The Effects And Potential Mechanisms Of Di-(2-ethylhexyl) Phthalate Disrupting Liver Insulin Signaling Pathway

Di-(2-ethylhexyl)-phthalate(DEHP),a ubiquitous industrial pollutant in our daily life,known as plasticizer in general,is widely used as polymer additives added in the plastic processing this kind of material in industry.It can promote flexibility,easy processing,can be legally used for industrial purposes.The personage inside course of study points out,however,DEHP,DINP plasticizer does not belong to food flavor materials.Therefore,DEHP must not only be added in the food,even not allowed to use in food packaging.It was reported to cause adverse effects on glucose homeostasis and insulin sensitivity in epidemiological studies previously.The molecular structure of some kinds of plasticizers is similar to hormones,which was defined as the "environmental hormone" by the world health organization(who).The long-term exposer to DEHP may cause abnormal reproductive system,and even cause teras,the risk of cancer.Environmental hormone refers to the external factors interfere with the biological endocrine chemicals.The remaining traces of such compounds in the environment,through the food chain into the body,form pseudo hormones,transmitting pseudo chemical signals,and affect the hormone content itself,and then the original mechanism of endocrine disruptors,will cause the endocrine disorder.Because of its role is similar to artificial hormones,harms male reproductive ability and promote female precocious puberty,a large number of long-term intake can lead to liver cancer.As the child is in pubertal reproductive system,the harm of DEHP to endocrine system will be even worse in children’s potential.Recently,it has been reported to be an endocrine disrupter and ligand to peroxisome proliferator activated receptor,which could influence the homeostasis of liver metabolic systems and contribute to the development of type-2 diabetes.However,the potential mechanisms are not known yet.Peroxisome proliferators-activated receptors(PPARs)are ligand-activated receptors of the nuclear hormone receptor family,three subtypes have been found in different species.They control of many cell metabolism,and belong to the ligands induced nuclear receptor.After ligand activated,PPARs combined with retinol X receptor(RXR)to form dimers,PPAR gamma/RXR reaction with PPAR upstream of the target gene promoter element(PPRE)combination,finally regulate the transcription of target genes.Its ligands are fat soluble molecules and produce biological effects through regulating the expression of target genes.PPARs and their conformational change of the binding of a ligand itself promote or inhibit the expression of target genes.This study was designed to solve these problems with male SD rats and normal human hepatocyte line,L02 cells,exposed to DEHP for toxicological experiments.Adult male SD rats were divided into four groups,normal group fed with regular diets and three DEHP-treated groups(dissolved in olive oil at doses of 0.05,5 and 500 mg/kg body weight,respectively,once daily through gastric intubations for 15 weeks).L02 cells were divided into 6 groups,normal group with 5,10,25,50,and 100 μmol/l DEHP groups.DEHP-exposed rats exhibited significant liver damage,glucose tolerance,and insulin tolerance along with reduced expression of insulin receptor and GLUT4 proteins in the liver tissues.The results of in vitro experiments could determine that the DEHP-induced activation of peroxisome proliferator activated receptor γ(PPARγ)played a key role in the production of oxidative stress and down-regulated expression of insulin receptor and GLUT4 proteins in L02 cells.This conclusion could be supported by the results of in vitro experiments,in which the cells were exposed to DEHP with GW9662(PPARγ inhibitor).In general,these results highlight the key role of PPARγ in the process of insulin resistance induced by DEHP.