Acrylamide-induced neurotoxicity in primary astrocytes and microglia: Roles of the Nrf2-ARE and NF-κB pathways

- AA induced oxidative stress in astrocytes and microglia.
- Oxidative damage via Nrf2 and NF-κB pathways contributed to its neurotoxicity.
- Microglia were more sensitive to AA-induced toxicity than astrocytes.

Acrylamide (AA) is a common food contaminant formed during food heat processing that has neurotoxic effects. We hypothesize that AA induces oxidative stress in astrocytes and microglia, leading to neurotoxicity. Oxidative status, translocation of Nrf2 and NF-κB, and related down-stream targets were measured in primary astrocytes and microglia obtained from BALB/c mice. The results showed that AA increased reactive oxygen species (ROS) formation and reduced glutathione levels, causing successive events associated with oxidative stress, including 4-hydroxynonenal and 8-hydroxy-2-deoxyguanosine adduct formation, in both cell types. Both Nrf2 and NF-κB pathways were activated, but Nrf2 and its downstream antioxidative genes acted at earlier stages in both cell types before NF-κB activation. After NF-κB activation, related cytokines, including IL-6, TNF-α, G-CSF, and IL-1β, were released and cell viability decreased. Greater ROS generation, faster glutathione reduction, and increased oxidative adduct formation were observed in microglia compared with astrocytes. Moreover, Nrf2/NF-κB and its downstream genes were up-regulated much faster and to greater degrees in microglia than astrocytes. These results clarify the roles of the Nrf2 and NF-κB pathways in AA-induced neurotoxicity. These cellular responses may provide new insights for the development of adverse outcome pathway approaches for risk assessments of AA.

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