Maternal di‐(2‐ethylhexyl) phthalate exposure alters hepatic insulin signal transduction and glucoregulatory events in rat F₁ male offspring

Abstract

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.

Early-Life Origins of Metabolic Syndrome: Mechanisms and Preventive Aspects

“…A broad range of early-life environmental chemical exposures have been related to increased risk for developing hypertension of developmental origins, as we reviewed elsewhere [94]. These chemicals, di-(2-ethylhexyl) phthalate (DEHP) and bisphenol A, have been studied for their impact on insulin resistance in adult progeny [63,65]. These findings are in agreement with epidemiological research data showing that endocrine-disrupting chemical exposure is linked to CVDs later in life [95].…”

Maternal Supplementation of Probiotics, Prebiotics or Postbiotics to Prevent Offspring Metabolic Syndrome: The Gap between Preclinical Results and Clinical Translation

“…Prior review showed adult rats exposed to several chemicals during early life developed hypertension, a major feature of MetS [ 78 ]. These chemicals, while only bisphenol A and di-(2-ethylhexyl) phthalate (DEHP), have shown their programming effects resulting in insulin resistance in adult progeny [ 79 , 80 ].…”

Investigation of combined effects of propyl paraben and methyl paraben on the hypothalamic-pituitary-adrenal axis in male rats

“…Studies with endocrine-disrupting chemicals show that they activate gluconeogenesis abnormally through the activation of enzymes involved in gluconeogenesis in the liver. It is also known that glucose uptake in tissues decreases as a result of exposure to endocrine disruptors (Rajagopal et al, 2019a(Rajagopal et al, , 2019b. So, exposure to MeP+PrP may have directly affected glucose metabolism.…”