Study On Mechanism And Intervention Of Fumonisin B₁-induced Neurotoxicity Based On Caenorhabditis Elegans Model

Fumonisin B₁（FB₁）is a typical Fusarium mycotoxin,which contaminates corn and its products.In recent years,the contamination rate has been increasing year by year.Studies have shown that FB₁induces neurotoxicity by sphingolipid metabolism disorders,neurotransmission abnormalities,oxidative stress,and apoptosis.FB₁has been found to be closely associated with neurological diseases such as equine leukomalacia and childhood neuronal tubule defect,which poses a serious threat to animal and human health.Therefore,it is particularly important to study the neurotoxic mechanism of FB₁and its intervention measures for food safety control.In this paper,based on the Caenorhabditis elegans（C.elegans）model,the neurotoxic effects and mechanism of FB₁exposure were analyzed.Then,the neuroprotective effect of Polygonatum sibiricum polysaccharide extract（PSPE）on FB₁-induced C.elegans was investigated.This study provided theoretical basis for neurotoxicity evaluation and intervention research of mycotoxins.The main contents are as follows:1.Analysis of behavior and neurotransmitter of induced by FB₁.The experimental results showed that FB₁inhibited motor behavior and induced damage to neurotransmitter system in C.elegans in a time-and dose-dependent manner.Exposure to 20μg/m L,100μg/m L,and 200μg/m L FB₁for 24 h and 48 h resulted in a significant decrease in the abilities of voluntary movements and learning in C.elegans.Exposure to 200μg/m L FB₁for 24 h accelerated the paralysis of CL4176 strains（p<0.01）,and enhanced Aβ-induced neurotoxicity.After exposure to 200μg/m L FB₁for 24 h and above 100μg/m L FB₁for 48 h,theγ-aminobutyric acid（GABA）-ergic and serotonergic neurons of C.elegans were damaged,and the relative contents of GABA and serotonin significantly reduced（p<0.05）.Indicators such as behavior and neurotransmitters can be used to quantitatively evaluate the neurotoxic effects,and the inhibitory effects indicated that FB₁had neurotoxic effects on C.elegans.2.Study on oxidative stress and mitochondrial dysfunction of C.elegans induced by FB₁.Exposure to 20–200μg/m L FB₁for 24 h increased the levels of reactive oxygen species（ROS）（p<0.05）,and reduced the activities of superoxide dismutase（SOD）and catalase（CAT）（p<0.05）,and induced the abnormal expression of cytochrome oxidase-related gene（cyp35A2）,SOD-related genes（sod-1 and sod-3）,CAT-related genes（ctl-2 and ctl-3）in C.elegans in a dose-dependent manner.In addition,100–200μg/m L FB₁induced a decrease in mitochondrial density,adenosine triphosphate（ATP）levels,and mitochondrial membrane potential in C.elegans（p<0.05）.Further studies showed that exposure to 200μg/m L FB₁for24 h significantly inhibited the expression of mitochondrial respiratory chain complexes I and V,and increased the expression level of drp-1 gene,thereby interfering with the processes of oxidative phosphorylation and dynamics in C.elegans.Correlation analysis showed that the expression of oxidative stress and mitochondrial function-related indicators were significantly correlated with the behavioral and neurotransmitter-related indicators in C.elegans.The results further suggested that oxidative stress,mitochondrial respiratory chain,and mitochondrial dynamics may play key roles in the mechanism of FB₁-induced neurotoxicity.3.The alleviation effect of PSPE on FB₁-induced C.elegans was analyzed by multiple indicators,and its intervention mechanism was discussed combined with plasma pseudotargeted metabolomics method.PSPE has strong ABTS,DPPH,and hydroxyl radical scavenging ability,and 2–200μg/m L PSPE had no significant effects on body bends and head thrashes of C.elegans.20–200μg/m L PSPE pretreatment can enhance the locomotor ability,alleviate the degeneration of GABAergic and serotonergic neurons,and increase the relative contents of GABA and serotonin in FB₁-induced C.elegans in a dose-dependent manner.Furthermore,PSPE intervention alleviated FB₁-induced oxidative stress and mitochondrial damage in C.elegans by reducing ROS levels,enhancing antioxidant enzyme activities,increasing ATP levels and mitochondrial membrane potential,and regulating the expression of antioxidant and mitochondria-related genes.In order to further monitor the changes of PSPE intervention on the metabolic process of FB₁-induced C.elegans,the results of metabolomics indicated that PSPE might reduce FB₁-induced mitochondrial oxidative damage in C.elegans by regulating related metabolic pathways such as citric acid,cysteine and methionine,tryptophan,glycerophospholipid and purine in C.elegans.In conclusion,based on C.elegans model,this paper found that FB₁may induce motor defect and neurotransmitter system damage through oxidative stress,mitochondrial respiratory chain,and mitochondrial dynamics.However,PSPE can regulate citric acid,tryptophan,and glycerophospholipid and other metabolic pathways in C.elegans,effectively alleviating FB₁-induced oxidative stress and mitochondrial dysfunction.This study lays a theoretical foundation for revealing the evaluation and intervention of mycotoxins-induced neurotoxicity.