Toxic Effects of Hyperglycemia Are Mediated by the Hexosamine Signaling Pathway and O-Linked Glycosylation in Early Mouse Embryos1
| Autor: | H. Y. Tan, Georgia R. Kafer, Peter L. Kaye, Marie Pantaleon |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
Programmed cell death
medicine.medical_specialty Glycosylation Embryonic Development Gestational Age Biology N-Acetylglucosaminyltransferases Models Biological Antibodies Mice Pregnancy Internal medicine Acetylglucosaminidase medicine Animals Blastocyst Maternal-Fetal Exchange Cell growth Hexosamines Cell Biology General Medicine Embryo Mammalian Embryonic stem cell Enzyme Activation Pregnancy Complications medicine.anatomical_structure Endocrinology Reproductive Medicine Apoptosis Hyperglycemia O-linked glycosylation Carbohydrate Metabolism Female Signal transduction Flux (metabolism) Research Article Signal Transduction |
| Zdroj: | Biology of Reproduction. 82:751-758 |
| ISSN: | 1529-7268 0006-3363 |
| Popis: | 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-GlcNAc-selective 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. |
| Databáze: | OpenAIRE |
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