Objectives: Fetal growth is dependent on substrate supply, which is dependent on substrate transport and its regulation by the placenta, and placental insufficiency contributes to altered maternal-fetal amino acid transfer, and thereby to poor fetal growth. An important placental function is the uptake of tryptophan and its metabolism to serotonin and kynurenine metabolites, which are essential for increased protein synthesis, fetal neuronal growth, and immune function. Whether these particular processes are affected in placental insufficiency leading to fetal growth restriction (FGR) has not been fully elucidated. We hypothesised that tryptophan metabolic pathway and serotonin transport will be disrupted in FGR. Methods: Using placentae collected from third trimester idiopathic FGR (n=20) and gestation-matched control pregnancies (n=15) relative mRNA expression of tryptophan metabolic pathway genes was assessed using Fluidigm single-cell DNAseq and TaqMan chemistry (Thermo Fisher Scientific). Data were analysed using Mann-Whitney test. Results: mRNA of the tryptophan metabolising enzymes IDO-1/2 and TDO-2, serotonin synthesis enzyme TPH-1, serotonin transporter SERT1 & 2; and serotonin receptors HTR5A and HTRB5 were detected in all human placental samples. IDO-1, TPH-1 and SERT-1 mRNA were significantly decreased in FGR placentae (p<0.05), while HTRB5 receptor mRNA was significantly increased in FGR compared to control (p<0.01). Furthermore, spatial distribution of HTR5B protein by immunohistochemistry revealed the presence of serotonin receptor in the syncytiotrophoblast and in the endothelial cells lining the fetal capillaries in both FGR and control placentae. Further functional analyses of tryptophan metabolic components in FGR pregnancies are currently being investigated using in vitro placental cell culture models and ex-vivo placental perfusion systems. Conclusion: Our study is the first to report the presence of mRNA and protein for the tryptophan and serotonin metabolic pathways in FGR placentae. These findings suggest that placental metabolism of tryptophan and serotonin transport systems are disrupted in FGR and may contribute to the pathogenesis of FGR.
|Number of pages||2|
|Publication status||Published - Sep 2016|
|Event||Meeting of the International-Federation-of-Placenta-Associations (IFPA) - Placenta-Back to the Basics - Portland, United States of America|
Duration: 13 Sep 2016 → 16 Sep 2016