Portions of this article were presented at the 67th Annual Meeting of the American Diabetes Association, June 22–26, 2007, Chicago, IL.
Oxidative stress during diabetic pregnancy disrupts cardiac neural crest migration and causes outflow tract defects†
Article first published online: 24 APR 2008
Copyright © 2008 Wiley-Liss, Inc.
Birth Defects Research Part A: Clinical and Molecular Teratology
Volume 82, Issue 6, pages 453–463, June 2008
How to Cite
Morgan, S. C., Relaix, F., Sandell, L. L. and Loeken, M. R. (2008), Oxidative stress during diabetic pregnancy disrupts cardiac neural crest migration and causes outflow tract defects. Birth Defects Research Part A: Clinical and Molecular Teratology, 82: 453–463. doi: 10.1002/bdra.20457
- Issue published online: 2 JUN 2008
- Article first published online: 24 APR 2008
- Manuscript Accepted: 14 FEB 2008
- Manuscript Revised: 12 FEB 2008
- Manuscript Received: 8 JAN 2008
- American Diabetes Association. Grant Number: 1-04-RA-65
- National Institutes of Health. Grant Number: DK52865 (M. R. L.)
- cardiac neural crest;
- outflow tract;
- diabetic pregnancy;
- oxidative stress;
- diabetic teratogenesis
BACKGROUND: Maternal diabetes increases risk for congenital malformations, particularly cardiac outflow tract defects. Maternal diabetes inhibits expression of Pax3 in neuroepithelium through hyperglycemia-induced oxidative stress. The neuroepithelium gives rise to the neural crest, and Pax3 expression in cardiac neural crest (CNC) is required for CNC migration to the heart and for outflow tract septation. Here we tested whether maternal diabetes, through hyperglycemia-induced oxidative stress, before the onset of CNC delamination, impairs CNC migration and cardiac outflow tract septation. METHODS: CNC migration was mapped in mouse embryos whose mothers were diabetic, or transiently hyperglycemic, or in which oxidative stress was transiently induced, using reporters linked to Pax3 expression. CNC apoptosis was examined by TUNEL assay. Outflow tract septation was examined histologically and by gross inspection. RESULTS: Few, if any, migrating CNC cells were observed in embryos of diabetic mice, and this was associated with increased apoptosis along the path of CNC migration. Outflow tract defects were significantly increased in fetuses of diabetic mice. Notably, induction of hyperglycemia or oxidative stress on the day prior to the onset of Pax3 expression and CNC migration also impaired CNC migration, increased apoptosis, and caused outflow tract defects. However, antioxidants administered on the day prior to the onset of Pax3 expression and CNC migration prevented these effects of hyperglycemia or oxidative stress. CONCLUSIONS: In diabetic pregnancy, oxidative stress, which inhibits expression of genes required for CNC viability, causes subsequent CNC depletion by apoptosis during migration, which leads to outflow tract defects. Birth Defects Research (Part A), 2008. © 2008 Wiley-Liss, Inc.