The Role Of Nuclear Receptor AHR/CAR/Nrf2 Cascade Signaling Pathway In The Nephrotoxicity Of Atrazine To Quails

Atrazine(ATR)was the most widely used organophosphate pesticides in agricultural production throughout the world.It circulates among organisms through the food chain,which endangers human beings and animals seriously.The kidney,a metabolic organ responsed to metabolism of exogenous substances,has been involved in the field of toxicology research.However,there is no report on the nephrotoxicity of ATR in birds.In order to reveal the mechanism of ATR-induced nephrotoxicity in birds,we have experimented on quails(Coturnix C.coturnix)which were treated with ATR by intragastric administration.Renal pathological alteration was observed and related indicators such as renal function,mitochondrial dysfunction,oxidative stress,apoptosis,the expression of nuclear receptor,CYP450 s and Nrf2 signaling pathway related genes were detected.The results indicated that:(1)ATR caused renal epithelial cells shedding,renal capsule space increased,renal tubular expansion,renal tubularepithelial cells disorders.It is suggested that ATR has significant nephrotoxicity.(2)ATR resulted inswelling,vacuolar degeneration and cristae rupture of mitochondria in renal cells.It is suggested that mitochondria is the target organelle of ATR toxicityinkidney.(3)ATR exposure resulted in nuclear DNA fragmentation,up regulation of pr-apoptotic genes(Fas,FasL,Bax and Caspase 3)transcription levels,down regulation of anti-apoptotic gene(Bcl-2)transcription level,indicating that ATR can induce nephrocyte apoptosis.(4)ATR exposure up-regulated nephricnuclear receptor(AHR/CAR)and CYPs subunits(CYP1A5,CYP1B1,CYP3A4,CYP3A9)genes expression and induced CYP450,Cyt-b5 content and CYP450-related enzymes activities,indicating that ATR could activate the nuclear receptor response sensitivity to exogenous substances,which involoved in metabolism ofATR toalleviate ATR-inducedtoxic effect.(5)ATR exposure increased gene and protein level of Nrf2,up regulated Nrf2 signaling pathway related factors(NQO1,HO-1,CAT,GST,GCLC,GCLM)mRNA levels,indicating that ATR activates the Nrf2 signaling pathway to regulate thegenesexpressionsofphase II detoxifying enzymes and antioxidant enzymes,enhance the the resistance on ATR-induced oxidative damage in kidney.In summary,ATR has significant nephrotoxicity.The organism activates the nuclear receptor response and the CYP450 enzyme system via the AHR/CAR/Nrf2 cascade signaling pathway to protect against the nephrotoxicity of ATR.