Selenium Can Alleviate Cadmium-induced Mitophagy By Regulating The Nuclear Xenobiotic Receptor Response And Oxidative Stress In Rabbit Liver

To explore the mechanism of selenium（Se）alleviating cadmium（Cd）induced mitphagy in liver,forty 3-month-old New Zealand white rabbits（2-2.5 kg）,half male and half female,were randomly divided into four groups:the Control group,the Se（0.5mg/kg body weight（BW））group,the Cd（1 mg/kg BW）group and the Se+Cd group.Cadmium chloride（CdCl₂）and sodium selenite（Na₂SeO₃）were used as the sources of Cd and Se,respectively.The test period was 30 days.The levels of trace elements in heart tissue were determined by ICP-MS;the pathological changes of cells and mitochondria were observed by tissue section and transmission electron microscope;the levels of oxidative stress and cytochrome P450（CYP450）enzyme related indicators were determined by commercial kit;the levels of nuclear xenobiotic receptor（NXR）,mitochondrial function and mitophagy related genes were detected by Quantitative real-time PCR and Western blotting;the localization and expression of PGC-1αwere observed by immunofluorescence.The experimental results show that:Cd decreased the contents/activities of CYP450 enzymes（CYP450,CYB5A,AH,APND,NCR and ERND）and antioxidant enzymes（T-AOC,T-SOD,Cu Zn-SOD,GSH-Px,GST and CAT）and increased the contents of malondialdehyde（MDA）and hydrogen peroxide（H₂O₂）and also increased the consumption of reduced glutathione（GSH）.Moreover,the mRNA levels of NXRs（CAR,PXR,AHR and Nrf2）,mitochondrial function-related factors（PGC-1α,Sirt1,Sirt3,Nrf1 and TFAM）and mitochondrial fusion factors（Mfn1,Mfn2and OPA1）were significantly downregulated（P<0.05 or P<0.01 or P<0.001）,but the mRNA levels of mitochondrial function factors（VDAC1,Cyt C and PRDX3）,mitochondrial fission factors（Fist1 and MFF）and signal molecules of mitophagy pathway（PINK1,Parkin,p62,Bnip3 and LC3）were significantly upregulated（P<0.05or P<0.01 or P<0.001）under Cd exposure.In addition,the protein expression levels of Nrf2,SOD2,PGC-1α,PINK1 and Parkin were consistent with the mRNA expression levels in the Cd group.Se alleviated the changes in the abovementioned factors induced by Cd.Se can reduce the oxidative stress caused by cadmium,activate the activities of CYP450 enzymes and antioxidant enzymes,promote the transcription of NXR,regulate the function of mitochondria,balance the fusion and division of mitochondria,so as to reduce mitophagy,and ultimately alleviate the liver injury caused by Cd.In conclusion,the results indicate that Cd can cause oxidative stress in rabbit livers by inhibiting NXRs and the antioxidation response leading to mitophagy,and these harmful changes caused by Cd can be alleviated by Se.