Study On The Mechanism Of Lycopene Relieving Cerebellar Endoplasmic Reticulum Stress Induced By DEHP In Mice

Phthalates（PAEs）,as plasticizers,can improve the ductility and plasticity of plastic products.Nowadays,Di（2-ethyl）hexyl phthalate（DEHP）is the most widely used PAEs.Due to the characteristics of non-covalent binding to polymers in plastic products and easy migration,the residue of DEHP in the environment has gradually become an environmental issue of widespread concern.Lycopene is a kind of natural carotenoid with strong antioxidant capacity.Therefore,it was chosen as an antagonist to alleviate the neurotoxicity induced by DEHP.To explore the role of lycopene in cerebellar injury induced by DEHP and its potential mechanism.In this experiment,mice were selected as experimental objects and divided into five groups:CON group（control group）,VCON group（vehicle control group）,LYC group（5 mg/kg lycopene group）,DEHP group（500 mg/kg DEHP）,DL group（5mg/kg LYC+500 mg/kg DEHP）,cerebellar tissue was collected after 28 days of gavage administration.After tissue collection,we observed pathological tissue sections of the cerebellum,detected the content of calcium and antioxidant indicators in the cerebellum,analyzed the changes of the tight junction（Tj）of the blood brain barrier,Ca²⁺transport,and endoplasmic reticulum（ER）stress related factors.The research results showed that:（1）Exposed to DEHP can lead to a decrease in the number of Purkinje cells in the cerebellum,nuclear aggregation and a decrease in the density of basket cells,resulting in cerebellar injury;The combined treatment of lycopene and DEHP can alleviate the damage of cerebellar tissue structure induced by DEHP.（2）Exposed to DEHP can decrease the expression of tight junction proteins（Claudin5 and Occludin）in the blood-brain barrier;The combined treatment of lycopene and DEHP can turn the expression of Claudin5 and Occludin to nomal levels.（3）Exposed to DEHP can induce the accumulation of ROS,8-OHDG,and MDA in the cerebellum caused by DEHP,decrease the activity of antioxidant enzyme systems（CAT,GSH-PX,T-SOD,T-AOC）;The combined treatment of lycopene and DEHP restore the levels of ROS,8-OHDG,and MDA,as well as the activity of CAT,GSH-PX,T-SOD,and T-AOC in the cerebellum（4）Lycopene can target binding to the calcium releasing factor IP3R1 and the calcium uptake factor SERCA2 in the ER of cerebellar Purkinje cells,changing the expression levels of gene and protein,alleviating abnormalities in the calcium transport function of cerebellar Purkinje cells caused by DEHP.（5）Exposed to DEHP can induce the increase of the phosphorylation level of PERK and the protein expression of GRP78 and its downstream related factor（p-elf2α,CHOP,ATF4）;The combined treatment of lycopene and DEHP inhibit ER stress caused by DEHP.In summary,lycopene can alleviate cerebellar oxidative stress,blood brain barrier damage,calcium homeostasis imbalance,and ER stress induced by DEHP.Lycopene alleviates cerebellar calcium homeostasis imbalance caused by DEHP through targeted binding to IP3R1 and SERCA2.This experiment provides a new idea for understanding the molecular mechanism of lycopene in alleviating injury of nervous system induced by DEHP.