Genetic ablation of Nrf2 exacerbates neurotoxic effects of acrylamide in mice
Genetic ablation of Nrf2 exacerbates neurotoxic effects of acrylamide in mice
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DOI：
10.1016/j.tox.2021.152785
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发表时间：
2021-04-20
期刊：
影响因子：
4.5
通讯作者：
Ichihara, Gaku
中科院分区：
文献类型：
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作者：
Ekuban, Frederick Adams;Zong, Cai;Ichihara, Gaku
丙烯酰胺（Acrylamide， ACR）是一种公认的人类和实验动物神经毒物，被广泛应用于工业和食品中，通过美拉德反应产生。核因子红细胞2相关因子2 （Nrf2）是细胞防御系统的主要调控因子，激活抗氧化剂和细胞保护基因。Nrf2在环境亲电诱导的神经毒性中的确切作用尚不清楚。本研究的目的是确定Nrf2在acr诱导的神经毒性中的作用，包括单胺能轴突变性和感觉运动功能障碍。将10周龄雄性C57BL/6JJcl nrf2敲除小鼠和野生型（WT）小鼠分为4组，每组12只，连续4周给予丙烯酰胺含量为0、67、110和200 ppm的饮用水。通过足部扩散试验、免疫组化检测去甲肾上腺素（NA）、血清素（5-HT）轴突和iba1阳性小胶质细胞，以及实时定量聚合酶链反应（qRT-PCR）检测丙烯酰胺对大鼠前额皮质抗氧化、促炎和抗炎基因的影响。与野生型相比，丙烯酰胺对nrf2基因敲除小鼠后肢展长、小胶质细胞面积和过程长度增加，NA和5- ht免疫反应轴突密度降低程度更大。此外，Nrf2基因的缺失抑制丙烯酰胺诱导的Nrf2抗氧化剂NAD的mRNA上调(P)：醌氧化还原酶1 （NQO1）、超氧化物歧化酶1 （SOD-1）和血红素加氧酶1 (HO-1)，以及炎性区1 （Fizz1）、几丁质酶样3 （Chi3l3）、白细胞介素4受体α (IL-4R α)、分化簇206 （CD206）和转化生长因子β -1 （TGF β 1）中存在的精氨酸酶1 （Arg1）等抗炎标志物，同时增强丙烯酰胺诱导的促炎细胞因子白介素1 β (IL-1 β)的上调，肿瘤坏死α (tnf - α)和诱导型一氧化氮合酶（iNOS）在前额叶皮层的表达。
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-4R alpha), cluster of differentiation 206 (CD206) and transforming growth factor beta-1 (TGF beta 1) while enhancing acrylamide-induced upregulation of pro-inflammatory cytokines, interleukin-1 beta (IL-1 beta), tumor necrosis-alpha (TNF-alpha) and inducible nitric oxide synthase (iNOS) in the prefrontal cortex.