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

Abstract

Fetal growth restriction (FGR) is a significant risk factor for stillbirth, neonatal complications and adulthood morbidity. Compared with those of appropriate weight for gestational age (AGA), FGR babies have smaller placentas with reduced activity of amino acid transporter systems A and L, thought to contribute to poor fetal growth. The amino acids glutamine and glutamate are essential for normal placental function and fetal development; whether transport of these is altered in FGR is unknown. We hypothesised that FGR is associated with reduced placental glutamine and glutamate transporter activity and expression, and propose the mammalian target of rapamycin (mTOR) signaling pathway as a candidate mechanism. FGR infants [individualised birth weight ratio (IBR) < 5th centile] had lighter placentas, reduced initial rate uptake of 14C-glutamine and 14C-glutamate (per mg placental protein) but higher expression of key transporter proteins (glutamine: LAT1, LAT2, SNAT5, glutamate: EAAT1) versus AGA [IBR 20th–80th]. In further experiments, in vitro exposure to rapamycin inhibited placental glutamine and glutamate uptake (24 h, uncomplicated pregnancies) indicating a role of mTOR in regulating placental transport of these amino acids. These data support our hypothesis and suggest that abnormal glutamine and glutamate transporter activity is part of the spectrum of placental dysfunction in FGR.

Nutrition and Metabolic Adaptations in Physiological and Complicated Pregnancy: Focus on Obesity and Gestational Diabetes

“…The sodium-dependent System b (TAUT) plays a key role in the transplacental transport of taurine to the fetus, where it is essential for antioxidant processes and neurological development (30). Moreover, the high affinity Excitatory Amino Acid Transporters (EAATs; System X AG-) exchange glutamate across the MVM and BM, being converted to glutamine in the placenta (31): abnormal glutamine and glutamate transporter activity is recently showed as part of placental dysfunctions in IUGR (32).…”

Metabolomics analysis of placental tissue obtained from patients with fetal growth restriction

“…The increased glutamine level in FGR may be associated with increased catabolic status 24,25 . Previous studies showed that there was abnormal glutamine and glutamate transport activity in FGR and that placental dysfunction was a part of FGR 26 . Previous studies have identified that in pregnancies with FGR, the mRNA and protein levels of the placenta glutamate dehydrogenase (GDH) enzyme were statistically significantly reduced compared to the normal pregnancies 24 …”

“…24,25 Previous studies showed that there was abnormal glutamine and glutamate transport activity in FGR and that placental dysfunction was a part of FGR. 26 Previous studies have identified that in pregnancies with FGR, the mRNA and protein levels of the placenta glutamate dehydrogenase (GDH) enzyme were statistically significantly reduced compared to the normal pregnancies. 24 Taurine is a nonessential amino acid produced by methionine and serine and their precursor cysteine.…”

Placental structure, function and mitochondrial phenotype relate to fetal size and sex in mice

“…Thus it is perhaps unsurprising that fetal weight is related to placental development, the uteroplacental blood supply of nutrients and oxygen, and the capacity of the placenta to transport substrates to the fetus [2][3][4][5][6][7][8] . Moreover, failure of the placenta to grow and function properly is associated with a divergence of the fetus away from their genetic growth potential and can lead to small for gestational age (SGA), fetal growth restriction (FGR) or large for gestational age (LGA) [9][10][11] . SGA, FGR and LGA not only increase the risk of perinatal morbidity and mortality, but also have long-term consequences for offspring health 12 .…”

“…Moreover, failure of the placenta to grow and function properly is associated with the divergence of the fetus away from their genetic growth potential and can lead to small for gestational age (SGA), fetal growth restriction (FGR) or large for gestational age (LGA) [9][10][11]. SGA, FGR and LGA not only increase the risk of perinatal morbidity and mortality, but also have long-term consequences for offspring health [12].…”