The Role of Nrf2 and MAPK Pathways in PFOS-induced Oxidative Stress in Zebrafish Embryos

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 factors 2 (Nrf2) and mitogen-activated protein kinases (MAPKs) mediated oxidative stress pathways in zebrafish embryos upon exposure to PFOS. Four-hour post-fertilization (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 (SOD), catalase (CAT) and glutathione peroxidase (GPx), were significantly induced in zebrafish larvae in all PFOS-treated groups relative to the control. Exposure to 1.0 mg/L PFOS significantly increased malondialdehyde (MDA) production in zebrafish larvae. The Nrf2 and heme oxygenase-1 (HO-1) gene expressions were both significantly up-regulated 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 up-regulated, which could be linked to PFOS-induced cell apoptosis in zebrafish larvae. In addition, we found that co-exposure with sulforaphane (SFN), an Nrf2 activator, could significantly protect against PFOS-induced ROS generation, while 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.