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

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.

Protein O-GlcNAcylation Promotes Trophoblast Differentiation at Implantation

“…The only previous attempt to elevate O-GlcNAcylation in pre-implantation embryos used the alternative OGA inhibitor PUGNAc [ 26 ], which is known to exhibit off-target effects [ 47 ]. In common with our study, Pantaleon et al also used immunostaining with RL2 anti-O-GlcNAcylated protein antibody and showed nuclear and nuclear membrane localisation, as did more recent studies [ 27 , 28 , 29 ]. These localisations likely reflect a concentration of O-GlcNAcylated proteins in nuclear pore complexes [ 48 ], which play important roles in early embryogenesis [ 27 , 28 ], and among DNA-associated proteins such as transcription complexes and histones [ 49 ].…”

“…Current evidence suggests that O-GlcNAcylation downstream of the HBP is required for embryonic genome activation and specification of the TE lineage, through regulation of nuclear localisation of tricarboxylic acid enzymes and Yes-associated protein 1 (YAP1), respectively [ 27 , 28 ]. However, a recent study reported that the increased O-GlcNAcylation observed in blastocysts and endometrium of a mouse model of diabetes is associated with reduced implantation [ 29 ]. Furthermore, placental O-GlcNAcylation is increased in response to stressors such as noise, restraint or disturbance during early gestation, giving rise to altered offspring growth and behaviour [ 30 ].…”

O-GlcNAc Modification During Pregnancy: Focus on Placental Environment

“…Embryos from diabetic mothers display exacerbated DNA damage, evidenced by the co - localization of H2AX. O- GlcNAcylation was observed in diabetic blastocyst-stage embryos, favoring impairment of pre-implantation embryo development ( Brown et al, 2018 ). That precursors coming from the metabolic flux have the ability to modulate nuclear function has been denominated metaboloepigenetics ( Donohoe and Bultman, 2012 ); this mechanism provides evidence for an epigenetic contribution to the vertical transmission of diabetes.…”

“…Reduced embryo implantation and impaired blastocyst development was observed in an experimental mouse model of diabetes. These findings were related to an inflammatory imbalance, elicited by increased expression of pro-inflammatory cytokines in the uterus, including IL-1α, TNF-α, and interferon gamma (IFNγ), and a pronounced reduction of anti-inflammatory regulatory T-cells within the uterus-draining lymph nodes ( Brown et al, 2018 ).…”

Mental health status among women of reproductive age from underserved communities in the United States and the associations between depression and physical health. A cross-sectional study

“…Self-rated health is measure of general health with the response items of "excellent," "very good," "good," "fair," or "poor." The conditions included in the analysis have been associated with potential pregnancy complications and fetal health [33][34][35][36].…”