Acrylamide (ACR) is present in high-temperature-processed high-carbohydrate foods, cigarette smoke, and industrial pollution. Chronic exposure to ACR may induce neurotoxicity from reactive oxygen species (ROS); however, the mechanisms underlying ACR-induced neurotoxicity remain unclear. We studied 28-day subacute ACR toxicity by repeatedly feeding ACR (0, 15, or 30 mg/kg) to rats. We conducted RNA sequencing and Western blot analyses to identify differences in mRNA expression in the blood and in protein expression in the brain tissues, respectively, of the rats. AQP4 transient transfection was performed to identify potential associations with protein regulation. The rats treated with 30 mg/kg ACR exhibited hind-limb muscle weakness. Matrix metalloproteinase (MMP9) expression was higher in the ACR-treated group than in the control group. ACR induced MMP-9 and AQP4 protein expression in the brain tissues of the rats, which subsequently presented with neurotoxicity. In the in vitro study, Neuro-2a cells were transiently transfected with AQP4, which inhibited MMP-9 and TNF receptor-associated factor 6 (TRAF6) expression, and inhibited ACR induced expression of TRAF6, IκBα, and nuclear factor κB (NFκB). Using a combination of in vivo and in vitro experiments, this study revealed that depressive symptoms associated with ACR-induced neurotoxicity are associated with downregulation of AQP4 and induction of the TRAF6 pathway.
Keywords: AQP4; MMP-9; TRAF6; acrylamide; depression; neurotoxicity.