Trehalose Protect Against Cadmium-Induced Hepatotoxicity In Rats

Cadmium?Cd?is a widely distributed environmental contamination.Cd is absorbed by humans or animals via contaminated food,air and water,then accumulated in the body.Cd exerts strong toxic effects on different organs and tissues such as liver,kidney,testis,spleen and bone,et al.As one of the most active organs of oxidative stress,the liver is also the important target organ for cadmium toxicity.Trehalose?Tr?protects against oxidative stress-mediated cytotoxicity through its antioxidant properties.The effect and mechanism of Tr antagonizing the toxicity of heavy metal Cd in vivo has not been elucidated.Thus,this study intend to explore the protective effect of Tr on Cd induced hepatotoxicity in rats and the possible protective mechanism.In this study,32 SD rats were randomly divided into 4 groups:control group?Cont group?,cadmium treatment group?Cd group?,trehalose protection group?Cd+Tr group?,and trehalose group?Tr group?.The corresponding treatments were given to each group of rats,CdCl₂ solution replaced drinking water in Cd group and Cd+Tr groups,Tr solution was administered daily in Cd+Tr group and Tr group,and the other groups were treated with corresponding control methods.After 8 weeks,the rats were anesthetized and sacrificed,blood samples and liver tissue samples were taken for corresponding detection.Firstly,serum biochemical indicators?three liver function marker enzymes:ALT,AST,and LDH?and liver histological changes were tested in the test rats.The results showed that Cd can significantly increase the activity of three serum enzymes and cause obvious histological damage to the liver.Tr significantly reduced the Cd-elevated serum biochemical parameters,and alleviated the Cd-induced liver histological damage,indicating that Tr antagonizes the toxicity of Cd and exerts the liver-protecting effect.Secondly,in order to investigate the protective mechanism of trehalose,this study measured the biomarker level of oxidative stress in serum?MDA,T-AOC,GSH,SOD,GPx and CAT?to examing the effect of Tr on Cd-induced oxidative stress.The results indicate that Tr alleviates Cd-induced whole body lipid peroxidation.Thirdly,in view of the regulatory role of Nrf2 signaling pathway in oxidative stress,this study further explored the role of Nrf2 signaling pathway in Tr mitigate Cd-induced hepatic oxidative damage.The results showed that trehalose significantly inhibited the Cd-activated Nrf2 signaling pathway and down-regulated the expression of Cd-enhanced enzymatic antioxidant proteins?CAT,GPx,SOD1 and SOD2?,which may be due to when trehalose enters the body through itself antioxidant properties replace Nrf2-activated endogenous antioxidant enzymes to exert antioxidant effects.Fourthly,the expression of LC3 and SQSTM1/p62 protein was detected by Western blotting and immunohistochemistry to investigate the effect of Tr on the Cd-induced autophagy inhibition.The results showed that Tr can alleviate the inhibition of autophagy induced by Cd.Finally,the apoptosis rate of liver cells was detected by TUNEL staining and the expression levels of cleaved-PARP,cleaved-caspase-9 and cleaved-caspase-3 were analyzed by Western blotting.We found that Tr inhibits Cd-mediated hepatic cell apoptosis by blocking caspase-dependent apoptosis pathway.In summary,we found that cadmium-induced oxidative stress is closely related to the activation of Nrf2 signaling pathway.Cadmium-induced oxidative stress also promotes autophagy inhibition and hepatocyte apoptosis in rats.As an autophagy promoter,trehalose also has an antioxidant effect,which can alleviate cadmium-induced oxidative stress and activation of the Nrf2 pathway,thereby restoring autophagy and inhibiting apoptosis to exerting the protective effect on Cd-induced hepatotoxicity.