Avermectin induces carp neurotoxicity by mediating blood-brain barrier dysfunction, oxidative stress, inflammation, and apoptosis through PI3K/Akt and NF-κB pathways

Tianmeng Zhang; Zhuhua Dong; Feixue Liu; Enzhuang Pan; Nana He; Fenfen Ma; Guanglu Wang; Yan Wang; Jingquan Dong

doi:10.1016/j.ecoenv.2022.113961

Avermectin induces carp neurotoxicity by mediating blood-brain barrier dysfunction, oxidative stress, inflammation, and apoptosis through PI3K/Akt and NF-κB pathways

Ecotoxicol Environ Saf. 2022 Sep 15:243:113961. doi: 10.1016/j.ecoenv.2022.113961. Epub 2022 Aug 12.

Authors

Tianmeng Zhang¹, Zhuhua Dong², Feixue Liu³, Enzhuang Pan³, Nana He³, Fenfen Ma⁴, Guanglu Wang³, Yan Wang⁵, Jingquan Dong⁶

Affiliations

¹ 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.
² Deapartment of Economics and Related Studies, University of York, York, YO10 5DD, United Kingdom.
³ 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.
⁴ 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.
⁵ 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. Electronic address: wangyan1358@163.com.
⁶ 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. Electronic address: 2018000029@jou.edu.cn.

PMID: 35969982
DOI: 10.1016/j.ecoenv.2022.113961

Abstract

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 LC₅₀ 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.

Keywords: Avermectin; Carp; NF-κB; Neurotoxicity; PI3K/Akt.

MeSH terms

Animals
Apoptosis
Blood-Brain Barrier / metabolism
Carps* / metabolism
Inflammation / chemically induced
Inflammation / pathology
Ivermectin / analogs & derivatives
NF-kappa B* / genetics
NF-kappa B* / metabolism
Oxidative Stress
Phosphatidylinositol 3-Kinases / metabolism
Proto-Oncogene Proteins c-akt / metabolism
Tumor Necrosis Factor-alpha / metabolism

Substances

NF-kappa B
Tumor Necrosis Factor-alpha
Ivermectin
avermectin
Proto-Oncogene Proteins c-akt