Characterization of a human placental clearance system to regulate serotonin levels in the fetoplacental unit

Reproductive Biology and Endocrinology

Research

Petr Kastner¹  Frantisek Staud²  Cilia Abad²  Rona Karahoda²  Veronika Vachalova²  Hana Horackova²  Udo R. Markert³  Xin Pan⁴  Xiaojing Dong⁴ 

[1]Department of Pharmaceutical Chemistry and Drug Analysis, Faculty of Pharmacy in Hradec Kralove, Charles University, Hradec Kralove, Czech Republic

[2]Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Kralove, Charles University, Hradec Kralove, Czech Republic

[3]Placenta-Lab, Department of Obstetrics, Jena University Hospital, Jena, Germany

[4]Placenta-Lab, Department of Obstetrics, Jena University Hospital, Jena, Germany

[5]Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Chongqing Medical University, 400010, Chongqing, China

关键词: Placenta;    Serotonin;    Fetal development;    Homeostasis;    Clearance;   

DOI  :  10.1186/s12958-023-01128-z

 received in 2023-06-28, accepted in 2023-08-14,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundSerotonin (5-HT) is a biogenic monoamine with diverse functions in multiple human organs and tissues. During pregnancy, tightly regulated levels of 5-HT in the fetoplacental unit are critical for proper placental functions, fetal development, and programming. Despite being a non-neuronal organ, the placenta expresses a suite of homeostatic proteins, membrane transporters and metabolizing enzymes, to regulate monoamine levels. We hypothesized that placental 5-HT clearance is important for maintaining 5-HT levels in the fetoplacental unit. We therefore investigated placental 5-HT uptake from the umbilical circulation at physiological and supraphysiological levels as well as placental metabolism of 5-HT to 5-hydroxyindoleacetic acid (5-HIAA) and 5-HIAA efflux from trophoblast cells.MethodsWe employed a systematic approach using advanced organ-, tissue-, and cellular-level models of the human placenta to investigate the transport and metabolism of 5-HT in the fetoplacental unit. Human placentas from uncomplicated term pregnancies were used for perfusion studies, culturing explants, and isolating primary trophoblast cells.ResultsUsing the dually perfused placenta, we observed a high and concentration-dependent placental extraction of 5-HT from the fetal circulation. Subsequently, within the placenta, 5-HT was metabolized to 5-hydroxyindoleacetic acid (5-HIAA), which was then unidirectionally excreted to the maternal circulation. In the explant cultures and primary trophoblast cells, we show concentration- and inhibitor-dependent 5-HT uptake and metabolism and subsequent 5-HIAA release into the media. Droplet digital PCR revealed that the dominant gene in all models was MAO-A, supporting the crucial role of 5-HT metabolism in placental 5-HT clearance.ConclusionsTaken together, we present transcriptional and functional evidence that the human placenta has an efficient 5-HT clearance system involving (1) removal of 5-HT from the fetal circulation by OCT3, (2) metabolism to 5-HIAA by MAO-A, and (3) selective 5-HIAA excretion to the maternal circulation via the MRP2 transporter. This synchronized mechanism is critical for regulating 5-HT in the fetoplacental unit; however, it can be compromised by external insults such as antidepressant drugs.

【 授权许可】

CC BY   
© BioMed Central Ltd., part of Springer Nature 2023

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