Catecholamines norepinephrine and dopamine have been implicated in numerous physiological processes within the central nervous system. Emerging evidence has highlighted the importance of tightly regulated monoamine levels for placental functions and fetal development. However, the complexities of synthesis, release, and regulation of catecholamines in the fetoplacental unit have not been fully unraveled. In this study, we investigated the expression of enzymes and transporters involved in synthesis, degradation, and transport of norepinephrine and dopamine in the human placenta and rat fetoplacental unit. Quantitative PCR and Western blot analyses were performed in early-to-late gestation in humans (first trimester vs. term placenta) and mid-to-late gestation in rats (placenta and fetal brain, intestines, liver, lungs, and heart). In addition, we analyzed the gene expression patterns in isolated primary trophoblast cells from the human placenta and placenta-derived cell lines (HRP-1, BeWo, JEG-3). In both human and rat placentas, the study identifies the presence of only PNMT, COMT, and NET at the mRNA and protein levels, with the expression of PNMT and NET showing gestational age dependency. On the other hand, rat fetal tissues consistently express the catecholamine pathway genes, revealing distinct developmental expression patterns. Lastly, we report significant transcriptional profile variations in different placental cell models, emphasizing the importance of careful model selection for catecholamine metabolism/transport studies. Collectively, integrating findings from humans and rats enhances our understanding of the dynamic regulatory mechanisms that underlie catecholamine dynamics during pregnancy. We identified similar patterns in both species across gestation, suggesting conserved molecular mechanisms and potentially shedding light on shared biological processes influencing placental development.

Department of Pharmacology and Toxicology Faculty of Pharmacy in Hradec Králové Charles University Prague Czech Republic

Zobrazit více v PubMed

Thomas SA, Matsumoto AM, Palmiter RD. Noradrenaline is essential for mouse fetal development. Nature. 1995;374:643–646. doi: 10.1038/374643a0. PubMed DOI

Johansson S, et al. Increased catecholamines and heart rate in children with low birth weight: Perinatal contributions to sympathoadrenal overactivity. J. Intern. Med. 2007;261:480–487. doi: 10.1111/j.1365-2796.2007.01776.x. PubMed DOI

Franco MC, et al. Circulating renin-angiotensin system and catecholamines in childhood: Is there a role for birthweight? Clin. Sci. (Lond) 2008;114:375–380. doi: 10.1042/cs20070284. PubMed DOI

Rosenfeld CS. The placenta-brain-axis. J. Neurosci. Res. 2021;99:271–283. doi: 10.1002/jnr.24603. PubMed DOI PMC

Maslen, C. L. recent advances in placenta–heart interactions. Front. Physiol.9 (2018). 10.3389/fphys.2018.00735 PubMed PMC

Chen X, et al. Gut dysbiosis induces the development of pre-eclampsia through bacterial translocation. Gut. 2020;69:513. doi: 10.1136/gutjnl-2019-319101. PubMed DOI

Karahoda, R. et al. Dynamics of tryptophan metabolic pathways in human placenta and placental-derived cells: Effect of gestation age and trophoblast differentiation. Front. Cell Dev. Biol.8, 1. 10.3389/fcell.2020.574034 (2020) PubMed PMC

Bonnin A, et al. A transient placental source of serotonin for the fetal forebrain. Nature. 2011;472:347–350. doi: 10.1038/nature09972. PubMed DOI PMC

Karahoda R, et al. Serotonin homeostasis in the materno-foetal interface at term: Role of transporters (SERT/SLC6A4 and OCT3/SLC22A3) and monoamine oxidase A (MAO-A) in uptake and degradation of serotonin by human and rat term placenta. Acta Physiol. 2020;229:e13478. doi: 10.1111/apha.13478. PubMed DOI PMC

Bzoskie L, et al. Placental norepinephrine clearance: In vivo measurement and physiological role. Am. J. Physiol. 1995;269:E145–149. doi: 10.1152/ajpendo.1995.269.1.E145. PubMed DOI

Ramamoorthy S, et al. Expression of a cocaine-sensitive norepinephrine transporter in the human placental syncytiotrophoblast. Biochemistry. 1993;32:1346–1353. doi: 10.1021/bi00056a021. PubMed DOI

Belisle, S. et al. Endocrine control of hPL and hCG production by the human placenta. Placenta13, 163–172. 10.1016/S0143-4004(05)80313-3 (1992).

Vaillancourt C, et al. Labelling of D2-dopaminergic and 5-HT2-serotonergic binding sites in human trophoblastic cells using [3H]-spiperone. J. Recept Res. 1994;14:11–22. doi: 10.3109/10799899409066993. PubMed DOI

Shi CZ, Zhuang LZ. Norepinephrine regulates human chorionic gonadotrophin production by first trimester trophoblast tissue in vitro. Placenta. 1993;14:683–693. doi: 10.1016/s0143-4004(05)80385-6. PubMed DOI

Ganapathy, V., Ramamoorthy, S. & Leibach, F. H. Transport and metabolism of monoamines in the human placenta: A review. Placenta14, 35–51. 10.1016/S0143-4004(05)80281-4 (1993).

