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

Area of Science:

• Neurotoxicology
• Environmental Health
• Biochemistry

Background:

• Nrf2 (nuclear factor erythroid 2-related factor 2) is a key regulator of antioxidant responses.
• Maneb, a widely used fungicide, has potential neurotoxic effects.
• Understanding the role of Nrf2 in maneb toxicity is crucial for assessing health risks.

Purpose of the Study:

• To investigate the neurotoxic effects of maneb in Nrf2 wildtype (WT) and knockout (KO) mice.
• To elucidate the role of the Nrf2 pathway in mediating maneb-induced toxicity.
• To assess biochemical and histological changes following maneb exposure.

Main Methods:

• C57BL/6 Nrf2 WT and KO mice were treated with maneb.
• Body weight, tissue manganese concentration (ICPAAS), antioxidant levels, and TBARS (thiobarbituric acid reactive substances) were measured.
• Gene expression of Nrf2-mediated genes (qPCR) and neuronal morphology (microscopy) were analyzed.

Main Results:

• Maneb-treated KO mice exhibited significant weight loss and increased tissue manganese compared to WT mice.
• Antioxidant levels (glutathione, glutathione reductase, heme oxygenase-1) were decreased, and TBARS levels were increased in KO mice.
• Glutathione peroxidase 4 (GPX4) was the only significantly modulated Nrf2-dependent gene, showing differential regulation in WT and KO mice.
• Microscopy revealed neuronal damage (pyknosis, cytoplasmic eosinophilia) in the hippocampi of both WT and KO mice at higher maneb doses.

Conclusions:

• Nrf2 deficiency exacerbates maneb-induced toxicity, including weight loss, oxidative stress, and neurotoxicity.
• Maneb exposure disrupts antioxidant defenses and causes neuronal damage, with a significant role for the Nrf2 pathway.
• These findings highlight the neuroprotective role of Nrf2 against maneb toxicity and inform risk assessment for pesticide exposure.