The role of Nrf2 and MAPK pathways in PFOS-induced oxidative stress in zebrafish embryos

Toxicol Sci. 2010 Jun;115(2):391-400. doi: 10.1093/toxsci/kfq066. Epub 2010 Mar 3.


Perfluorooctane sulfonate (PFOS) is a persistent organic pollutant and causes oxidative stress, apoptosis, and developmental toxicity in zebrafish embryos. In the present study, we examined nuclear factor erythroid 2-related factor 2 (Nrf2)- and mitogen-activated protein kinases (MAPKs)-mediated oxidative stress pathways in zebrafish embryos upon exposure to PFOS. Four-hour postfertilization (hpf) zebrafish embryos were exposed to 0.2, 0.4, and 1.0 mg/l PFOS until 96 hpf. PFOS enhanced production of reactive oxygen species (ROS) in a concentration-dependent manner. Activity of antioxidative enzymes, including superoxide dismutase, catalase, and glutathione peroxidase, was significantly induced in zebrafish larvae in all PFOS-treated groups relative to the control. Exposure to 1.0 mg/l PFOS significantly increased malondialdehyde production in zebrafish larvae. The Nrf2 and heme oxygenase-1 (HO-1) gene expressions were both significantly upregulated compared with the control group. For MAPKs, we investigated gene expression profiles of extracellular signal-regulated protein kinase (ERK), c-Jun NH (2)-terminal kinase (JNK), and p38. The ERK gene expression levels were unchanged, whereas JNK and p38 gene expressions were significantly upregulated, which could be linked to PFOS-induced cell apoptosis in zebrafish larvae. In addition, we found that coexposure with sulforaphane, an Nrf2 activator, could significantly protect against PFOS-induced ROS generation, whereas inhibition of MAPKs did not exhibit significant effects on PFOS-induced HO-1 gene expression and ROS production. Furthermore, we showed that morpholino-mediated knockdown of Nrf2 reduced PFOS-induced HO-1 gene expression. These findings demonstrate that Nrf2 is protective against PFOS-induced oxidative stress in zebrafish larvae.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkanesulfonic Acids / toxicity*
  • Animals
  • Dose-Response Relationship, Drug
  • Embryo, Nonmammalian / drug effects*
  • Embryo, Nonmammalian / metabolism
  • Fluorocarbons / toxicity*
  • Gene Expression Profiling
  • Gene Expression Regulation, Developmental / drug effects
  • Heme Oxygenase-1 / genetics
  • Heme Oxygenase-1 / metabolism
  • Isothiocyanates
  • MAP Kinase Signaling System / drug effects*
  • MAP Kinase Signaling System / genetics
  • Malondialdehyde / metabolism
  • Mitogen-Activated Protein Kinases / genetics
  • Mitogen-Activated Protein Kinases / metabolism*
  • NF-E2-Related Factor 2 / antagonists & inhibitors
  • NF-E2-Related Factor 2 / genetics
  • NF-E2-Related Factor 2 / metabolism*
  • Oxidative Stress / drug effects*
  • Reactive Oxygen Species / metabolism
  • Thiocyanates / pharmacology
  • Water Pollutants, Chemical / toxicity*
  • Zebrafish
  • Zebrafish Proteins / antagonists & inhibitors
  • Zebrafish Proteins / genetics
  • Zebrafish Proteins / metabolism*


  • Alkanesulfonic Acids
  • Fluorocarbons
  • Isothiocyanates
  • NF-E2-Related Factor 2
  • Reactive Oxygen Species
  • Thiocyanates
  • Water Pollutants, Chemical
  • Zebrafish Proteins
  • nfe2l2a protein, zebrafish
  • Malondialdehyde
  • perfluorooctane sulfonic acid
  • Heme Oxygenase-1
  • Mitogen-Activated Protein Kinases
  • sulforaphane