DEHP and DBP, common phthalates, induce glucose metabolism disorders in rats via oxidative damage of PI3K/Akt/GLUT4 signaling

Abstract

Phthalic acid esters (PAEs) are environmental endocrine disruptors thought to interfere with glucose metabolism in humans. Most of the related research has focused on population epidemiological studies, with the underlying mechanisms remaining unresolved. Using an in vivo animal model, we examined the effects of oral administration of two commonly used PAEs [di(2-ethylhexyl) phthalate (DEHP) and dibutyl phthalate (DBP)] on glucose homeostasis and insulin secretion. DEHP (750 mg/kg, 1/40 LD₅₀), DBP (500 mg/kg, 1/40 LD₅₀), and DEHP (750 mg/kg) + DBP (500 mg/kg) exert an influence on glucose metabolism and elicit a reduction in insulin sensitivity in rats. Furthermore, these substances induce detrimental effects on the structure and functionality of pancreatic β-cells. DEHP and/or DBP triggered an increase in plasma malondialdehyde (MDA) and reduction in superoxide dismutase (SOD) activity; a reduction in the phosphorylation of phosphatidyl inositol 3 kinase (PI3K) and phospho-protein kinase B (p-Akt⁴⁷³) proteins; an increase in the relative expression of Bax, Caspase-8, cleaved-Caspase-9, and cleaved-Caspase-3; and a reduction in the relative expression of Bcl-2-related Bax in pancreatic tissue and of gastrocnemius glucose transporter 4 (GLUT4) in the gastrocnemius muscle. Based on these findings, these PAEs can disrupt glucose metabolism, possibly via oxidative damage of the PI3K/Akt/GLUT4 pathway; this damage induces pancreatic β-cell apoptosis, affects pancreatic β-cell function, and affects glucose metabolism and insulin resistance in rats. To the best of our knowledge, this study was the first to show that the combined effect of the two PAEs affects glucose metabolism and insulin resistance in rats that is significantly higher than the effects of each PAE. Thus, safety standards and studies do not consider this effect as a significant oversight when blending PAEs. We assert that this must be addressed and corrected for establishing more impactful and safer standards.

Keywords: Apoptosis; Glucose metabolism; Metabolic disorder; Oxidative damage; Pancreas; Phthalic acid ester.