Tryptophan and serotonin in the placenta: role in fetal programming

L-tryptophan (TRP) is an essential amino acid for numerous physiological processes. In addition to protein synthesis, TRP is a precursor of many important metabolites, e.g. immunosuppressive kynurenine and the neuroactive compounds serotonin, melatonin and quinolinic acid. TRP metabolism has been described in tumour cells and various organs such as liver, brain and intestine . Intensive research during the last decade has also suggested several pathways of tryptophan metabolism in the placenta with importance for foetal brain development and programming. Very importantly, several pathological conditions (inflammation, stress, or hypoxia), endogenous compounds (glucocorticoids) and xenobiotics/toxins (including pharmacotherapeutics) reportedly modulate the expression and activity of enzymes involved in TRP metabolism. Although TRP may be metabolised via several pathways, here we focus on the two major ones: the serotonin pathway, leading to formation of serotonin (and subsequently melatonin); and the kynurenine pathway, which generates metabolites with immunosuppressive, neurochemical and redox properties.

The serotonin pathway: Serotonin (5-HT), an essential trophic factor for foetal brain development, was previously believed to cross the placenta from mother to foetus. However, recent work suggests that maternal 5-HT is largely degraded by placental monoamine oxidases, and the placenta serves as a transient source of 5-HT for the foetus, synthesizing it from maternal TRP. The rate-limiting enzyme of the 5-HT pathway is TRP hydroxylase (TPH), identified in both human and murine placenta. Placenta-derived 5‑HT is then released into the foetal circulation and plays a crucial role in foetal brain development. 5-HT in the placenta may be further transformed into melatonin, which is associated with foetal circadian rhythmicity. Since the placenta is an essential source of 5-HT for the foetal brain, perturbations in placental TRP metabolism may disrupt 5-HT signalling in specific regions of the developing foetal brain and lead to abnormal programming of the major axonal pathways.

The kynurenine pathway: The kynurenine pathway in the placenta has received great attention in recent years following the discovery that its products play important roles in health and disease, particularly conditions associated with immune dysfunction and central nervous system disorders. In placenta, the pathway also putatively plays crucial roles in preventing foetal rejection by the maternal immune system. However, intermediates in this pathway include several potentially neuroprotective (kynurenic acid) or neurotoxic metabolites (quinolinic acid).

serotonin-kynurenine-pathway.gif

Figure 1. Schematic depiction of serotonin and kynurenine pathways of tryptophan metabolism in the placenta and effects of inflammation on induction or inhibition of rate-limiting transporters and enzymes. Important metabolites are also shown. Although these metabolites are known to be produced in the adult brain, liver, and monocytes, their production in the syncytiotrophoblast has not been fully described and their transport from the placenta to foetal circulation has not been elucidated.

 

Both 5-HT and KYN pathways are reportedly modulated by interferon gamma (IFN-γ) and pro-inflammatory cytokines, which influence the expression and activities (inter alia) of rate-limiting transporters and enzymes such as serotonin transporter (SERT), tryptophan hydroxylase (TPH), indoleamine 2,3-dioxygenase (IDO), and tryptophan 2,3-dioxygenase (TDO) (see Figure 1). Therefore, both metabolic pathways of TRP are modulated during inflammatory insults.

Importantly, KYN is further metabolized by either KYN amino transferase (KYAT1) or KYN monooxygenase (KMO), which respectively generate neuroprotective kynurenic acid (KYNA) or neurotoxic quinolinic acid (QUIN). Moreover, while inflammatory cytokines inhibit KYAT1 (and KYNA production) they upregulate expression of KMO (and QUIN production) (Figure 1). Thus, inflammation likely shifts the KYNA/QUIN balance in favour of neurotoxic QUIN, with potentially deleterious effects on the developing foetus. Accordingly, increased levels of QUIN in umbilical blood have been detected in pregnant women with intrauterine infection. Several other studies have demonstrated increases in TRP metabolism via the KYN pathway in the placenta of women with intrauterine infections and related them to increases in risks of autism spectrum disorders associated with prenatal infection. However, further tests of these hypotheses with various experimental approaches are required, particularly confirmatory tests of the transport of KYNA and QUIN from the placenta to the foetal circulation, which has not been elucidated.

For article on Trophoblast and it importance for fetal growth, protection and programming click here.

 

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