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Advances in Understanding the Molecular Causes of Diabetes-Induced Birth Defects

Section on Developmental and Stem Cell Biology, Joslin Diabetes Center, Department of Medicine, Harvard Medical School, Boston, Massachusetts; mary.loeken{at}joslin.harvard.edu

Objective: To review the current understanding of the molecular causes of birth defects resulting from diabetic pregnancy, with a focus on neural tube defects.

Methods: A mouse model of diabetic pregnancy is described, in which embryo gene expression associated with neural tube defects is examined. Chemical, physiologic, or genetic manipulations are employed to elucidate critical pathways affected by increased glucose metabolism, and how abnormal gene expression disrupts neural tube closure.

Results: Increased glucose delivery to embryos, or activation of pathways that are stimulated by high glucose, such as the hexosamine biosynthetic pathway or hypoxia, increase oxidative stressin embryos, inhibit expression of Pax3, a gene that encodes a transcription factor that is required for neural tube closure, and increase neural tube defects. Conversely, blocking these pathways, or providing the antioxidants, reduced glutathione or vitamin E, suppress the adverse effects of excess glucose. Pax3 decreases steady-state levels of the p53 tumor-suppressor protein, such that when Pax3 is deficient, p53 protein increases, leading to increased neuroepithelial apoptosis prior to completion of neural tube closure. Embryos that lack both functional Pax3 protein and p53 do not display neuroepithelial apoptosis or neural tube defects.

Conclusions: Excess glucose metabolism by embryos resulting from maternal hyperglycemia disturbs a complex network of biochemical pathways, leading to oxidative stress. Oxidative stress inhibits expression of genes, such as Pax3, which control essential developmental process. Pax3 protein is required during neural tube development to suppress p53-dependent cell death and consequent abortion of neural tube closure, but is not required to control expression of genes that direct neural tube closure. Impaired embryo gene expression resulting from oxidative stress, and consequent apoptosis or disturbed organogenesis, may be a general mechanism to explain diabetic embryopathy.

Key Words: Diabetic embryopathy • diabetic pregnancy • neural tube defect • Pax3 • p53

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