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Profiling of Tryptophan Metabolic Pathways in the Rat Fetoplacental

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Profiling of Tryptophan Metabolic Pathways in the Rat Fetoplacental International Journal of Molecular Sciences Article Profiling of Tryptophan Metabolic Pathways in the Rat Fetoplacental Unit during Gestation 1, 1, 2 1 1 Cilia Abad y, Rona Karahoda y , Petr Kastner , Ramon Portillo , Hana Horackova , Radim Kucera 2, Petr Nachtigal 3 and Frantisek Staud 1,* 1 Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Kralove, Charles University, Akademika Heyrovskeho 1203, 500 05 Hradec Kralove, Czech Republic; [email protected] (C.A.); [email protected] (R.K.); [email protected] (R.P.); [email protected] (H.H.) 2 Department of Pharmaceutical Chemistry and Pharmaceutical Analysis, Faculty of Pharmacy in Hradec Kralove, Charles University, Akademika Heyrovskeho 1203, 500 05 Hradec Kralove, Czech Republic; [email protected] (P.K.); [email protected] (R.K.) 3 Department of Biological and Medical Sciences, Faculty of Pharmacy in Hradec Kralove, Charles University, Akademika Heyrovskeho 1203, 500 05 Hradec Kralove, Czech Republic; [email protected] * Correspondence: [email protected]; Tel.: +420-495-067-407 These authors contributed equally to this work. y Received: 23 September 2020; Accepted: 11 October 2020; Published: 14 October 2020 Abstract: Placental homeostasis of tryptophan is essential for fetal development and programming. The two main metabolic pathways (serotonin and kynurenine) produce bioactive metabolites with immunosuppressive, neurotoxic, or neuroprotective properties and their concentrations in the fetoplacental unit must be tightly regulated throughout gestation. Here, we investigated the expression/function of key enzymes/transporters involved in tryptophan pathways during mid-to-late gestation in rat placenta and fetal organs. Quantitative PCR and heatmap analysis revealed the differential expression of several genes involved in serotonin and kynurenine pathways. To identify the flux of substrates through these pathways, Droplet Digital PCR, western blot, and functional analyses were carried out for the rate-limiting enzymes and transporters. Our findings show that placental tryptophan metabolism to serotonin is crucial in mid-gestation, with a subsequent switch to fetal serotonin synthesis. Concurrently, at term, the close interplay between transporters and metabolizing enzymes of both placenta and fetal organs orchestrates serotonin homeostasis and prevents hyper/hypo-serotonemia. On the other hand, the placental production of kynurenine increases during pregnancy, with a low contribution of fetal organs throughout gestation. Any external insult to this tightly regulated harmony of transporters and enzymes within the fetoplacental unit may affect optimal in utero conditions and have a negative impact on fetal programming. Keywords: fetal programming; tryptophan metabolism; rat model; fetal organs; pregnancy; placenta–brain axis 1. Introduction Throughout gestation, the catabolism of tryptophan (TRP), which is an essential amino acid, is critical for proper placental and fetal development [1] Therefore, the placental homeostasis of TRP, including transport and metabolism, must be tightly regulated [2]. In several organs, including the placenta, TRP is principally metabolized via the serotonin (5-HT) and kynurenine (KYN) pathways, and the relative flux of the resulting metabolites changes, depending on the stage of pregnancy and fetal demands [3]. TRP metabolism in the placenta has recently attracted considerable attention since various metabolites possess immunoprotective or neuroactive properties, with the ultimate effect on Int. J. Mol. Sci. 2020, 21, 7578; doi:10.3390/ijms21207578 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2020, 21, 7578 2 of 20 fetal neurodevelopment [4,5]. Subsequently, insults or challenges to placental TRP catabolism, such as pathologies (inflammation and diabetes), epigenetics, or polymorphisms of essential genes, have been associated with poor pregnancy outcomes and the development of mental or metabolic diseases later in life [1]. In addition, the timing of these insults is critical for fetal development [6] and, therefore, understanding TRP catabolic pathways in the placenta and fetal organs throughout gestation is of importance for identifying the biological roots of developmental origins of health and disease. TRP catabolism along the 5-HT pathway gives rise to active metabolites, such as 5-HT and melatonin, which are important for fetal development and programming [7]. The key enzymes of this pathway are the 5-HT-producing tryptophan hydroxylase (TPH) and 5-HT-degrading monoamine oxidase (MAO) [8–10]. At the early stages of pregnancy, the placental synthesis of 5-HT is particularly important for successful blastocyst