Carter AM. Animal models of human placentation—a review. Placenta. 2007;28(Suppl A):S41–47. doi: 10.1016/j.placenta.2006.11.002. PubMed DOI

Chau K, Welsh M, Makris A, Hennessy A. Progress in preeclampsia: The contribution of animal models. J. Hum. Hypertension. 2022;36:705–710. doi: 10.1038/s41371-021-00637-x. PubMed DOI PMC

Rosario FJ, Kanai Y, Powell TL, Jansson T. Increased placental nutrient transport in a novel mouse model of maternal obesity with fetal overgrowth. Obesity (Silver Spring) 2015;23:1663–1670. doi: 10.1002/oby.21165. PubMed DOI PMC

Winterhager, E. & Gellhaus, A. Transplacental nutrient transport mechanisms of intrauterine growth restriction in rodent models and humans. Front. Physiol.8. 10.3389/fphys.2017.00951 (2017). PubMed PMC

Furukawa S, Tsuji N, Sugiyama A. Morphology and physiology of rat placenta for toxicological evaluation. J. Toxicol. Pathol. 2019;32:1–17. doi: 10.1293/tox.2018-0042. PubMed DOI PMC

Boyd, J. D. & Hamilton, W. J. The Human Placenta. (Macmillan Press, 1975).

Benirschke K, Kaufmann P, Baergen R. Pathology of the human placenta. Springer; 2016.

Badawy, A. A. B. Tryptophan metabolism, disposition and utilization in pregnancy. Biosci. Rep.35, e00261. 10.1042/BSR20150197 (2015). PubMed PMC

Abad C, et al. Profiling of tryptophan metabolic pathways in the rat fetoplacental unit during gestation. Int. J. Mol. Sci. 2020;21:1. doi: 10.3390/ijms21207578. PubMed DOI PMC

Horackova H, Vachalova V, Abad C, Karahoda R, Staud F. Perfused rat term placenta as a preclinical model to investigate placental dopamine and norepinephrine transport. Clin. Sci. 2023;137:149–161. doi: 10.1042/cs20220726. PubMed DOI

Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001;25:402–408. doi: 10.1006/meth.2001.1262. PubMed DOI

Kliman HJ, Nestler JE, Sermasi E, Sanger JM, Strauss JF., 3rd Purification, characterization, and in vitro differentiation of cytotrophoblasts from human term placentae. Endocrinology. 1986;118:1567–1582. doi: 10.1210/endo-118-4-1567. PubMed DOI

Wice B, Menton D, Geuze H, Schwartz AL. Modulators of cyclic AMP metabolism induce syncytiotrophoblast formation in vitro. Exp. Cell Res. 1990;186:306–316. doi: 10.1016/0014-4827(90)90310-7. PubMed DOI

Macaron C, Famuyiwa O, Singh SP. In vitro effect of dopamine and pimozide on human chorionic somatomammotropin (hCS) secretion*. J. Clin. Endocrinol. Metab. 1978;47:168–170. doi: 10.1210/jcem-47-1-168. PubMed DOI

Petit A, et al. Presence of D2-dopamine receptors in human term placenta. J. Receptor Res. 1990;10:205–215. doi: 10.3109/10799899009064666. PubMed DOI

Vachalova V, et al. Functional reorganization of monoamine transport systems during villous trophoblast differentiation: Evidence of distinct differences between primary human trophoblasts and BeWo cells. Reprod. Biol. Endocrinol. 2022;20:112. doi: 10.1186/s12958-022-00981-8. PubMed DOI PMC

Hertz R. Choriocarcinoma of women maintained in serial passage in hamster and rat. Proc. Soc. Exp. Biol. Med. 1959;102:77–81. doi: 10.3181/00379727-102-25149. PubMed DOI

Li X, Li Z-H, Wang Y-X, Liu T-H. A comprehensive review of human trophoblast fusion models: Recent developments and challenges. Cell Death Discov. 2023;9:372. doi: 10.1038/s41420-023-01670-0. PubMed DOI PMC

Siaterli MZ, Vassilacopoulou D, Fragoulis EG. Cloning and expression of human placental L-Dopa decarboxylase. Neurochem. Res. 2003;28:797–803. doi: 10.1023/a:1023246620276. PubMed DOI

Manyonda IT, et al. A role for noradrenaline in pre-eclampsia: Towards a unifying hypothesis for the pathophysiology. Br. J. Obstet. Gynaecol. 1998;105:641–648. doi: 10.1111/j.1471-0528.1998.tb10179.x. PubMed DOI

Peleg D, Munsick RA, Diker D, Goldman JA, Ben-Jonathan N. Distribution of catecholamines between fetal and maternal compartments during human pregnancy with emphasis on L-dopa and dopamine. J. Clin. Endocrinol. Metab. 1986;62:911–914. doi: 10.1210/jcem-62-5-911. PubMed DOI

Herregodts P, et al. Development of monoaminergic neurotransmitters in fetal and postnatal rat brain: Analysis by HPLC with electrochemical detection. J. Neurochem. 1990;55:774–779. doi: 10.1111/j.1471-4159.1990.tb04559.x. PubMed DOI

