Maternal and fetal tryptophan metabolism in gestating rats: effects of intrauterine growth restriction

Abstract

L-Tryptophan (L-Trp) is a precursor for serotonin (5-HT) and nicotinamide adenine dinucleotide (NAD) synthesis. Both 5-HT and NAD may impact energy metabolism during gestation given that recent studies have demonstrated that increased 5-HT production is crucial for increasing maternal insulin secretion, and that sirtuin, an NAD(+)-dependent protein deacetylase, regulates endocrine signaling. Infants born with intrauterine growth restriction (IUGR) are at a higher risk of metabolic disease once they reach adulthood. IUGR is associated with altered maternal-fetal amino acid transfer. Whether IUGR affects L-Trp metabolism in mother and fetus has not been fully elucidated. Recently, we developed an analytical method using stable isotope-labeled L-Trp to explore the metabolism of L-Trp and its main metabolites, L-kynurenine (L-Kyn), 5-HT and quinolinic acid (QA). In this study, dams submitted to dietary protein restriction throughout gestation received intravenous infusions of stable isotope-labeled (15)N2-L-Trp to determine whether L-Trp metabolism is affected by IUGR. Samples were obtained from maternal, fetal and umbilical vein plasma, as well as the amniotic fluid (AF), placenta and liver of the mother and the fetus after isotope infusion. We observed evidence for active L-Trp transfer from mother to fetus, as well as de novo synthesis of 5-HT in the fetus. Plasma 5-HT was decreased in undernourished mothers. In IUGR fetuses, maternal-fetal L-Trp transfer remained unaffected, but conversion to QA was impaired, implying that NAD production also decreased. Whether such alterations in tryptophan metabolism during gestation have adverse consequences and contribute to the increased risk of metabolic disease in IUGR remains to be explored.

Restraint Stress during Pregnancy Rapidly Raises Kynurenic Acid Levels in Mouse Placenta and Fetal Brain

“…KP metabolites and enzymes, too, may play a role in the placenta both under physiological conditions and when the organ is compromised [32,50–53]. Notably, as both TRP and KYN pass easily from the placenta to the fetus [42,51,54,55], the transient increases in the fetal levels of these two compounds seen here in response to maternal stress may be at least in part caused by direct transfer from the placenta. KYNA, in contrast, does not penetrate readily from the placenta into the fetus [55], i.e.…”

Maternal protein restriction during gestation and lactation in the rat results in increased brain levels of kynurenine and kynurenic acid in their adult offspring

“…; Sano et al . ). We found no differences between control and PR animals in the placental concentrations of KYN and kynurenine metabolites at E13 with the exception of a 59% increase in the concentration of XA in placenta from PR dams as compared with the levels in control tissue.…”

“…A similar conclusion was reached by Sano et al . () who observed that protein restriction does not alter the transfer of stable isotope‐labelled tryptophan from the mother to the foetus. Further studies are therefore required to determine the mechanisms underlying the altered metabolism of KYN in the offspring of protein‐restricted dams.…”

Redox Properties of Tryptophan Metabolism and the Concept of Tryptophan Use in Pregnancy

“…The NAD pathway is also enhanced in pregnant rats and women [ 109 ]. In tissues, the regulation of gene expression and endocrine signaling by the NAD-dependent protein deacetylase sirtuin may be affected during gestation [ 110 ].…”