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

作者全名："Staud, Frantisek; Pan, Xin; Karahoda, Rona; Dong, Xiaojing; Kastner, Petr; Horackova, Hana; Vachalova, Veronika; Markert, Udo R.; Abad, Cilia"

作者地址："[Staud, Frantisek; Karahoda, Rona; Horackova, Hana; Vachalova, Veronika; Abad, Cilia] Charles Univ Prague, Fac Pharm Hradec Kralove, Dept Pharmacol & Toxicol, Hradec Kralove, Czech Republic; [Pan, Xin; Dong, Xiaojing; Markert, Udo R.] Jena Univ Hosp, Dept Obstet, Placenta Lab, Jena, Germany; [Pan, Xin; Dong, Xiaojing] Chongqing Med Univ, Affiliated Hosp 2, Dept Obstet & Gynecol, Chongqing 400010, Peoples R China; [Kastner, Petr] Charles Univ Prague, Fac Pharm Hradec Kralove, Dept Pharmaceut Chem & Drug Anal, Hradec Kralove, Czech Republic"

通信作者："Staud, F (通讯作者)，Charles Univ Prague, Fac Pharm Hradec Kralove, Dept Pharmacol & Toxicol, Hradec Kralove, Czech Republic."

来源：REPRODUCTIVE BIOLOGY AND ENDOCRINOLOGY

ESI学科分类：BIOLOGY & BIOCHEMISTRY

WOS号：WOS:001053700500002

JCR分区：Q1

影响因子：4.2

年份：2023

卷号：21

期号：1

开始页：　

结束页：　

文献类型：Article

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

摘要："Background Serotonin (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. Methods We 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. Results Using 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. Conclusions Taken 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."

基金机构："The authors would like to thank Prof. Marian Kacerovsky, Ph.D., Dr. Jaroslav Stranik, Ph.D., and Martina Hudeckova from the Department of Obstetrics and Gynecology, Faculty Hospital in Hradec Kralove for supplying us with placental tissues and gathering re; Department of Obstetrics, Jena University Hospital, Germany"

基金资助正文："The authors would like to thank Prof. Marian Kacerovsky, Ph.D., Dr. Jaroslav Stranik, Ph.D., and Martina Hudeckova from the Department of Obstetrics and Gynecology, Faculty Hospital in Hradec Kralove for supplying us with placental tissues and gathering relevant patient data. We also gratefully acknowledge all the physicians and midwives from the Department of Obstetrics, Jena University Hospital, Germany, for providing intensive patient care and support during placenta collection."