Periconception onset diabetes is associated with embryopathy and fetal growth retardation, reproductive tract hyperglycosylation and impaired immune adaptation to pregnancy View Full Text


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Article Info

DATE

2018-02-01

AUTHORS

Hannah M. Brown, Ella S. Green, Tiffany C. Y. Tan, Macarena B. Gonzalez, Alice R. Rumbold, M. Louise Hull, Robert J. Norman, Nicolle H. Packer, Sarah A. Robertson, Jeremy G. Thompson

ABSTRACT

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. More... »

PAGES

2114

References to SciGraph publications

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  • 2013-09-29. Diabetic Hyperglycemia activates CaMKII and Arrhythmias by O linked Glycosylation in NATURE
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  • 2004-02-01. Regulatory T cells mediate maternal tolerance to the fetus in NATURE IMMUNOLOGY
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  • Identifiers

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    http://scigraph.springernature.com/pub.10.1038/s41598-018-19263-8

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    31 schema:description 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.
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    39 GlcNAcylation
    40 IFNG
    41 IL1A
    42 Peri-conception changes
    43 Periconception onset diabetes
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    54 conception
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    56 cytokine TRAIL
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    66 embryo implantation rate
    67 embryos
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    71 fetal growth retardation
    72 foundation
    73 glycosylation
    74 growth
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    77 heat shock chaperones
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    81 immune adaptation
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    83 impact
    84 impaired fertility
    85 implantation rate
    86 increased expression
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    90 lymph nodes
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    93 mice
    94 mid-gestation growth
    95 model
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    98 nuclear proteins
    99 offspring
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