Serotonin Delivery and Metabolism are Affected by High Maternal BMI in the Human Fetus.

Introduction: More Scottish expectant mothers are overweight or obese than of a healthy weight. Both pregnancy and offspring are impacted by high maternal BMI although disease mechanisms remain unclear. Due to the importance of serotonin for fetal neurodevelopment, altered signalling may contribute to the increased incidence of behavioural and neurodevelopmental problems in children born to mothers with high BMI. It is uncertain whether the human placenta synthesizes serotonin, or if the developing fetus depends on maternal supply and subsequent transplacental transfer. Methods: Electively terminated products of conception from normally progressing pregnancies (8-18 weeks gestation) were collected from Aberdeen (NHS Grampian, REC 15/NS/0123) and Newcastle (HDBR, Newcastle & North Tyneside, R&D 15/1/010). Multiple biopsies were taken from placentas (n=89) and whole fetal brains were pulverised (n=41) to ensure representative sampling. Placental plasma membrane proteins were isolated using liquid-liquid phase partitioning then quantified by LC-MS/MS. Serotonin and 5-hydroxyindoleacetic acid were quantified in fetal brain by HPLC/electrochemical detection. Transcripts involved in the serotonin synthesis pathway were measured by RT-qPCR in both placenta and fetal brain. Multivariate regression analyses were performed with maternal BMI (<25 vs ≥25), fetal age and fetal sex as covariates. Results: The major serotonin uptake transporter (SERT) was decreased in the placenta from mothers with BMI≥25 (P=0.01). Serotonin synthesizing enzymes (TPH1 and AADC) were expressed in very low levels in the placenta but were significantly increased in fetal brain if the mother had high BMI (P=0.04 and P=0.03, mean across gestation). Levels of the serotonin inactivating enzyme MAOA (and the MAOA/MAOB ratio) were decreased in fetal brains from high BMI pregnancies (P=0.03 and P=0.02). Fetal brain serotonin and metabolite levels were not affected by maternal BMI. There were no fetal sex-effects related to these changes. Conclusion: High maternal BMI is associated with compromised serotonin transport to the fetus. The placenta displays low expression of serotonin synthesizing enzymes suggesting serotonin delivery to the fetus depends on maternal supply and appropriate expression of SERT. Adaptations in the fetal brain likely contributed to unchanged brain serotonin levels in overweight/obese pregnancies. The pattern of homeostatic fetal enzymatic adaptations, especially in MAOA, has been associated with autism and impaired brain development in rodent models, suggesting mechanistic links between high maternal BMI and aberrant neurodevelopment in the child.