Evidence of adaptation of maternofetal transport of glutamine relative to placental size in normal mice, and in those with fetal growth restriction

Abstract

Key points Fetal growth restriction (FGR) is a major risk factor for stillbirth and has significant impact upon lifelong health. A small, poorly functioning placenta, as evidenced by reduced transport of nutrients to the baby, underpins FGR. It remains unclear how a small but normal placenta differs from the small FGR placenta in terms of ability to transfer nutrients to the fetus. Placental transport of glutamine and glutamate, key amino acids for fetal growth, was assessed in normal mice and those with FGR. Glutamine and glutamate transport was greater in the lightest versus heaviest placenta in a litter of normally grown mice. Placentas of mice with FGR had increased transport capacity in mid‐pregnancy, but this adaptation was insufficient in late pregnancy. Placental adaptations, in terms of increased nutrient transport (per gram) to compensate for small size, appear to achieve appropriate fetal growth in normal pregnancy. Failure of this adaptation might contribute to FGR. Abstract Fetal growth restriction (FGR), a major risk factor for stillbirth, and neonatal and adulthood morbidity, is associated with reduced placental size and decreased placental nutrient transport. In mice, a small, normal placenta increases its nutrient transport, thus compensating for its reduced size and maintaining normal fetal growth. Whether this adaptation occurs for glutamine and glutamate, two key amino acids for placental metabolism and fetal growth, is unknown. Additionally, an assessment of placental transport of glutamine and glutamate between FGR and normal pregnancy is currently lacking. We thus tested the hypothesis that the transport of glutamine and glutamate would be increased (per gram of tissue) in a small normal placenta [C57BL6/J (wild‐type, WT) mice], but that this adaptation fails in the small dysfunctional placenta in FGR [insulin‐like growth factor 2 knockout (P0) mouse model of FGR]. In WT mice, comparing the lightest versus heaviest placenta in a litter, unidirectional maternofetal clearance (Kmf) of 14C‐glutamine and 14C‐glutamate (glutamineKmf and glutamateKmf) was significantly higher at embryonic day (E) 18.5, in line with increased expression of LAT1, a glutamine transporter protein. In P0 mice, glutamineKmf and glutamateKmf were higher (P0 versus wild‐type littermates, WTL) at E15.5. At E18.5, glutamineKmf remained elevated whereas glutamateKmf was similar between groups. In summary, we provide evidence that glutamineKmf and glutamateKmf adapt according to placental size in WT mice. The placenta of the growth‐restricted P0 fetus also elevates transport capacity to compensate for size at E15.5, but this adaptation is insufficient at E18.5; this may contribute to decreased fetal growth.

Human placental uptake of glutamine and glutamate is reduced in fetal growth restriction

“…In both AGA and FGR, we estimate that approximately twice as much glutamate as glutamine is transported across the MVM (taking into account that different concentrations of these radiolabeled amino acids were used for the initial rate uptake experiments: see Methods). This is probably reflective of the fact that glutamate is readily metabolised to glutamine in the cytosol of the syncytiotrophoblast for subsequent transfer to the fetus and reinforces the importance of glutamate, albeit indirectly, for fetal growth as previously suggested in mice 32 . Worthy of note is that measures of 14 C uptake in these studies are unable to discriminate between glutamine and glutamate should interconversion have taken place.…”

Exposure to two-dimensional ultrathin Ti3C2 (MXene) nanosheets during early pregnancy impairs neurodevelopment of offspring in mice

“…Among these metabolites, amino acids-the principal nutrient supplements, were especially important for normal foetal growth. The high concentration of placental amino acids, particularly glutamic acid and histidine enhances the nutrient transport to the foetus, can functionally adapt to satisfy foetal normal growth at late pregnancy period [ 54 , 55 ]. As a result of this adaptation, the foetus stays within a normal birth weight range at term, which is in accordance with our results.…”

mTORC1 Transcriptional Regulation of Ribosome Subunits, Protein Synthesis, and Molecular Transport in Primary Human Trophoblast Cells

“…Down-regulated transcripts belonging to plasma membrane cellular component category included KCNC, SLC38A6, SLC30A5, and DSTYK. SLC38A6 [sodium-coupled amino acid transporter-6 (SNAT-6)] is involved in the regulation of the placental glutamate-glutamine cycle, which has been associated to fetal growth (Wu et al, 2015;Simner et al, 2017;McIntyre et al, 2019). SLC30A5 encodes a zinc transporter-5 (ZnT5) protein which is localized at the apical membrane of the placental syncytiotrophoblast and believed to play an essential role in the transfer of Zn to fetus.…”