Prenatal inflammation as a link between placental expression signature of tryptophan metabolism and preterm birth

Abstract

Spontaneous preterm birth is a serious medical condition responsible for substantial perinatal morbidity and mortality. Its phenotypic characteristics, preterm labor with intact membranes (PTL) and preterm premature rupture of the membranes (PPROM), are associated with significantly increased risks of neurological and behavioral alterations in childhood and later life. Recognizing the inflammatory milieu associated with PTL and PPROM, here we examined expression signatures of placental tryptophan metabolism, an important pathway in prenatal brain development and immunotolerance. The study was performed in a well-characterized clinical cohort of healthy term pregnancies (n = 39) and 167 preterm deliveries (PTL, n = 38 and PPROM, n = 129). Within the preterm group, we then investigated potential mechanistic links between differential placental tryptophan pathway expression, preterm birth and both intra-amniotic markers (such as amniotic fluid interleukin-6) and maternal inflammatory markers (such as maternal serum C-reactive protein and white blood cell count). We show that preterm birth is associated with significant changes in placental tryptophan metabolism. Multifactorial analysis revealed similarities in expression patterns associated with multiple phenotypes of preterm delivery. Subsequent correlation computations and mediation analyses identified links between intra-amniotic and maternal inflammatory markers and placental serotonin and kynurenine pathways of tryptophan catabolism. Collectively the findings suggest that a hostile inflammatory environment associated with preterm delivery underlies the mechanisms affecting placental endocrine/transport functions and may contribute to disruption of developmental programming of the fetal brain.

KCNJ11 and KCNQ1 Gene Polymorphisms and Placental Expression in Women with Gestational Diabetes Mellitus

“…To normalize mRNA levels between different samples, we used β-2 microglobulin ( BMG ) as reference gene. The reference gene was determined based on the available literature [ 15 , 16 , 17 ]. Each sample was analyzed in two technical replications, and mean cycle threshold (CT) values were used for further analysis.…”

The Function of the Kynurenine Pathway in the Placenta: A Novel Pharmacotherapeutic Target?

“…Already in 1979, tryptophan concentrations were measured in the umbilical veins of term and preterm born infants [ 37 ]. The placentas of preterm pregnancies displayed an increased expression of IDO1 that was further augmented in cases of preterm premature rupture of membranes (PPROM) [ 96 ]. Other kynurenine pathway alterations included increased expression of HAAO and the transporter LAT1, but decreased expression of the enzyme KYNU, although the fold change in the latter was minimal [ 96 ].…”

“…Other kynurenine pathway alterations included increased expression of HAAO and the transporter LAT1, but decreased expression of the enzyme KYNU, although the fold change in the latter was minimal [ 96 ]. IDO2 and TDO expression were unaltered [ 96 ].…”

“…Although Manuelpillai et al [ 48 ] observed an even further increased expression of IDO, TDO and KYNU in preterm pregnancies with intrauterine infection compared to without [ 48 ], Karahoda et al [ 96 ] showed no influence of intrauterine infection on the overall expression pattern kynurenine pathway enzymes. Interestingly, the latter authors did identify an association between intra-amniotic and maternal inflammatory markers, and placental expression of tryptophan pathway genes [ 96 ]. This suggests that there is a relation between certain inflammatory markers and placental kynurenine pathway function.…”

Preterm Labor, a Syndrome Attributed to the Combination of External and Internal Factors

“…Genes involved in tryptophan metabolism/transport were highly expressed in placentas associated with sPTL. 83 Placenta RNA-seq and metabolomics studies suggest that placenta mitochondrial function and energy metabolism are altered, and the imbalanced glycolysis and unconventional lactate oxidation may be associated with sPTL. 84,85 The placenta-derived extracellular vesicles proteins proteome revealed that nonspecific inflammation coagulation was upregulated while complement activation-related proteins were downregulated in cargo from first trimester in sPTL.…”