Maternal immune activation disrupts the kynurenine pathway of tryptophan metabolism in the placenta–fetal brain axis in rats

Abstract

Abstract Background Maternal immune activation is a major risk factor for neurodevelopmental disorders; however, the molecular mechanisms linking gestational inflammation to fetal brain vulnerability remain incompletely defined. The tryptophan–kynurenine pathway is highly responsive to immune signaling and represents a potential mediator of placenta–fetal brain communication. Methods Pregnant rats received Poly I:C (5 or 15 mg/kg) or lipopolysaccharide (1 mg/kg) on gestational days 17–18. Maternal plasma, amniotic fluid, placenta, decidua, and fetal brain were collected 4, 24, and 48 h after the final injection. Cytokines, gene expression, protein levels, and kynurenine-pathway metabolites were quantified, and multivariate analyses were performed to assess temporal and compartment-specific responses. Results Maternal inflammation was confirmed by increased IL-6 and IL-1β in plasma, together with elevated CRP and TNF-α in amniotic fluid. The placenta showed rapid remodeling of the kynurenine pathway, including induction of indoleamine 2,3-dioxygenase 1 protein and time-dependent changes in downstream enzymes and in the expression of amino acid transporters. These effects were sex dependent at the protein levels, with female placentas showing increased kynurenine aminotransferase expression, while placental kynurenine and quinolinic acid concentrations increased with treatment independent of sex. The decidua displayed limited and non–sex-dimorphic responses. In the fetal brain, transcriptional changes emerged later and were strongly sex dependent, with broader downregulation of kynurenine-pathway and transporter genes in females. Multivariate analyses indicated that placental responses preceded and were associated with fetal brain transcriptional remodeling. Conclusion Following maternal immune activation, the placenta showed early and pronounced remodeling of the kynurenine pathway that preceded and was statistically associated with sex-specific changes in the fetal brain. This temporal and associative pattern identifies placental kynurenine metabolism as a candidate mediator linking maternal inflammation to differential neurodevelopmental vulnerability.