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.
Highlights
Worldwide, one in seven pregnancies are complicated by diabetes[1]
At d3.5 p.c., fewer viable embryos were flushed from the uterus (Fig. 1D,E) and many had evidence of arrest at cleavage or morula stages with a 60% reduction in their development to blastocyst (Fig. 1F). γH2AX was used to assess DNA damage in these embryos and RL2 was used to assess β-O-GlcNAc status
To examine if the effect extended throughout the reproductive tract, we examined the abundance of O-GlcNAc in the ovary in the streptozotocin-treated mice on d1.5 p.c. of pregnancy, but no difference in staining was evident
Summary
One in seven pregnancies are complicated by diabetes[1]. Pregnancy in women with diabetes is associated with increased risk of fetal, neonatal and obstetric complications, maternal morbidity and mortality, and a 4- to 10-fold elevated risk that infants will develop diabetes as adults[2]. Altered O-GlcNAc signalling is directly involved in the pathogenesis of diabetes and new insights are revealing the importance of O-GlcNAc in diabetic complications[12] It is not known whether O-GlcNAc is altered within the reproductive tract in diabetes, whether this is evident during early development, and if maternal hyperglycemia influences O-GlcNAc in embryos. Given the well-described role of O-GlcNAc in immune cell regulation and cytokine signalling[18], the impact of hyperglycaemia on inflammatory parameters[19], and the significance of the maternal immune response for fetal growth and offspring health[20], we predicted a role for the local and systemic immune milieu in mediating the adverse effect of diabetes on early development. We utilise the well-defined streptozotocin-induced diabetes mouse model to define the impact of periconception-onset diabetes on biochemical and inflammatory parameters in the reproductive tract, and the consequences for early embryo development and pregnancy progression
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