The role of oxidative stress in DNA damage in pancreatic β cells induced by di-(2-ethylhexyl) phthalate

Chem Biol Interact. 2017 Mar 1;265:8-15. doi: 10.1016/j.cbi.2017.01.015. Epub 2017 Jan 20.


Di(2-ethyhexyl) phthalate (DEHP) is commonly used as a plasticizer, which loosely binds to plastic materials and easily leaches out of these products and enters into the environment. Exposure to DEHP can impair pancreatic beta cells (INS-1 cells)function, which is associated with Insulin Resistance (IR) and type 2 diabetes. However, the mechanism of how DEHP leads to Insulin Resistance is unknown. Our results showed that the cell viability of INS-1 cells exposed to DEHP (0-1600 μM) were decreased in a concentration-dependent manner. DEHP caused significant increases of DNA migration and oxidative damage in INS-1 cells. Lysosomal membrane permeability was increased and mitochondrial membrane potential was reduced after INS-1 cells treated with DEHP. DEHP was also shown to induce ROS production and cause GSH depletion in INS-1 cells. DEHP brought a significant decrease in super oxide dismutase (SOD) and led to accumulation of malondialdehyde (MDA) in the INS-1 cells. DEHP increased significantly the expression of P53 and ATM gene of INS-1 cell at high dose levels. Simultaneously, Pyrroloquinoline Quinone (PQQ), an antioxidant, and alcohol were used in the study to determine their effects on DEHP-induced INS-1 cells damage. PQQ could protect the INS-1 cells from the damage induced by DEHP to some extent, while alcohol aggravated the toxic effects of DEHP. These results indicate that DEHP-mediated INS-1 cell dysfunction through a lysosomal-mitochondrial pathway, involving oxidative stress and p53 and ATM activation.

Keywords: Di(2-ethyhexyl) phthalate; Insulin Resistance; Oxidative DNA damage; Oxidative stress; PQQ.

MeSH terms

  • Animals
  • Ataxia Telangiectasia Mutated Proteins / genetics
  • Cell Line
  • DNA / drug effects*
  • DNA Damage*
  • Diethylhexyl Phthalate / toxicity*
  • Intracellular Membranes / drug effects
  • Islets of Langerhans / drug effects*
  • Islets of Langerhans / enzymology
  • Islets of Langerhans / metabolism
  • Malondialdehyde / metabolism
  • Membrane Potential, Mitochondrial / drug effects
  • Oxidative Stress*
  • Permeability
  • RNA, Messenger / genetics
  • Rats
  • Superoxide Dismutase / metabolism
  • Tumor Suppressor Protein p53 / genetics


  • RNA, Messenger
  • Tumor Suppressor Protein p53
  • Malondialdehyde
  • DNA
  • Diethylhexyl Phthalate
  • Superoxide Dismutase
  • Ataxia Telangiectasia Mutated Proteins