Toxic effects of hyperglycemia are mediated by the hexosamine signaling pathway and O-linked glycosylation in early mouse embryos

Marie Pantaleon, Hwee Y. Tan, Georgia R. Kafer and Peter L. Kaye (2009) Toxic effects of hyperglycemia are mediated by the hexosamine signaling pathway and O-linked glycosylation in early mouse embryos. Biology of Reproduction, 82 4: 751-758. doi:10.1095/biolreprod.109.076661


Author Marie Pantaleon
Hwee Y. Tan
Georgia R. Kafer
Peter L. Kaye
Title Toxic effects of hyperglycemia are mediated by the hexosamine signaling pathway and O-linked glycosylation in early mouse embryos
Formatted title
Toxic effects of hyperglycemia are mediated by the hexosamine signaling pathway and O-linked glycosylation in early mouse embryos
Journal name Biology of Reproduction   Check publisher's open access policy
ISSN 0006-3363
1529-7268
0523-6754
Publication date 2009-12
Year available 2009
Sub-type Article (original research)
DOI 10.1095/biolreprod.109.076661
Volume 82
Issue 4
Start page 751
End page 758
Total pages 8
Place of publication Madison, WI, United States
Publisher Society for the Study of Reproduction
Collection year 2011
Language eng
Formatted abstract
Maternal hyperglycemia is believed to be the metabolic derangement associated with both early pregnancy loss and congenital malformations in a diabetic pregnancy. Using an in vitro model of embryo exposure to hyperglycemia, this study questioned if increased flux through the hexosamine signaling pathway (HSP), which results in increased embryonic O-linked glycosylation (O-GlcNAcylation), underlies the glucotoxic effects of hyperglycemia during early embryogenesis. Mouse zygotes were randomly allocated to culture treatment groups that included no glucose (no flux through HSP), hyperglycemia (27 mM glucose, excess flux), 0.2 mM glucosamine (GlcN) in the absence of glucose (HSP flux alone), and O-GlcNAcylation levels monitored immunohistochemically. The impact of HSP manipulation on the first differentiation in development, blastocyst formation, was assessed, as were apoptosis and cell number in individual embryos. The enzymes regulating O-GlcNAcylation, and therefore hexosamine signaling, are the beta-linked-O-GlcNAc transferase (OGT) and an O-GlcNAcselective beta-N-acetylglucosaminidase (O-GlcNAcase). Inhibition of these enzymes has a negative impact on blastocyst formation, demonstrating the importance of this signaling system to developmental potential. The ability of the OGT inhibitor benzyl-2-acetamido-2-deoxy-alpha-D-galactopyranoside (BADGP) to reverse the glucotoxic effects of hyperglycemia on these parameters was also sought. Excess HSP flux arising from a hyperglycemic environment or glucosamine supplementation reduced cell proliferation and blastocyst formation, confirming the criticality of this signaling pathway during early embryogenesis. Inhibition of OGT using BADGP blocked the negative impact of hyperglycemia on blastocyst formation, cell number, and apoptosis. Our results suggest that dysregulation of HSP and O-GlcNAcylation is the mechanism by which the embryotoxic effects of hyperglycemia are manifested during preimplantation development. © 2010 by the Society for the Study of Reproduction, Inc.
Keyword Apoptosis
Early development
Embryo
Embryo metabolism
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Available online 23 December 2009

Document type: Journal Article
Sub-type: Article (original research)
Collections: 2010 Higher Education Research Data Collection
School of Biomedical Sciences Publications
 
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Created: Wed, 24 Mar 2010, 11:42:10 EST by Timothy Hazelton on behalf of School of Biomedical Sciences