AQP4 Attenuated TRAF6/NFκB Activation in Acrylamide-Induced Neurotoxicity.

Chia-Yu Hung,Hsin-Hui Yi,Yu-Ru Chen,Tzu-Jung Lin,Yng-Tay Chen,Nian-Zhen Tsai,Chih-Han Chang

doi:10.3390/molecules27031066

Chia-Yu Hung, Hsin-Hui Yi + Show 5 more

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https://doi.org/10.3390/molecules27031066

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Abstract

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.

Highlights

Acrylamide (ACR) is a water-soluble unsaturated amide mainly used to produce polyacrylamide for industrial purposes [1]
As the ACR-regulated genetic pathways and molecular mechanisms of depressive symptoms remain poorly understood, we investigated the roles of neurotoxicity-related genes—namely, aquaporin 4 (AQP4), MMP-9, and TNF receptor-associated factor 6 (TRAF6), in an in vivo rat model and in vitro cell models of ACR-induced neurotoxicity
Rats treated with 30 mg/kg ACR exhibited hindlimb muscle weakness, difficulty in walking, limb numbness, decreased tactile sensation, and disappearance of tendon reflexes, indicating that ACR induced neurotoxicity in the rats

Summary

Introduction

Acrylamide (ACR) is a water-soluble unsaturated amide mainly used to produce polyacrylamide for industrial purposes [1]. Among the types of ACR-induced toxicity, neurotoxicity is the earliest to present and has been studied the most thoroughly. Several studies have reported that ACR-induced oxidative stress may contribute to neurotoxicity; common symptoms exhibited by rats exposed to ACR have included hind-limb foot splay, ataxia, and skeletal muscle weakness [7]. The early symptoms exhibited by workers exposed to ACR are skin peeling on the hands, impairment of vibration sensation in the toes, weakness in the leg muscles, and numbness in the hands and legs; workers with long-term ACR exposure experience limb weakness, anorexia, truncal ataxia, and horizontal nystagmus [8]

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