Acrylamide (ACR), a recognized neurotoxicant in humans and experimental animals, is widely used in industry and in food generated through Maillard reaction. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a master regulator of the cellular defense system and activates
antioxidants and cytoprotective genes. The exact roles of Nrf2 in environmental electrophile-induced neurotoxicity is poorly understood. The aim of this study was to determine the roles of Nrf2 in ACR-induced neurotoxicity including degeneration of monoaminergic axons and sensorimotor dysfunction. Male 10-week-old C57BL/6JJcl Nrf2-knockout mice and wild type (WT) counterparts were each divided into four groups of 12 and provided with
drinking water containing acrylamide at 0, 67, 110 or 200 ppm for four weeks. The effects of acrylamide were examined by landing foot spread test, immunohistochemistry for
noradrenaline (NA) and
serotonin (5-HT)-containing axons and Iba1-positive microglia in the prefrontal cortex as well as quantitative real-time polymerase chain reaction (qRT-PCR) on
antioxidant, proinflammatory and anti-inflammatory genes in the prefrontal cortex. Relative to the wild type, exposure of Nrf2-knockout mice to acrylamide increased hindlimb splay length, microglial area and process length as well as decreasing the density of NA and 5-HT-immunoreactive axons to a greater extent. Moreover, deletion of Nrf2 gene suppressed acrylamide-induced
mRNA upregulation of Nrf2-antioxidants,
NAD(P):
quinone oxidoreductase 1 (NQO1),
superoxide dismutase-1 (SOD-1) and
heme oxygenase-1 (HO-1) as well as anti-inflammatory markers such as, arginase-1 (Arg1), found in the inflammatory zone-1 (Fizz1),
chitinase-like 3 (Chi3l3),
interleukin-4 receptor alpha (IL-4Rα), cluster of differentiation 206 (CD206) and
transforming growth factor beta-1 (TGFβ1) while enhancing acrylamide-induced upregulation of pro-inflammatory
cytokines,
interleukin-1 beta (IL-1β),
tumor necrosis-alpha (TNF-α) and
inducible nitric oxide synthase (iNOS) in the prefrontal cortex. The results demonstrate susceptibility of mice lacking the Nrf2 gene to acrylamide-induced neurotoxicity and
neuroinflammation with the activation of microglia. Moreover, the results suggest the role of Nrf2 not only in induction of
antioxidant gene expression, but also in suppression of proinflammatory
cytokine gene expression.