Endocrine Abstracts

The in utero environment is crucial for both the prenatal and long-term health of the offspring. The placenta is able to modify its structure/function in response to maternal growth and nutritional signals to actively regulate maternal-to-fetus nutrient transfer and consequently optimum fetal development. Little is known about the molecular mechanisms involved in placental sensing of maternal nutrients. However, we postulate that nutrient flux through the hexosamine biosynthetic pathway (HBP), and the subsequent O-GlcNAcylation of proteins influences placental growth and hormone secretion and in turn, modulate its capacity to supply nutrients to the fetus. Immunostaining of a human placental cell line (BeWo) and first trimester placental tissue confirmed the presence of O-GlcNAc modified proteins and revealed the presence of the enzymes responsible for O-GlcNAc addition (O-GlcNAc-transferase; OGT) and removal (O-GlcNAcase; OGA). In order to investigate the effect of altering O-GlcNAcylation levels on placental function, BeWo cells (n=3) and first trimester explants (n=5) were treated with a specific substrate of the HBP pathway, D-glucosamine (0.25 mM, 1 mM or 10 mM) for 6, 24 or 48 h. Treatment enhanced the level of O-GlcNAc-modified proteins (in a dose and time dependant manner) and also altered their cellular distribution as staining was predominantly located in nuclear speckles. Interestingly, the increase in O-GlcNAcylation was accompanied by a significant decrease in growth factor-stimulated trophoblast proliferation (15% and 60% in BeWo and explants respectively; P<0.05). Furthermore, placental leptin secretion, a key regulator of placental amino acid uptake, was reduced (4-fold) in response to treatment with D-glucosamine for 48 h (P<0.05). These data localise OGT and OGA in placental tissue for the first time and reveal a potential role of the HBP pathway and the ensuing O-GlcNAc modifications in regulating human placental growth and function. The use of D-glucosamine and glucosamine-like supplements may be inadvisable during the first trimester of pregnancy.

Declaration of interest: There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding: No specific grant from any funding agency in the public, commercial or not-for-profit sector.