The Role Of Mitochondrial Quality Control In Lycopene Antagonizing DEHP-induced Cardiotoxicity In Mice

Di(2-ethylhexyl)phthalate(DEHP)is the most widely used plasticizer and can cause cardiotoxicity by inducing oxidative stress.Lycopene has a strong antioxidant effect and can prevent cardiovascular diseases.However,whether lycopene can antagonize DEHP-induced cardiotoxicity remains unclear.This study aims to reveal the detoxification effect of lycopene on DEHP-induced cardiotoxicity.The mice were randomly divided into 7 groups:Con group(control group),VCon group(vehicle control group),LYC group(5 mg/kg lycopene group),DEHPI group(500 mg/kg DEHP group),DEHPII group(1000 mg/kg DEHP group),DEHPI+LYC group(500 mg/kg DEHP+5mg/kg lycopene group)and DEHPII+LYC group(1000mg/kg DEHP+5 mg/kg lycopene group).The drug was administered by gavage,and heart samples were collected after 28 consecutive days.The heart tissues were subjected to histopathological observation with HE staining and ultrastructural observation,determined cardiac serum biochemical indicators and antioxidant-related indicators,and the use of real-time fluorescent quantitative PCR and Western Blot experimental methods to mitochondrial biogenesis and dynamics,mitophagy-related factors.The results showed that:(1)DEHP can cause pathological damage such as focal heart hemorrhage,disordered muscle fiber arrangement and rupture,cell vacuolar degeneration,mitochondrial cristae rupture and other pathological damages.The activity of enzymes related to cardiac function(CK,LDH,?-HBDH)is enhanced.After adding lycopene,it can effectively alleviate the heart disease damage caused by DEHP and restore heart function.(2)Lycopene can alleviate the increase in MPO activity and H₂O₂ content caused by DEHP exposure,restore T-AOC activity,and alleviate the oxidative stress damage of heart tissue by activating the antioxidant enzyme system(GSH,GSH-PX,GSH-ST).(3)Lycopene regulates the expression of genes and protein content of mitochondrial biogenesis-related factors(SIRT1,SIRT3,PGC-1?,NRF1),and regulates mitochondrial fusion-related proteins(MFN1,MFN2,OPA1)and division-related protein DRP1 expression,can inhibit DEHP-induced cardiac mitochondrial damage and mitochondrial fusion/division homeostasis imbalance,thereby restoring mitochondrial function and reducing heart damage;(4)Lycopene inhibits DEHP-induced mitophagy activation by reducing the expression of PINK1 and Parkin protein and the expression of related mitochondrial autophagy factors(P62,Bnip3,VDAC1,FUNDC1,TOMM20,TOMM40,and TOMM70).Remove damaged mitochondria,restore mitochondrial activity,and ultimately protect the mice heart from damage.In summary,DEHP causes oxidative stress in the mice heart and leads to the imbalance of cardiac mitochondrial homeostasis and mitochondrial dynamics.Lycopene antagonizes the heart oxidative stress caused by DEHP by reducing PINK1/Parkin-mediated mitophagy,and at the same time exerts cardioprotective functions by regulating mitochondrial biogenesis and mitochondrial fusion and division.