Steroid hormones play a crucial role in supporting a successful pregnancy and ensuring proper fetal development. The placenta is one of the principal tissues in steroid production and metabolism, expressing a vast range of steroidogenic enzymes. Nevertheless, a comprehensive characterization of steroidogenic pathways in the human placenta and potential developmental changes occurring during gestation are poorly understood. Furthermore, the specific contribution of trophoblast cells in steroid release is largely unknown. Thus, this study aimed to (i) identify gestational age-dependent changes in the gene expression of key steroidogenic enzymes and (ii) explore the role of trophoblast cells in steroid biosynthesis and metabolism. Quantitative and Droplet Digital PCR analysis of 12 selected enzymes was carried out in the first trimester (n = 13) and term (n = 20) human placentas. Primary trophoblast cells (n = 5) isolated from human term placentas and choriocarcinoma-derived cell lines (BeWo, BeWo b30 clone, and JEG-3) were further screened for gene expression of enzymes involved in placental synthesis/metabolism of steroids. Finally, de novo steroid synthesis by primary human trophoblasts was evaluated, highlighting the functional activity of steroidogenic enzymes in these cells. Collectively, we provide insights into the expression patterns of steroidogenic enzymes as a function of gestational age and delineate the cellular origin of steroidogenesis in the human placenta.

• Klíčová slova
• gestation, placenta, steroid metabolism, steroidogenesis, trophoblast,
• MeSH
• choriokarcinom metabolismus   patologie   MeSH
• dospělí MeSH
• gestační stáří MeSH
• kultivované buňky MeSH
• lidé MeSH
• novorozenec MeSH
• placenta cytologie   metabolismus   MeSH
• první trimestr těhotenství metabolismus   MeSH
• regulace genové exprese * MeSH
• steroidhydroxylasy genetika   metabolismus   MeSH
• steroidy metabolismus   MeSH
• těhotenství MeSH
• trofoblasty cytologie   metabolismus   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• novorozenec MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• steroidhydroxylasy MeSH
• steroidy MeSH

AIM: Serotonin is crucial for proper foetal development, and the placenta has been described as a 'donor' of serotonin for the embryo/foetus. However, in later stages of gestation the foetus produces its own serotonin from maternally-derived tryptophan and placental supply is no longer needed. We propose a novel model of serotonin homeostasis in the term placenta with special focus on the protective role of organic cation transporter 3 (OCT3/SLC22A3). METHODS: Dually perfused rat term placenta was employed to quantify serotonin/tryptophan transport and metabolism. Placental membrane vesicles isolated from human term placenta were used to characterize serotonin transporters on both sides of the syncytiotrophoblast. RESULTS: We obtained the first evidence that serotonin is massively taken up from the foetal circulation by OCT3. This uptake is concentration-dependent and inhibitable by OCT3 blockers of endogenous (glucocorticoids) or exogenous (pharmaceuticals) origin. Population analyses in rat placenta revealed that foetal sex influences placental extraction of serotonin from foetal circulation. Negligible foetal serotonin levels were detected in maternal-to-foetal serotonin/tryptophan transport and metabolic studies. CONCLUSION: We demonstrate that OCT3, localized on the foetus-facing membrane of syncytiotrophoblast, is an essential component of foeto-placental homeostasis of serotonin. Together with serotonin degrading enzyme, monoamine oxidase-A, this offers a protective mechanism against local vasoconstriction effects of serotonin in the placenta. However, this system may be compromised by OCT3 inhibitory molecules, such as glucocorticoids or antidepressants. Our findings open new avenues to explore previously unsuspected/unexplained complications during pregnancy including prenatal glucocorticoid excess and pharmacotherapeutic risks of treating pregnant women with OCT3 inhibitors.

• Klíčová slova
• foetal development, pharmacotherapy, placenta, pregnancy, serotonin, transport,
• MeSH
• homeostáza MeSH
• krysa rodu Rattus MeSH
• lidé MeSH
• membránové transportní proteiny pro serotonin metabolismus   MeSH
• monoaminoxidasa metabolismus   MeSH
• placenta * metabolismus   MeSH
• plod MeSH
• proteiny přenášející organické kationty metabolismus   MeSH
• serotonin * metabolismus   MeSH
• sexuální faktory MeSH
• těhotenství MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• membránové transportní proteiny pro serotonin MeSH
• monoaminoxidasa MeSH
• proteiny přenášející organické kationty MeSH
• serotonin * MeSH
• SLC6A4 protein, human MeSH Prohlížeč
• solute carrier family 22 (organic cation transporter), member 3 MeSH Prohlížeč