AJP - Endo Fuel your research with LabChart
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Am J Physiol Endocrinol Metab 289: E591-E599, 2005. First published May 31, 2005; doi:10.1152/ajpendo.00441.2004
0193-1849/05 $8.00
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
289/4/E591    most recent
00441.2004v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via ISI Web of Science (12)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Li, R.
Right arrow Articles by Loeken, M. R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Li, R.
Right arrow Articles by Loeken, M. R.

Hypoxic stress in diabetic pregnancy contributes to impaired embryo gene expression and defective development by inducing oxidative stress

Rulin Li,1,2 Martha Chase,1 Sung-Kwon Jung,3 Peter J. S. Smith,3 and Mary R. Loeken1,2

1Section on Developmental and Stem Cell Biology, Joslin Diabetes Center, Boston; 2Department of Medicine, Harvard Medical School, Boston; and 3BioCurrents Research Center, Program in Molecular Physiology, Marine Biological Laboratory, Woods Hole, Massachusetts

Submitted 16 September 2004 ; accepted in final form 25 May 2005

We have shown that neural tube defects (NTD) in a mouse model of diabetic embryopathy are associated with deficient expression of Pax3, a gene required for neural tube closure. Hyperglycemia-induced oxidative stress is responsible. Before organogenesis, the avascular embryo is physiologically hypoxic (2–5% O2). Here we hypothesized that, because O2 delivery is limited at this stage of development, excess glucose metabolism could accelerate the rate of O2 consumption, thereby exacerbating the hypoxic state. Because hypoxia can increase mitochondrial superoxide production, excessive hypoxia may contribute to oxidative stress. To test this, we assayed O2 flux, an indicator of O2 availability, in embryos of glucose-injected hyperglycemic or saline-injected mice. O2 flux was reduced by 30% in embryos of hyperglycemic mice. To test whether hypoxia replicates, and hyperoxia suppresses, the effects of maternal hyperglycemia, pregnant mice were housed in controlled O2 chambers on embryonic day 7.5. Housing pregnant mice in 12% O2, or induction of maternal hyperglycemia (>250 mg/dl), decreased Pax3 expression fivefold, and increased NTD eightfold. Conversely, housing pregnant diabetic mice in 30% O2 significantly suppressed the effect of maternal diabetes to increase NTD. These effects of hypoxia appear to be the result of increased production of mitochondrial superoxide, as indicated by assay of lipid peroxidation, reduced glutathione, and H2O2. Further support of this interpretation was the effect of antioxidants, which blocked the effects of maternal hypoxia, as well as hyperglycemia, on Pax3 expression and NTD. These observations suggest that maternal hyperglycemia depletes O2 in the embryo and that this contributes to oxidative stress and the adverse effects of maternal hyperglycemia on embryo development.

diabetic embryopathy; neural tube; hypoxia; Pax3


Address for reprint requests and other correspondence: M. R. Loeken, Joslin Diabetes Center, One Joslin Pl., Boston, MA 02215 (e-mail: Mary.loeken{at}joslin.harvard.edu)






HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online
Copyright © 2005 by the American Physiological Society.