RESEARCH ARTICLE Maternal di‐(2‐ethylhexyl) phthalate exposure alters hepatic insulin signal transduction and glucoregulatory events in rat F 1 male offspring Gokulapriya Rajagopal | Ravi Sankar Bhaskaran | Balasubramanian Karundevi Department of Endocrinology, Dr ALM Post Graduate Institute of Basic Medical Sciences, University of Madras, Taramani, Chennai 600 113, India Correspondence Balasubramanian Karundevi, UGC‐BSR Faculty Fellow, Department of Endocrinology, Dr. ALM PG Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai 600 113, India. Email: kbala82@hotmail.com Funding information UGC‐BSR Fellowship Abstract Di‐(2‐ethylhexyl) phthalate (DEHP) is a commonly used plasticizer with endocrine disrupting properties. Its widespread use resulted in constant human exposure includ- ing fetal development and postnatal life. Epidemiological and experimental data have shown that DEHP has a negative influence on glucose homeostasis. However, the evi- dence regarding the effect of maternal DEHP exposure on hepatic glucose homeosta- sis is scarce. Hence, we investigated whether DEHP exposure during gestation and lactation disrupts glucose homeostasis in the rat F 1 male offspring at adulthood. Preg- nant 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 pro- teins increased in DEHP‐exposed groups whereas its phosphorylated forms decreased. Treated groups showed decreased glycogen synthase activity and glyco- gen 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 develop- ment of type 2 diabetes in F 1 male offspring. KEYWORDS DEHP, gluconeogenesis, glucose homeostasis, glycogenesis, insulin resistance, insulin signaling 1 | INTRODUCTION Di‐2‐ethylhexyl phthalate (DEHP) is the most common member of the class of phthalates, which is used as a plasticizer in polyvinyl chloride products to make plastic flexible. It is a colorless, viscous and lipophilic liquid, which is more soluble in organic solvents than in water and has almost no odor (Hauser & Calafat, 2005; Rowdhwal & Chen, 2018; Schettler, 2006). Phthalates are used in a wide variety of consumer products, including flooring, carpeting, roofing, vinyl wall covering, upholstery, wire, cable sheathing, clothing, personal care products, pharmaceuticals, medical devices, children's toys, food packaging and building materials (Dodson et al., 2012; Heudorf, Mersch‐ Sundermann, & Angerer, 2007; Koch, Preuss, & Angerer, 2006; Koniecki, Wang, Moody, & Zhu, 2011; Wittassek & Angerer, 2008). World production of this compound is about several million tons per year (Gomez‐Hens & Aguilar‐Caballos, 2003). Owing to its low cost, Received: 27 August 2018 Revised: 13 November 2018 Accepted: 13 November 2018 DOI: 10.1002/jat.3764 J Appl Toxicol. 2018;1–13. © 2018 John Wiley & Sons, Ltd. wileyonlinelibrary.com/journal/jat 1