Maternal di-(2-ethylhexyl) phthalate exposure alters hepatic insulin signal transduction and glucoregulatory events in rat F 1 male offspring

J Appl Toxicol. 2019 May;39(5):751-763. doi: 10.1002/jat.3764. Epub 2018 Dec 18.


Di-(2-ethylhexyl) phthalate (DEHP) is a commonly used plasticizer with endocrine disrupting properties. Its widespread use resulted in constant human exposure including fetal development and postnatal life. Epidemiological and experimental data have shown that DEHP has a negative influence on glucose homeostasis. However, the evidence regarding the effect of maternal DEHP exposure on hepatic glucose homeostasis is scarce. Hence, we investigated whether DEHP exposure during gestation and lactation disrupts glucose homeostasis in the rat F1 male offspring at adulthood. Pregnant rats were divided into three groups and administered with DEHP (10 and 100 mg/kg/day) or olive oil from gestational day 9 to postnatal day 21 (lactation period) through oral gavage. DEHP-exposed offspring exhibited hyperglycemia, impaired glucose and insulin tolerances along with hyperinsulinemia at postnatal day 80. DEHP exposure significantly reduced the levels of insulin signaling molecules such as insulin receptors, IRS1, Akt and its phosphorylated forms. GSK3β and FoxO1 proteins increased in DEHP-exposed groups whereas its phosphorylated forms decreased. Treated groups showed decreased glycogen synthase activity and glycogen concentration. Glucose-6-phosphatase and phosphoenolpyruvate carboxykinase mRNA level and enzyme activity increased in DEHP-treated groups. The interaction between FoxO1-glucose-6-phosphatase and FoxO1-phosphoenolpyruvate carboxykinase was also increased. This study suggests that DEHP exposure impairs insulin signal transduction and alters glucoregulatory events leading to the development of type 2 diabetes in F1 male offspring.

Keywords: DEHP; gluconeogenesis; glucose homeostasis; glycogenesis; insulin resistance; insulin signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Diethylhexyl Phthalate / therapeutic use*
  • Female
  • Glucose Tolerance Test
  • Glycogen / metabolism*
  • Insulin / blood
  • Insulin / metabolism*
  • Liver / drug effects*
  • Liver / embryology
  • Liver / metabolism
  • Liver Function Tests
  • Male
  • Maternal Exposure / adverse effects*
  • Pregnancy
  • Prenatal Exposure Delayed Effects / chemically induced*
  • Prenatal Exposure Delayed Effects / metabolism
  • Rats
  • Rats, Wistar
  • Signal Transduction


  • Insulin
  • Glycogen
  • Diethylhexyl Phthalate