Almqvist PM, et al. First trimester development of the human nigrostriatal dopamine system. Exp. Neurol. 1996;139:227–237. doi: 10.1006/exnr.1996.0096. PubMed DOI

Arevalo R, Castro R, Palarea MD, Rodriguez M. Tyrosine administration to pregnant rats induces persistent behavioral modifications in the male offspring. Physiol. Behav. 1987;39:477–481. doi: 10.1016/0031-9384(87)90376-3. PubMed DOI

Garabal MV, Arévalo RM, Díaz-Palarea MD, Castro R, Rodríguez M. Tyrosine availability and brain noradrenaline synthesis in the fetus: control by maternal tyrosine ingestion. Brain Res. 1988;457:330–337. doi: 10.1016/0006-8993(88)90703-2. PubMed DOI

Ohtani N, Goto T, Waeber C, Bhide PG. Dopamine modulates cell cycle in the lateral ganglionic eminence. J. Neurosci. 2003;23:2840–2850. doi: 10.1523/JNEUROSCI.23-07-02840.2003. PubMed DOI PMC

Nguyen TT, et al. Placental biogenic amine transporters: in vivo function, regulation and pathobiological significance. Placenta. 1999;20:3–11. doi: 10.1053/plac.1998.0348. PubMed DOI

Ebert SN, Thompson RP. Embryonic epinephrine synthesis in the rat heart before innervation: Association with pacemaking and conduction tissue development. Circ. Res. 2001;88:117–124. doi: 10.1161/01.res.88.1.117. PubMed DOI

Huang MH, et al. An intrinsic adrenergic system in mammalian heart. J. Clin. Invest. 1996;98:1298–1303. doi: 10.1172/jci118916. PubMed DOI PMC

Gennser G, Von Studnitz W. Noradrenaline synthesis in human fetal heart. Experientia. 1975;31:1422–1424. doi: 10.1007/bf01923223. PubMed DOI

Ebert SN, Taylor DG. Catecholamines and development of cardiac pacemaking: An intrinsically intimate relationship. Cardiovasc. Res. 2006;72:364–374. doi: 10.1016/j.cardiores.2006.08.013. PubMed DOI

Zhou Q-Y, Quaife CJ, Palmiter RD. Targeted disruption of the tyrosine hydroxylase gene reveals that catecholamines are required for mouse fetal development. Nature. 1995;374:640–643. doi: 10.1038/374640a0. PubMed DOI

Tanaka T, et al. Molecular cloning and sequencing of a cDNA of rat dopa decarboxylase: partial amino acid homologies with other enzymes synthesizing catecholamines. Proc. Natl. Acad. Sci. USA. 1989;86:8142–8146. doi: 10.1073/pnas.86.20.8142. PubMed DOI PMC

Mcnay JL, Mcdonald RH, Goldberg LI, Davis C. Direct renal vasodilatation produced by dopamine in the dog. Circ. Res. 1965;16:510–517. doi: 10.1161/01.RES.16.6.510. PubMed DOI

Chua BA, Perks AM. The effect of dopamine on lung liquid production by in vitro lungs from fetal guinea-pigs. J. Physiol. 1998;513(Pt 1):283–294. doi: 10.1111/j.1469-7793.1998.283by.x. PubMed DOI PMC

Padbury JF, Lam RW, Hobel CJ, Fisher DA. Identification and partial purification of phenylethanolamine N-methyl transferase in the developing ovine lung. Pediatr. Res. 1983;17:362–367. doi: 10.1203/00006450-198305000-00011. PubMed DOI

Axelrod J. Noradrenaline: Fate and control of its biosynthesis. Science. 1971;173:598–606. doi: 10.1126/science.173.3997.598. PubMed DOI

Meyer JS, Dupont SA. Prenatal cocaine administration stimulates fetal brain tyrosine hydroxylase activity. Brain Res. 1993;608:129–137. doi: 10.1016/0006-8993(93)90783-j. PubMed DOI

Field T, et al. Prenatal dopamine and neonatal behavior and biochemistry. Infant Behav. Dev. 2008;31:590–593. doi: 10.1016/j.infbeh.2008.07.007. PubMed DOI PMC

Martineau J, Barthélémy C, Jouve J, Muh JP, Lelord G. Monoamines (serotonin and catecholamines) and their derivatives in infantile autism: Age-related changes and drug effects. Dev. Med. Child Neurol. 1992;34:593–603. doi: 10.1111/j.1469-8749.1992.tb11490.x. PubMed DOI

Vuillermot S, Weber L, Feldon J, Meyer U. A longitudinal examination of the neurodevelopmental impact of prenatal immune activation in mice reveals primary defects in dopaminergic development relevant to schizophrenia. J. Neurosci. 2010;30:1270–1287. doi: 10.1523/jneurosci.5408-09.2010. PubMed DOI PMC

Kapoor A, Petropoulos S, Matthews SG. Fetal programming of hypothalamic-pituitary-adrenal (HPA) axis function and behavior by synthetic glucocorticoids. Brain Res. Rev. 2008;57:586–595. doi: 10.1016/j.brainresrev.2007.06.013. PubMed DOI