Postnatal exposure to di-(2-ethylhexyl)phthalate alters cardiac insulin signaling molecules and GLUT4 Ser488 phosphorylation in male rat offspring

J Cell Biochem. 2019 Apr;120(4):5802-5812. doi: 10.1002/jcb.27866. Epub 2018 Oct 25.


Di-(2-ethylhexyl)phthalate (DEHP), a distinctive endocrine-disrupting chemical, is widely used as a plasticizer in a variety of consumer products. It can easily cross the placenta and enter breast milk and then it is rapidly absorbed by offspring. Since it is generally accepted that individuals are more sensitive to chemical exposure during vital developmental periods, we investigated whether DEHP exposure during lactation affects cardiac insulin signaling and glucose homeostasis in the F1 male rat offspring at postnatal day 22 (PND22). Lactating Wistar rats were administered with DEHP (1, 10, and 100 mg/kg/d) or olive oil from lactation day 1 to 21 by oral gavage. All the male pups were perfused and killed on PND22. On the day before the killing, they were kept for fasting overnight and blood was collected. The cardiac muscle was dissected out, washed in ice-cold physiological saline repeatedly and used for the assay of various parameters. DEHP-exposed offspring had significantly lower body weight than the control. DEHP-exposed offspring showed elevated blood glucose, decreased 14 C-2-deoxyglucose uptake and 14 C-glucose oxidation in cardiac muscle at PND22. The concentration of upstream insulin signaling molecules such as insulin receptor subunit β (InsRβ) and insulin receptor substrate 1 (IRS1) were downregulated in DEHP-exposed offspring. However, no significant alterations were observed in protein kinase B (Akt) and Akt substrate of 160 kDa (AS160). Surprisingly, phosphorylation of IRS1 Tyr632 and Akt Ser473 were diminished. Low levels of glucose transporter type 4 (GLUT4) protein and increased GLUT4 Ser488 phosphorylation which decreases its intrinsic activity and translocation towards plasma membrane were also recorded. Lactational DEHP exposure predisposes F 1 male offspring to cardiac glucometabolic disorders at PND22, which may impair cardiac function.

Keywords: cardiac insulin signaling; endocrine disruptor; pGLUT4Ser488; phthalate; plasticizer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Blood Glucose / metabolism
  • Diethylhexyl Phthalate / toxicity*
  • Female
  • Glucose Transporter Type 4 / genetics
  • Glucose Transporter Type 4 / metabolism*
  • Insulin / metabolism*
  • Insulin Receptor Substrate Proteins / genetics
  • Insulin Receptor Substrate Proteins / metabolism
  • Insulin Resistance*
  • Lactation
  • Male
  • Myocardium / metabolism
  • Myocardium / pathology*
  • Phosphorylation
  • Plasticizers / toxicity*
  • Pregnancy
  • Rats
  • Rats, Wistar


  • Blood Glucose
  • Glucose Transporter Type 4
  • Insulin
  • Insulin Receptor Substrate Proteins
  • Plasticizers
  • Slc2a4 protein, rat
  • Diethylhexyl Phthalate