Maneb causes pro-oxidant effects in the hippocampus of Nrf2 knockout mice

•Treatment with maneb causes a decrease in antioxidant enzymes in Nrf2 KO animals.•Treatment with maneb causes an upregulation of GPX4 in WT animals.•Treatment with maneb causes a downregulation of GPX4 in KO animals.•Treatment with maneb leads to an accumulation of Mn in hippocampi of KO animals.

The effects of maneb were investigated in C57BL/6 Nrf2 wildtype and knockout mice. Treated KO mice showed significant weight loss as compared to WT counterparts. ICPAAS analysis demonstrated a significant increase in manganese concentration in the tissues of treated KO mice as compared to WT. Biochemical analysis revealed significant decreases of antioxidants including glutathione, glutathione reductase and heme oxygenase-1. Levels of TBARS were significantly increased in hippocampal tissue in Nrf2 KO mice at the 30 and 60 mg doses. qPCR demonstrated that the only gene mediated by the Nrf2 transcription pathway that was significantly modulated by at least 1.5 fold was glutathione peroxidase 4. GPX4 was significantly upregulated in Nrf2 WT mice treated with 30 mg/kg maneb and significantly downregulated in Nrf2 KO mice treated with the same dose. Microscopy revealed neuronal pyknosis and eosinophilia of the cytoplasm in the hippocampi of both WT and KO animals treated with 60 mg/kg maneb.