Effect And Mechanism Of T-2 Toxin-induced Cerebral Cortex Injury In Mice

Objective: T-2 toxin is one of the most toxic mycotoxins in group A monotricytoplasmoenes.It is widely distributed in nature and can be ingested directly or indirectly by humans and animals after entering the food chain and reaching the brain through blood circulation.More and more evidence suggests that T-2 toxins can induce neurotoxicity in the body,and the cerebral cortex is an important part of the nervous system,and T-2 toxins can cause significant damage to it.However,there is a lack of research on this damaging effect and its damage mechanism.More studies have shown that mitochondrial function and mitochondrial biosynthesis are related to T-2 toxin-induced neurotoxicity.In many kinds of research on neurotoxicity and neuroprotection,SIRT1(Sirtuin 1)and PGC-1α(Peroxisome proliferator-activated receptor-γ coactivator-1α)are believed to play an important regulatory role.This is closely related to mitochondrial function biosynthesis.This study aimed to reveal the damaging effect of T-2 toxin exposure on the cerebral cortex of mice and to investigate the role of SIRT1/PGC-1α in the damaging effect.Methods: Five-week-old male C57BL/6J mice were purchased from Spiff(Beijing)Biotechnology Co.,LTD.,and raised in the animal house of PLA Center for Disease Control and Prevention,and quarantine observation was conducted for one week.Then,the mice were divided into four experimental groups: solvent Control group(Control group),T-2 toxin low dose group(0.5 mg/kg group),medium dose group(1.0 mg/kg group)and high dose group(2.0 mg/kg group),and the neurotoxic animal model of mice was established after continuous 28 days of T-2 toxin gavage.1.The Morris water maze(MWM)training was conducted on Day 4(day-3)of the quarantine period,followed by the Open field test(OFT)and water maze tests on Day7(Day 0).In addition,water maze training began again on Day 25,and open field test and water maze test were conducted on all mice on Day 28,to observe the effects of T-2 toxin on the neurobehavior of mice.2.The mice were weighed daily by electronic balance,and the infected volume was adjusted according to the weighing result every day.In addition,the mouse brain tissue was weighed immediately after sampling.3.HE staining was used to observe the pathological changes of the cerebral cortex in mice.4.GSH/GSSG and MDA test kits were used to determine the level of oxidative stress in the cerebral cortex of mice;5.The productivity of the cerebral cortex was tested by an ATP test kit.The ultrastructure of mitochondria in the cerebral cortex of mice was observed by transmission electron microscope and the number of mitochondria was counted,suggesting the effects of T-2 toxin on mitochondrial function and biogenesis in mice.6.The mRNA and protein expressions of SIRT1,PGC-1α,NRF1,and COX-IV in the cerebral cortex of mice were detected by RT-qPCR and Western Blot assay to observe the effects of T-2 toxin on SIRT1/PGC-1α pathway in the cerebral cortex.7.Western blot assay was used to detect the protein expression of Casapse-3 and Cleaved caspase-3 in the cerebral cortex of mice and to observe whether T-2 toxin caused apoptosis of cerebral cortex cells.8.R-language was used to analyze the correlation between T-2 toxin-induced toxic effects and the induced SIRT1/PGC-1α pathway.Result: T-2 toxin exposure can induce cerebral cortex damage and neurotoxicity in mice,and the SIRT1/PGC-1α pathway is involved in the occurrence and development of such damage effects.1.The water maze test showed that T-2 toxin could affect the total swimming distance,swimming speed,time in the central area,and the number of piercing times of mice to a certain extent,but there was no statistically significant difference.The open field test showed that T-2 toxin could significantly reduce the total distance,speed,and time of activity of mice;2.Continuously repeated lavage infected T 2 toxin 28 days has no effect on body weight in mice,but brain dirty body weight as the infected increases with the significant increase in dose;3.T-2 toxin can induce mouse cerebral cortex oxidative damage occurs,the decrease in the number of mitochondria and capacity decreased,and mitochondrial ultrastructure changes,including mitochondrial swelling disappearance,cavitation,and crest;4.T-2 toxin exposure decreased the mRNA and protein expressions of SIRT1,PGC-1α,NRF1,and COX-IV.In contrast,protein expression of Caspase-3,the signature regulator of apoptosis,and Cleaved caspase-3 increased significantly;And this change is closely related to oxidative stress and mitochondrial biosynthesis.Conclusion:1.T-2 toxin exposure affected the neural behavior of mice,increased the proportion of brain viscera,induced oxidative damage and apoptosis of nerve cells,and resulted in mitochondrial morphological and structural changes,mitochondrial function decline,and mitochondrial number decrease;2.T-2 toxic exposure cause SIRT1,PGC-1α,NRF1,COX–IV,and Caspase 3 gene and protein expression changes,and this change is associated with oxidative stress and mitochondrial biosynthesis,It is suggested that the SIRT1/PGC-1α pathway may be involved in the process of T-2 toxin-mediated toxic damage of the cerebral cortex in mice.