Placental transfer of proteogenic amino acids and taurine in healthy term pregnancies: a human in vivo study

Abstract

Normal fetal growth and development depends on a continuous supply of amino acids. Furthermore, the nutritional environment in which the fetus develops has a major impact on both the immediate and the future health of the newborn child. The placenta constitutes the interface between the maternal and fetal circulations, and virtually all compounds that are exchanged between the mother and the fetus must pass through the placental tissue. Thus, to a large extent the placenta governs the fetal environment in utero, and a thorough comprehension of the functions of this complex organ is a key to understand fetal nutrition and its impact on fetal and adult health. Our knowledge of the human placenta is mainly derived from animals and in vitro and ex vivo models, since it is difficult to access and study this organ in vivo in humans without imposing ethically unacceptable risks on the ongoing pregnancy. We therefore aimed to establish a sampling method to study the human placenta in vivo (“the 4-vessel method”), and to employ this method to assess placental transfer of amino acids in healthy human pregnancies. Paper I In paper I we aimed to make our established 4-vessel method accessible for the international research community, by in depth description and live visualization of the sampling techniques. We demonstrated that the sampling method is feasible in a busy clinical setting, and showed that our method can be used to investigate different aspects of the functions of the human placenta. Paper II In paper II we aimed to explore the interplay between uptake and release of amino acids in the fetal-placental unit in vivo. We determined and assessed the paired relationships between concentrations and arteriovenous differences of 19 proteogenic amino acids on the maternal and fetal sides of the placenta in our 4-vessel plasma samples from non-complicated human term pregnancies. We showed that in a fasting state, there are large individual differences in the flux of amino acids across the placental membrane in both the maternal and fetal circulations, indicating that placental amino acid transfer in the human at term is a highly dynamic process. We observed a net uptake of most amino acids in the fetus, but only a net uteroplacental uptake of a few amino acids from the maternal circulation. There was no correlation between the fetal uptake from the umbilical circulation and the uteroplacental uptake from the maternal circulation in our mother-fetus pairs. Our findings illustrate the complex relationship between uteroplacental and fetal amino acid uptake, and highlight the role of placental metabolism and properties in the immediate government of amino acid transfer to the healthy human term fetus. Paper III Taurine is a vital non-proteogenic amino acid in fetal life. In paper III, we aimed to study the transfer of taurine between the maternal, placental and fetal compartments in vivo in healthy term pregnancies. Unexpectedly, we observed that the human placenta has the capacity for a concomitant bilateral release of taurine to both the maternal and fetal circulations, indicating that taurine may play a fundamental role in the placental homeostasis beyond the supply to the fetus. The pattern of placental taurine transfer led us to re-evaluate the prevailing view that human placental tissue lacks the ability to synthesize taurine. To this end, we studied the placental expression of both CSAD mRNA and protein. We found that the term placenta expresses CSAD mRNA, but our data regarding expression of CSAD protein were not consistent. Taken together, however, our results may suggest a potential for taurine synthesis in the human placenta. In conclusion, we have established the 4-vessel sampling approach to promote in vivo studies of the human placenta and demonstrated that this method can be used to study and integrate a variety of placental properties. We have explored the impact of the placenta in determining amino acid uptake by the fetus in non-complicated term pregnancies, and, finally, we have shown that some current experimentally based concepts of placental functions are challenged by the results obtained by our human in vivo model.