Kynurenine production and catabolism in fetal sheep with embolized or nonembolized placentas

The effect of maternal tryptophan loading on fetal plasma and brain, kynurenic acid, and quinolinic acid concentrations was compared in late gestation fetal sheep with either chronically embolized or nonembolized placentas.

The placentas of 4 ewes were embolized by daily injection of mucopolysaccharide microspheres into the umbilical artery from 120 days gestation in amounts sufficient to reduce the fetal arterial PO2 to < or = 12 mm Hg. Four fetuses with nonembolized placentas were the control group. At 135 to 138 days gestation, the ewe received an infusion of tryptophan (100 mg/kg, intravenously) or an equivalent volume of saline solution (100 mL) over 2 hours. Maternal and fetal arterial blood samples were obtained between 2 and 48 hours from the start of the infusion for the measurement of plasma tryptophan and kynurenine metabolites. Brains were then obtained from embolized and nonembolized fetuses 24 hours after a further maternal tryptophan loading experiment and from nonembolized non-tryptophan-treated fetuses for analysis of regional kynurenic acid and quinolinic acid content.

Maternal tryptophan infusion resulted in a significant increase of kynurenine in fetal plasma, but this increase was significantly smaller in fetuses with an embolized placenta compared with a nonembolized placenta. Both kynurenic acid and quinolinic acid levels increased significantly in fetal plasma, with no differences between the groups. Kynurenic acid and quinolinic acid levels were increased in all regions of the fetal brain after maternal tryptophan loading, but these increases were greater in the fetuses with an embolized placenta, compared with a nonembolized placenta.

Fetal tryptophan and kynurenine metabolism is significantly altered when placental function is chronically compromised in late gestation. The decreased production of kynurenine from tryptophan may result from the compromise of hepatic function in the fetus, whereas the increased production of kynurenic acid and quinolinic acid in the brain is likely to reflect alterations of metabolism of tryptophan and kynurenine to these neuroactive products by glial cells in the fetal brain.