Postnatal exposure to di‐(2‐ethylhexyl)phthalate alters cardiac insulin signaling molecules and GLUT4Ser488 phosphorylation in male rat offspring

• Published in: Journal of cellular biochemistry 2019-04, Vol.120 (4), p.5802-5812
• Main Authors: Parsanathan, Rajesh, Maria Joseph, Angelaalincy, Karundevi, Balasubramanian
• Format: Article
• Language: English
• Subjects: AKT protein; Blood; Blood glucose; Body weight; Breast milk; Breastfeeding & lactation; Carbon 14; cardiac insulin signaling; Cardiac muscle; Consumer products; Deoxyglucose; endocrine disruptor; Endocrine disruptors; Exposure; Genetic crosses; Glucose; Glucose transporter; Homeostasis; Hyperglycemia; Insulin; Insulin receptor substrate 1; Kinases; Lactation; Muscles; Offspring; Oils & fats; Olive oil; Organic chemistry; Oxidation; pGLUT4Ser488; Phosphorylation; phthalate; Placenta; plasticizer; Proteins; Signaling; Substrates; Translocation
• ISSN: 0730-2312; 1097-4644
• DOI: 10.1002/jcb.27866

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 14C‐2‐deoxyglucose uptake and 14C‐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. Postnatal developmental exposure to environmentally relevant concentrations of di‐(2‐ethylhexyl)phthalate (DEHP) can disrupt cardiac glucometabolic activities which may impair the cardiac function of F1 male rat offspring. 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 postnatal day 22 (PND22) which may impair cardiac function.