Placental O-GlcNAc-transferase expression and interactions with the glucocorticoid receptor are sex specific and regulated by maternal corticosterone exposure in mice

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.

Long-term patterns of fasting blood glucose levels and pancreatic cancer incidence

“…5,6 Yet, previous studies yielded conflicting results on the association between duration of diabetes and PaC incidence. 10 Given that a sizable proportion of diabetes remain undiagnosed in the general population, 11 previous studies that relied on self-reported diabetes may have considerably misclassified duration of T2D. In addition, pathophysiologic processes such as hyperinsulinemia and hyperglycemia occur before the overt diagnosis of T2D.To address the complex temporal relationship of pre-diabetes and diabetes with PaC, a defining characteristic of the optimal study setting is the availability of repeated measurements of fasting blood glucose (FBG) spanning a long period.…”

Maternal corticosterone in the mouse alters oxidative stress markers, antioxidant function and mitochondrial content in placentas of female fetuses

“…; Pantaleon et al . ). The investigators within the study understand the ethical requirements and have complied with the principles and standards for reporting animal experiments in The Journal of Physiology and Experimental Physiology checklist.…”

“…Total protein was extracted from 50 mg of frozen placental or maternal liver tissue as described previously (Pantaleon et al . ). All samples were normalized to a protein content of 3 μg μl −1 for use in each of the activity assays and western blotting procedures.…”

“…), as well as protein modifications including increased O‐GlcNacylation and reduced phosphorylation of Akt (Pantaleon et al . ). In contrast, maternal corticosterone exposure had minimal effects on these molecular pathways in placentas from females.…”

Role of omega‐6 and omega‐3 fatty acids in fetal programming

“…Despite many studies investigating the impact of adverse maternal condition on sex‐specific fetal outcomes, the underlying mechanism behind an altered sex ratio is still unclear . However, studies have suggested that the expression of several stress‐responsive proteins within the placenta may escape X inactivation, meaning that females are better able to survive in response to a stressful stimulus, whereas males may be lost . If this occurs early in pregnancy, before recognition of pregnancy, this may appear as though male fetuses were never conceived.…”