of Environmental Health Sciences.
The research has been performed in collaboration with Dr. Alicia Timme-Laragy (UMASS Amherst).