Di-(2-ethylhexyl) phthalate could disrupt the insulin signaling pathway in liver of SD rats and L02 cells via PPARγ

Toxicol Appl Pharmacol. 2017 Feb 1:316:17-26. doi: 10.1016/j.taap.2016.12.010. Epub 2016 Dec 23.


Di-(2-ethylhexyl)-phthalate (DEHP), a ubiquitous industrial pollutant in our daily life, has been reported to cause adverse effects on glucose homeostasis and insulin sensitivity in epidemiological studies previously. 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. 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 500mg/kg body weight, respectively, once daily through gastric intubations for 15weeks). L02 cells were divided into 6 groups, normal group with 5, 10, 25, 50, and 100μmol/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.

Keywords: DEHP; GLUT4; Insulin resistance; Liver; PPARγ; ROS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Glucose / drug effects
  • Blood Glucose / metabolism
  • Diethylhexyl Phthalate / toxicity*
  • Dose-Response Relationship, Drug
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism
  • Humans
  • Insulin / metabolism*
  • Liver / drug effects*
  • Liver / metabolism*
  • Liver / pathology
  • Male
  • PPAR gamma / metabolism*
  • Plasticizers / toxicity
  • Random Allocation
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction / drug effects*
  • Signal Transduction / physiology


  • Blood Glucose
  • Insulin
  • PPAR gamma
  • PPAR gamma, rat
  • Plasticizers
  • Diethylhexyl Phthalate