implantation, placentation, and decidualization [11,12]. In addition, 5-HT is crucial for the development of 5-HT-dependent organs, including the brain [13] and cardiac system [14]. However, the placental homeostasis of 5-HT remains controversial; current evidence suggests that in the early stages of pregnancy, maternal 5-HT is critical for embryonic development [15]; nevertheless, at E10.5 of mouse [16] and 11 weeks of human gestation [17] this role is taken up by the placenta’s own 5-HT neosynthetic capacity. With advancing gestation, however, the fetus is able to synthesize its own 5-HT from maternally-derived TRP [18]. Moreover, we have recently demonstrated that rat and human term placentas rapidly extract 5-HT from the fetal circulation into trophoblast cells by the organic cation transporter (OCT3/SLC22A3), where it is degraded by MAO-A [19]. Since both hyper- and hypo-serotonemia are detrimental for fetal development [20] and an excess of 5-HT is lethal due to its vasoconstrictive properties [21] placenta and fetal organs must tightly regulate the expression and activity of the key enzymes and transporters involved in 5-HT homeostasis in the fetoplacental unit during the whole period of gestation. Concurrently, the second branch of placental TRP metabolism—the KYN pathway—plays an essential role in allogeneic fetal rejection and is important for achieving immunotolerance for the fetus [22,23]. The human placenta functionally expresses indoleamine 2,3-dioxygenase (IDO)—the initial and rate-limiting enzyme for the KYN pathway [24]. Moreover, the gene expression of all enzymes involved in the KYN pathway has been reported [25]. Neuroactive in nature, several end-products of KYN metabolism may be released into the fetal circulation [26] and affect fetal development. Specifically, through their opposing activity on the N-methyl-D-aspartate (NMDA) receptor, KYN metabolites affect neuronal functions. While kynurenic acid (KYNA) is an antagonist with neuroprotective properties, quinolinic acid (QUIN) acts as an agonist with neurotoxic activity [27]. Additionally, KYN metabolites such as 3-hydroxykynurenine, anthranilic acid, and 3-hydroxyanthranilic acid have been reported to exert cytotoxic activity [28–31]. Collectively, malfunctions of the KYN pathways in rats have been linked to poor pregnancy outcomes [1,32] and it has been suggested that placenta-derived KYN metabolites may be involved in the etiology of prenatal brain damage [32]. We have recently reported that the human placental catabolism of TRP is subject to developmental changes during pregnancy and trophoblast differentiation [33]. In this study, we hypothesized, that apart from the placenta, fetal organs also contribute to overall TRP homeostasis in the fetoplacental unit. Since experiments in pregnant women are limited due to ethical and technical reasons, current research depends on the use of alternative approaches, including experimental animals. Therefore, here, we used the Wistar rat as the most suitable model for placental TRP metabolism in health and disease [3] in order to provide in-depth evidence on the regulation of TRP homeostasis in the fetoplacental unit during gestation. 2. Results 2.1. Basal Levels of TRP, KYN, KYNA, 5-OH-TRP, and 5-HT in the Maternal Plasma and Placenta We first analyzed the metabolite concentrations in the rat placenta and maternal plasma on different gestation days (GDs). Maternal plasma levels of TRP, KYN, KYNA, 5-OH-TRP, and 5-HT Int. J. Mol. Sci. 2020, 21, 7578 3 of 20 Int. J. Mol. Sci. 2020, 21 3 of 21 remained stable during gestation (Table 1). Likewise, metabolite/precursor ratios, specifically remained stable during gestation (Table1). Likewise, metabolite /precursor ratios, specifically KYN/TRP, KYN/TRP, KYNA/KYN, and 5-OH-TRP/TRP ratios, remained steady, suggesting that the metabolic KYNA/KYN, and 5-OH-TRP/TRP ratios, remained steady, suggesting that the metabolic activity activity displayed by maternal organs is not significantly affected by advancing pregnancy; displayednevertheless, by maternal considerable organs interindividual is not significantly variability aff ectedwas detected. by advancing pregnancy; nevertheless, considerable interindividual variability was detected. Table 1. Descriptive Statistics of the Pregnant Wistar Rats Used in the Study and Biochemically TableAssayed 1. Descriptive Metabolite Statistics Concentrations of the Pregnant in Maternal Wistar Pl Ratsasma. Used Results in theAre Study Expres andsed Biochemicallyas the Mean ± SD; Assayed n = Metabolite5. Concentrations in Maternal Plasma. Results Are Expressed as the Mean SD; n = 5. ± ParameterParameter GDGD 12 12 GDGD 15 15 GDGD 18 18 GD 2121 NumberNumber of fetusesof fetuses (n) (n) NANA 11.3311.33 4.61± 4.61 10.5010.50 ±2.89 2.89 8.258.25 ± 5.50 ± ± ± RatRat weight weight (g) (g) 333.00333.0039.15 ± 39.15
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