Developmental exposure to DEHP alters hepatic glucose uptake and transcriptional regulation of GLUT2 in rat male offspring

Abstract

Type-2-diabetes (T2D) is a long term metabolic disorder characterized by high blood glucose and insulin resistance. It has become an alarming issue globally due to tremendous increase in number of new subjects every year. Apart from the classical factors, there are few non-classical factors such as environmental pollutants, endocrine disrupting chemicals (EDCs) which also play a major role in pathogenesis of T2D. Di-(2-ethylhexyl) phthalate (DEHP) is a commonly used plasticizer which is an endocrine disrupting chemical. It is used in the plastic industry to give flexibility and durability. Its widespread use resulted in constant presence in the environment and human are under high risk of exposure to this compound. There are literature available stating that DEHP has an impact on glucose homeostasis. Glucose transporter 2 (GLUT2) is a principal transporter of glucose in liver and it is a bi-directional transporter. We investigated whether DEHP exposure during gestation and lactation alters transcriptional regulation of GLUT2 and epigenetics changes 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 (GD) 9- to postnatal day (PND) 21 through oral gavage. DEHP treated rats showed decreased glucose uptake and oxidation, decreased mRNA levels of insulin receptor (IR), GLUT2 and reduced GLUT2 protein in cytosol but unaltered level in plasma membrane. There are three main transcription factors (SREBP1c, HNF3β and HNF1α) involved in the regulation of GLUT2 gene and all these proteins were reduced in DEHP exposed groups. A weak interaction of the transcription factors (SREBP1c & HNF1α) with GLUT2 gene promoter was observed in DEHP-treated groups. Hyper- methylation of IR and GLUT2 gene promoter was observed in both the DEHP-exposed groups compared to control. The present study reveals that DEHP exposure alters transcriptional regulation of GLUT2 and imposes epigenetic alteration in IR and GLUT2 gene promoters which plays a significant role in the development of metabolic abnormality in F₁ male offspring at adulthood.

Keywords: DEHP; Epigenetics; GLUT2; Glucose homeostasis; Insulin resistance.