Diminished Maternal Tryptophan Leads to Sexually Dimorphic Differences in the Placenta-Brain Axis

Nutrients. 2026 Aug 6;18(15):2575. doi: 10.3390/nu18152575.

ABSTRACT

Background: Tryptophan (Trp) is critical to mothers and their conceptuses, and this amino acid is the precursor to serotonin (5-HT). 5-HT modulates placenta function and fetal neurodevelopment. It is not clear if the placenta directly synthesizes 5-HT or uses the serotonin transporter (SERT/Slc6a4) to accrue 5-HT from the dam. The hypothesis tested herein is that reduction in maternal Trp leads to reductions in maternal Trp, 5-HT, and 5-hydroxy-3-indoleacetic acid (5-HIAA, metabolite of serotonin) and reductions in these metabolites within the placenta and fetal brain of female and male conceptuses. Methods: Female mice were placed on a reduced tryptophan (Trp) diet (0.1%) or control diet (0.2%). Diets were provided for two weeks prior to breeding (periconception period) until conceptuses were collected at approximately 12.5 days post-coitus (dpc). Results: While no reductions in maternal Trp and 5-HT were observed, both metabolites were significantly reduced in the placenta and fetal brain of male and female conceptuses (p < 0.05). Female conceptuses were susceptible to reductions in maternal Trp with 549 and 29 transcripts altered in the female placenta and fetal brain, respectively, of reduced Trp dams compared to control dams. Transcriptomic changes, such as reduced expression in Slc6a4 and Slc6a19 (transporter for Trp), in placenta of female conceptuses correlated with reductions in Trp and 5-HT amounts. Conclusions: Findings might have clinical importance to pregnant women as they reveal even subtle reductions in one amino acid profoundly influence conceptus development and might lead to sexual disparity in risk for later diseases, including neurobehavioral disorders.

PMID:42588198 | DOI:10.3390/nu18152575