阿维菌素通过介导血脑屏障功能障碍、氧化应激、炎症和细胞凋亡，通过 PI3K/Akt 和 NF-κB 途径诱导鲤鱼神经毒性。
Avermectin induces carp neurotoxicity by mediating blood-brain barrier dysfunction, oxidative stress, inflammation, and apoptosis through PI3K/Akt and NF-κB pathways.
机构信息
Jiangsu Key Laboratory of Marine Bioresources and Environment, Co-Innovation Center of Jiangsu Marine Bio-industry Technology, Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, Jiangsu Ocean University, Lianyungang 222005, China; Department of Medicine Laboratory, Department of Cardiac Function Examination, The Second People's Hospital of Lianyungang City, Lianyungang Hospital Affiliated to Jiangsu University, The Second People's Hospital of Lianyungang Affiliated to Kangda College of Nanjing Medical University, Lianyungang, 222000, China.
Deapartment of Economics and Related Studies, University of York, York, YO10 5DD, United Kingdom.
出版信息
Ecotoxicol Environ Saf. 2022 Sep 15;243:113961. doi: 10.1016/j.ecoenv.2022.113961. Epub 2022 Aug 12.
Avermectin, a "low toxicity insecticide", has been widely used in recent years, but its non-target toxicity, especially to aquatic organisms, has been neglected. In this study, we evaluated the neurotoxic effects of avermectin on carp by establishing a 96 h avermectin acute toxicity test, and its possible mechanism was discussed. The 96 h LC of avermectin in carp was found to be 24.04 μg/L. Therefore, 3.005 μg/L and 12.02 μg/L were used as the low-dose and high-dose groups, respectively, to investigate the neurotoxic effects of avermectin on carp. The results of high-performance liquid chromatography (HPLC) analysis showed that avermectin accumulated in the carp brain. Histopathological observation and immunohistochemical analysis (IHC) of TNF-α and Bax showed that avermectin exposure led to inflammatory cell infiltration and neuronal necrosis. The mRNA levels of tight junction genes and the IHC results of ZO-1 and Occludin showed that the structure of the blood-brain barrier (BBB) was destroyed. Biochemical analysis showed that avermectin induced the accumulation of MDA in the brain and decreased the activity of antioxidant enzymes CAT and SOD, leading to oxidative stress. In addition, avermectin induces brain inflammation by activating NF-κB pathway and releasing inflammatory factors IL-1β, IL-6, TNF-α and iNOS. TEM and TUNEL assays showed that exposure to avermectin induced apoptosis in brain. what is more, the expression of apoptosis-related genes and proteins suggested that avermectin-induced apoptosis may be associated with inhibition of the PI3K/Akt signaling pathway. This study also showed that avermectin-induced NF-κB signaling activation was partially dependent on its upstream PI3K/Akt signaling pathway. Therefore, this study concludes that avermectin can induce neurotoxicity in carp by disrupting the blood-brain barrier structure and generating oxidative stress, inflammation, and apoptosis and that NF-κB and PI3K/Akt signaling pathways are involved in this process.
阿维菌素是一种“低毒杀虫剂”，近年来被广泛应用，但对其非靶标毒性，特别是对水生生物的毒性，却被忽视了。本研究通过建立 96 h 阿维菌素急性毒性试验，评价了阿维菌素对鲤鱼的神经毒性作用，并探讨了其可能的作用机制。结果发现，鲤鱼的 96 h LC50 为 24.04μg/L。因此，本研究选用 3.005μg/L 和 12.02μg/L 作为低剂量组和高剂量组，研究阿维菌素对鲤鱼的神经毒性作用。高效液相色谱（HPLC）分析结果表明，阿维菌素在鲤鱼脑中蓄积。组织病理学观察和 TNF-α、Bax 的免疫组化（IHC）分析表明，阿维菌素暴露导致炎症细胞浸润和神经元坏死。紧密连接基因的 mRNA 水平以及 ZO-1 和 Occludin 的 IHC 结果表明，血脑屏障（BBB）的结构被破坏。生化分析表明，阿维菌素诱导脑内 MDA 积累，降低 CAT 和 SOD 等抗氧化酶的活性，导致氧化应激。此外，阿维菌素通过激活 NF-κB 通路和释放炎症因子 IL-1β、IL-6、TNF-α 和 iNOS 诱导脑炎症。TEM 和 TUNEL 检测结果表明，暴露于阿维菌素会诱导脑中细胞凋亡。更重要的是，凋亡相关基因和蛋白的表达表明，阿维菌素诱导的凋亡可能与抑制 PI3K/Akt 信号通路有关。本研究还表明，阿维菌素诱导的 NF-κB 信号通路激活部分依赖于其上游的 PI3K/Akt 信号通路。综上所述，本研究认为阿维菌素通过破坏血脑屏障结构、产生氧化应激、炎症和凋亡，诱导鲤鱼产生神经毒性，NF-κB 和 PI3K/Akt 信号通路参与了这一过程。
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