Mechanism Of Cadmium Induced-Mitochondrial Damage In Chicken Spleen

Cadmium（Cd）is one kind of major contaminants in the environment.It accumulates in multiple organs through the food chain and produces toxicity,endangering human and animal health.Cd has the ability of significant splenic toxicity,but the mechanism of toxicity remains unclear.In this experiment,male Hyland white chicken were used as the experimental animal.The chicken fed different concentrations of diet,the pathological changes of chicken spleen were observed,and mitochondrial membrane potential and function-related molecules,mitochondrial dynamics related factors,oxidative stress,CYP450 s,exogenous substance-sensitive nuclear receptor response and Nrf2 signaling pathway were detected.The results show that:（1）Cd exposure caused the boundary zone between the white and red pulp of the spleen to be blurred,lymphocytes to be sparsely arranged and a significant decrease in the number of lymphocytes,and the thickness of the sheath artery wall to be increased significantly,which indicated that Cd has significant spleen toxicity.（2）Cd exposure caused a decrease in mitochondrial membrane potential in the spleen and disrupted the expression of mitochondrial function-related genes.Low-dose Cd（<35 mg/kg）exposure significantly up-regulated the expression of mitochondrial dynamics-related factors（OPA1,MFF,Mfn1 and Mfn2）,high-dose（>70 mg/kg）Cd exposure down-regulated the expression of mitochondrial dynamics-related factors,resulting in Mitochondrial dynamics,which suggested that Cd caused mitochondrial dysfunction and changes in mitochondrial dynamics.（3）Cd exposure can increase the content of H₂O₂ and MDA in spleen tissue,reduce the total antioxidant capacity（T-AOC）and antioxidant enzymes（CAT,T-SOD,Cu-Zn SOD）activity,induce oxidative stress;Meanwhile,Cd exposure can up-regulate the expression of Nrf2,and increase the expression level of Nrf2 signaling pathway targeting factors（HO-1,NQO1,SOD1,SOD3,GCLC）,indicating that Cd could activate Nrf2 signaling pathway and regulate the expression of antioxidant enzyme gene.These results suggest that Nrf2 plays an important role suggests that Nrf2 plays an important role in Cd-induced oxidative damage,which may be an important mechanism of Cd-induced spleen mitochondrial damage in chickens.（4）Cd exposure can increase the content of CYP450 and Cyt-b5,affect the activity of CYP450（APND,ERND,AH,NCR）,regulate the transcription of nuclear receptor（AHR/PXR/CAR）and CYP subunit（CYP1B1,CYP1A5,CYP1A1,CYP2C18,CYP2D6,CYP3A4）,indicating that Cd can activate AHR/PXR/CAR-mediated nuclear receptor response,affect the steady-state regulation of CYP450 s,which may be one of the mechanisms of Cd-induced spleen toxicity in chickens.In summary,Cd exposure induced oxidative stress,activated Nrf2 antioxidant defense response,caused changes of mitochondrial dynamics and cytochrome P450 homeostasis,activate nuclear receptor（AHR/CAR/PXR）response,damage mitochondrial function,leading to the toxicity on the spleen.