An adverse intrauterine environment can program adult disease in a sexually dimorphic manner. Female offspring appear to be more resistant to a stressful environment in utero whereas male offspring are adversely affected. Our previous studies of short-term (60h) glucocorticoid exposure in the mouse, during gestation suggest that male vulnerability to stress may occur at the level of the placenta (1). The mechanisms by which the fetal/placental unit senses and responds to a stressful environment however are not understood. Cellular ability to respond to multiple forms of stress is associated with the ability to rapidly increase glucose uptake and metabolise it through the hexosamine signalling pathway and O-linked glycosylation. This is an essential survival response of adaptive importance in healthy cells. Interestingly, the X-linked O-linked-N-acetylglucosamine transferase (OGT), responsible for regulating numerous survival factors, such as Akt, by O-linked glycosylation (O-GlcNAcylation), has recently been identified as a placental biomarker of maternal stress (2). Using our mouse model of maternal glucocorticoid exposure associated with sexually dimorphic programming and placental outcomes (above), we examined levels of key enzymes of hexosamine biosynthesis and signalling as well as levels of O-GlcNAcylation in mouse placentae at E14.5 by RT-PCR and immunoblotting. Our results demonstrate that the O-linked GlcNAcylation response to stress is blunted in male placentae relative to female placentae suggesting that dysregulation of this signaling pathway may underlie the sexually dimorphic response to a stressful environment in utero. Increased levels of the stress-responsive, pro-survival factor, Akt2 in placentae from female (P<0.05), but not male fetuses following glucocorticoid administration further supports this notion. Given that dysregulation of O-GlcNAcylation is implicated in a growing number of adult diseases our results suggest that sex-specific alterations in placental OGT levels in response to stress may act to protect the female fetus from propensity to adult disease in later life.