Abstract
Diabetes mellitus in early pregnancy causes birth defects, including neural tube defects (NTDs). Hyperglycemia increases production of nitric oxide (NO) through NO synthase 2 (Nos2) and reactive oxygen species (ROS), generating nitrosative and oxidative stress conditions in the embryo. The present study aimed to target nitrosative stress using a naturally occurring Nos2 inhibitor, quercetin, to prevent NTDs in the embryos of diabetic mice. Daily administration of quercetin to diabetic pregnant mice during the hyperglycemia-susceptible period of organogenesis significantly reduced NTDs and cell apoptosis in the embryos, compared with those of vehicle-treated diabetic pregnant mice. Using HPLC-coupled ESI-MS/MS, quercetin metabolites, including methylated and sulfonylated derivatives, were detected in the conceptuses. The methylated metabolite, 3-O-methylquercetin, was shown to reduce ROS level in embryonic stem cells cultured in high glucose. Quercetin treatment decreased the levels of Nos2 expression, protein nitrosylation, and protein nitration, alleviating nitrosative stress. Quercetin increased the expression of superoxide dismutase 1 and 2, and reduced the levels of oxidative stress markers. Expression of genes of redox regulating enzymes and DNA damage repair factors was upregulated. Our study demonstrates that quercetin ameliorates intracellular stresses, regulates gene expression, and reduces embryonic malformations in diabetic pregnancy.
Highlights
Diabetes mellitus in early pregnancy causes birth defects, including neural tube defects (NTDs)
Diabetes mellitus in early pregnancy increases the risk of birth defects in infants, a complication known as diabetic embryopathy[1,2]
After treatments with quercetin (QC), we examined the effects on NTD formation in the embryos of diabetic (DM) mice
Summary
Diabetes mellitus in early pregnancy causes birth defects, including neural tube defects (NTDs). Structural abnormalities, including exencephaly and spina bifida, most commonly occur in the central nervous system as the result of incomplete closure of the neural tube during early embryogenesis[3,4] These anomalies are referred to as neural tube defects (NTDs), and cause significant morbidity and mortality[5,6]. Maternal hyperglycemia alters the morphology and function of mitochondria and elevates levels of reactive oxygen species (ROS) in the embryo[14,15] It diminishes endogenous antioxidative buffering, including depletion of antioxidants, such as glutathione, and reduction of the expression and activity of antioxidative enzymes, including superoxide dismutases (SODs) and glutathione peroxidases (GPXes), resulting in oxidative stress[16,17]
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