The Role Of Nuclear Receptor And Nrf2 Mediated Defense Response In DEHP-induced Quail Nephrotoxicity

Di(2-ethylhexyl)phthalate(DEHP),as a plasticizer with excellent comprehensive performance,is widely used in daily consumables and medical consumables.Due to difficult degradation characteristics,DEHP poses a serious threat to the ecological environment and human health.Kidney has the functions of regulating the body’s water,electrolyte and acid-base balance,and is the main target organ of DEHP.However,there are few clinical studies on DEHP-induced nephrotoxicity in poultry.Hence,in order to investigate the mechanism of renal toxicity caused by DEHP,300 8-day-old female Japanese quails were randomly divided into 5 groups,including blank control group(Con),vehicle control group(Vcon),250mg/kg,500mg/kg and 1000mg/kg DEHP treatment groups Histopathological observations were performed on the kidneys of quail exposed to DEHP to detect the antioxidant function,the expression of Nrf2 signaling pathway-related regulatory genes and proteins,the homeostasis of CYP450 enzymes,and the expression of genes and proteins related to nuclear receptor response.The results show:(1)Histopathological observation revealed that DEHP exposure caused obvious structural abnormalities in quail kidneys,including glomerular dilatation,renal capsule atrophy,tubular columnar epithelial cell swelling,glomerular and renal interstitial hyperemia phenomenon.(2)In the kidneys of quails exposed to DEHP,the total antioxidant capacity(T-AOC)was decreased,and the activities of antioxidant enzymes(T-SOD,GST,and GSH-Px)were inhibited,and the expression level of lipid peroxide(MDA)was increased,and the activities of antioxidant enzymes(CAT and GSH)were activated in renal tissues,thus inducing oxidative stress.The expression levels of Nrf2 gene and protein in the nucleus of kidney cells were significantly increased,and the expression levels of Nrf2 signaling pathway related factors(GST,CAT,GCLM,GCLC,SOD1,SOD2,SOD3,HO-1)were significantly increased.These results indicates that DEHP activates the Nrf2 signaling pathway and induces Nrf2 and downstream genes to participate in Nrf2-mediated quail kidney damage and antioxidant defense to resist the oxidative stress of DEHP-induced kidney damage.(3)DEHP exposure induced renal nuclear receptor(AHR/CAR/PXR)and CYPs subtypes(CYP1A1,CYP1A2,CYP1A4,CYP1A5,CYP2C18,CYP2J3,CYP3A12)gene expression,increased CYP450,Cytb5 content and enhance the activity of its enzyme system(APND,ERND).These results indicate that DEHP can interfere with nuclear receptor responses and cause CYP450 s homeostasis imbalance,thereby exerting its renal toxicity.In summary,DEHP has significant nephrotoxicity.It can induce oxidative stress in kidney,but kidney resisted the nephrotoxic effects of DEHP by regulating the response of nuclear receptors(AHR/CAR/PXR)and the Nrf2 signaling pathway.