Periconception onset diabetes is associated with embryopathy and fetal growth retardation, reproductive tract hyperglycosylation and impaired immune adaptation to pregnancy
| Autor: | M. Louise Hull, Hannah M. Brown, Jeremy G. Thompson, Macarena B. Gonzalez, Alice R. Rumbold, Ella S. Green, Tiffany C. Y. Tan, Sarah A. Robertson, Robert J. Norman, Nicolle H. Packer |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Glycosylation Offspring Pregnancy in Diabetics lcsh:Medicine Embryonic Development Article Diabetes Mellitus Experimental Andrology 03 medical and health sciences Mice 0302 clinical medicine Immune system Pregnancy Diabetes mellitus medicine Conceptus Animals Blastocyst lcsh:Science 030219 obstetrics & reproductive medicine Multidisciplinary Fetal Growth Retardation business.industry Reproduction lcsh:R Uterus Embryo Acquired immune system medicine.disease Embryo Mammalian Mice Inbred C57BL Pregnancy Complications 030104 developmental biology medicine.anatomical_structure Fertilization lcsh:Q Female business |
| Zdroj: | Scientific Reports Scientific Reports, Vol 8, Iss 1, Pp 1-13 (2018) |
| ISSN: | 2045-2322 |
| Popis: | Diabetes has been linked with impaired fertility but the underlying mechanisms are not well defined. Here we use a streptozotocin-induced diabetes mouse model to investigate the cellular and biochemical changes in conceptus and maternal tissues that accompany hyperglycaemia. We report that streptozotocin treatment before conception induces profound intra-cellular protein β-O-glycosylation (O-GlcNAc) in the oviduct and uterine epithelium, prominent in early pregnancy. Diabetic mice have impaired blastocyst development and reduced embryo implantation rates, and delayed mid-gestation growth and development. Peri-conception changes are accompanied by increased expression of pro-inflammatory cytokine Trail, and a trend towards increased Il1a, Tnf and Ifng in the uterus, and changes in local T-cell dynamics that skew the adaptive immune response to pregnancy, resulting in 60% fewer anti-inflammatory regulatory T-cells within the uterus-draining lymph nodes. Activation of the heat shock chaperones, a mechanism for stress deflection, was evident in the reproductive tract. Additionally, we show that the embryo exhibits elevated hyper-O-GlcNAcylation of both cytoplasmic and nuclear proteins, associated with activation of DNA damage (ɣH2AX) pathways. These results advance understanding of the impact of peri-conception diabetes, and provide a foundation for designing interventions to support healthy conception without propagation of disease legacy to offspring. |
| Databáze: | OpenAIRE |
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