Placental tryptophan metabolism linking maternal inflammation and foetal neurodevelopmental disorders

Intrauterine or systemic inflammation occurs in ca. 20% of all pregnancies, and epidemiological observations indicate that they are associated with various neurodevelopmental disorders in the offspring, including autism spectrum disorders, cognitive delay, and schizophrenia. However, the underlying cellular and molecular mechanisms have not been fully elucidated. Recent research indicates that
inflammatory cytokines (e.g. interferon gamma and interleukin 6) may modulate the expression and activity of key enzymes involved in placental tryptophan metabolism and hence production of neuroactive molecules (e.g. serotonin, melatonin, kynurenine, kynurenic acid and quinolinic acid). After release from the placenta into the foetal circulation, these neuroactive compounds may interfere with foetal brain development and programming. Thus, in the proposed project we aim to clarify links between prenatal inflammation, inflammatory cytokines, placental tryptophan metabolism and infant neurodevelopment, thereby identifying potential avenues for addressing
neurological disorders in utero. 

The aim of the project is to contribute, through several experimental approaches, to understanding the mechanisms linking prenatal inflammation with neurological developmental disorders in offspring. Analysing an extensive cohort (n > 400) of clinical samples from women with pregnancies complicated by preterm prelabour rupture of membranes (of which ca. 50-60% show signs of inflammation),
we will detect and quantify effects of pro-inflammatory cytokines on placental expression of enzymes involved in tryptophan metabolism. In addition, we will analyse production of neuroactive tryptophan metabolites (mainly serotonin, melatonin, kynurenine, kynurenic acid, and quinolinic acid). Using alternative experimental models (e.g. ex vivo human placenta explants and homogenates, in situ dually perfused rat placenta) we will further quantify effects of local/systemic inflammation on placental handling of tryptophan and its main metabolites. Children from pregnancies complicated by prenatal inflammation will be followed for at least 5 years and subjected to Bayley scales of infant development and SON-R 2.5-7 non-verbal intelligence tests to assess their cognitive development. Possible correlations between independent inflammation markers and results of gene/protein expression of placental enzymes, tryptophan metabolism analyses, infant development measurements and intelligence tests will be statistically explored. Elucidating these associations will help
efforts to understand the complex processes linking maternal/intrauterine inflammatory events and poor neurodevelopmental outcomes. Ultimately, this knowledge will help clinicians optimize and individualize the diagnostic and therapeutic strategy for pregnancies complicated by intrauterine or systemic inflammation, with the ultimate goal of reducing the incidence of psychomotor complications in children from these pregnancies.

This project recieved funding from the Czech Health Research Council (grant no. NU20-01-00264). 

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.




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