Abstract
Maternal stress programs offspring disease in a sexually dimorphic manner with males often more adversely affected. Previous studies of maternal glucocorticoid exposure suggest male vulnerability may derive from placental alterations. The hexosamine signalling pathway and O-linked glycosylation (O-GlcNAcylation) are part of an essential adaptive survival response in healthy cells. The key enzyme involved is O-linked-N-acetylglucosamine transferase (OGT), a gene recently identified as a sex-specific placental biomarker of maternal stress. Using a mouse model of maternal corticosterone (Cort) exposure, we examined components of hexosamine biosynthesis/signalling and O-GlcNAcylation in whole placentae at E14.5. Our results demonstrate sex-specific differences in OGT levels and O-GlcNAcylation during Cort exposure which impacts on key mediators of cell survival, in particular AKT as well as the stress responsive OGT/GR transrepression complex. In male placentae only, Cort exposure increased Akt O-GlcNacylation which correlated with decreased phosphorylation. Female placentae had higher basal OGT and OGT/GR complex compared with male placentae. Cort exposure did not alter these levels in female placentae but increased global O-GlcNacylation. In male placentae Cort increased OGT and OGT/GR complex with no change in global O-GlcNacylation. These findings suggest that sex-specific differences in placental OGT play a key role in the sexually dimorphic responses to stress.
Highlights
A sub-optimal or stressful environment in utero has long been recognised as having the potential to alter adult disease propensity[1]
We have recently demonstrated a similar magnitude of change in Cort concentrations in rats that were subjected to acute restraint stress[21] and previous studies have demonstrated a similar relative increase in women with a stressful labour[22]. Using this physiologically relevant model of Cort exposure, our results lead us to conclude that changes in O-linked-N-acetylglucosamine transferase (OGT) and hexosamine signalling in the placenta in response to maternal stress is likely to be a key mechanism through which sex-specific fetal programming occurs
Using the same model as utilised in the current study, we have previously demonstrated that maternal Cort exposure induced sexually dimorphic placental adaptations at 48 hours of exposure (E14.5)[4]
Summary
A sub-optimal or stressful environment in utero has long been recognised as having the potential to alter adult disease propensity[1]. Recent studies suggest that the X-linked OGT may be a placental biomarker of maternal stress[7] and implicated as a driver of sex disparity in disease[8] This key nucleoplasmic enzyme catalyses the terminal transfer step in the hexosamine signalling pathway which results in the post-translational modification of numerous cellular regulatory proteins in the nucleus and cytoplasm with a single moiety of N-acetyl glucosamine (N-GlcNAc) through O-linked glycosylation (O-GlcNAcylation) of key serine and threonine residues[9]. We have recently demonstrated a similar magnitude of change in Cort concentrations in rats that were subjected to acute restraint stress[21] and previous studies have demonstrated a similar relative increase in women with a stressful labour[22] Using this physiologically relevant model of Cort exposure, our results lead us to conclude that changes in OGT and hexosamine signalling in the placenta in response to maternal stress is likely to be a key mechanism through which sex-specific fetal programming occurs
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