Reevaluation of Antioxidative Strategies for Birth Defect Prevention in Diabetic Pregnancies

Diabetes mellitus in early pregnancy is the most severe maternal disease that is counted for 10% of newborn infants with structural defects. With the rapid increases in the number of diabetic women in childbearing age, the birth defect rate is projected to elevate dramatically. Thus, prevention of embryonic malformations becomes an urgent task. Animal studies have revealed an involvement of oxidative stress in diabetic embryopathy and treatment with antioxidants can reduce embryonic abnormalities. However, the failure of clinical trials using free radical-scavenging antioxidants to alleviate oxidative stress-related diseases prompts researchers to reevaluate the strategy in birth defect prevention. Hyperglycemia also disturbs other intracellular homeostasis, generating aberrant conditions. Perturbed folding of newly synthesized proteins causes accumulation of unfolded and misfolded proteins in the lumen of the endoplasmic reticulum (ER). The ER under the stress activates signaling cascades, known as unfolded protein response, to suppress cell mitosis and/or trigger apoptosis. ER stress can be ameliorated by chemical chaperones, which promote protein folding. Hyperglycemia also stimulates the expression of nitric oxide (NO) synthase 2 (NOS2) to produce high levels of NO and reactive nitrogen species and augment protein nitrosylation and nitration, resulting in nitrosative stress. Inhibition of NOS2 using inhibitors has been demonstrated to reduce embryonic malformations in diabetic animals. Therefore, targeting ER and nitrosative stress conditions using specific agents to prevent birth defects in diabetic pregnancies warrant further investigations. Simultaneously targeting multiple stress conditions using combined agents is a potentially effective and feasible approach.