ERO1α DNA methylation is associated with intergenerational effects of zinc, selenium, and chromium on ER stress and glucose homeostasis in female offspring of gestational diabetes rats

Introduction Zinc, selenium, and chromium supplementation improved hepatic endoplasmic reticulum (ER) stress in gestational diabetes mellitus (GDM) rats and had beneficial intergenerational effects on glucose homeostasis in female offspring. However, whether the epigenetic molecular mechanism is involved in the intergenerational effects of zinc, selenium, and chromium is relatively unknown. Methods Here, female Sprague Dawley rats were fed with either a high-fat and sucrose (HFS), to induce the GDM model, or a low-fat (LF) diet for three consecutive generations (F0, F1, and F2), and supplemented with zinc (10 mg/kg.bw), selenium (20 μg/kg.bw), and chromium (20 μg/kg.bw) daily by gavage. Global DNA methylation levels and methylation status of ER stress-related genes promoter regions were investigated in the liver of F1 and F2 female neonates. Results GDM caused glucose intolerance, insulin resistance, hepatic ER stress, and increased global DNA methylation in F1 and F2 female neonates. Pyrosequencing revealed increased ERO1α promoter methylation in F1 and F2 female neonates, accompanied by reduced ERO1α gene expression and increased hepatic ER stress. Combined zinc, selenium, and chromium supplementation attenuated these alterations and improved glucose homeostasis in female offspring of GDM rats. Discussion These findings suggest that ERO1α promoter methylation may be associated with alterations in glucose homeostasis and hepatic ER stress across generations.