Placental serotonergic system dysregulation is associated with early impairments in infant neurodevelopment

Arturo Alejandro Canul-Euan¹Arturo Flores-Pliego²Juan Mario Solis Paredes³Aurora Espejel-Núñez²Sandra Parra-Hernandez²Tahiri Mendoza-Hernández⁴Carmen Hernández-Chávez⁵Gabriela Gil-Martínez⁵Carmen J. Zamora-Sánchez²Otilia Perichart-Perera⁶Guadalupe Estrada-Gutierrez^2*IGNACIO CAMACHO-ARROYO^7*

• ¹Star Medica, Hospital Infantil Privado, Mexico City, Mexico
• ²Department of Immunobiochemistry, Instituto Nacional de Perinatologia, Mexico City, Mexico
• ³Department of Reproductive and Perinatal Health Research, Instituto Nacional de Perinatologia, Mexico City, Mexico
• ⁴Department Immunobiochemistry, Instituto Nacional de Perinatologia, Mexico City, Mexico
• ⁵Department of Developmental Neurobiology, The National Institute of Perinatology Isidro Espinosa de los Reyes, Mexico City, Mexico
• ⁶Nutrition and Bioprogramming Coordination, Instituto Nacional de Perinatologia, Mexico City, Mexico
• ⁷National Autonomous University of Mexico, México City, Mexico

Serotonin (5-hydroxytryptamine, 5-HT) plays a fundamental role in fetal neurodevelopment. While 5-HT is synthesized in the fetal brain, the placenta significantly contributes to fetal 5-HT levels during early gestation. However, little is known about the influence of placental serotonergic components on early neurodevelopmental outcomes. In this study, we have evaluated the association between the expression of key components of the placental serotonergic system and neurodevelopmental status in infants of mother-child dyads enrolled in the OBESO (Origen Bioquímico y Epigenético del Sobrepeso y la Obesidad) perinatal cohort at the first month of life. We analyzed 5-HT concentrations in maternal serum, umbilical cord serum, and placental tissue, and investigated the expression of key proteins of the serotonergic system in the placenta. All samples were obtained from full-term healthy pregnancies. 5-HT levels were measured by ELISA, and protein expression in placental tissue was Código de campo cambiado This is a provisional file, not the final typeset article evaluated by Western blot. Neurodevelopment was assessed at one month of age using the Bayley Infant Development Scale III (BSID-III). Infants with two or more domains with (BSID-III) scores ≤7 were grouped as impaired neurodevelopment. Placentas from infants with impaired neurodevelopment exhibited higher expression of tryptophan hydroxylase types 1 and 2 (TPH1 and TPH2) —the rate-limiting enzymes in 5-HT synthesis —as well as the serotonin transporter (SERT), compared to those from infants with normal neurodevelopment. In contrast, expression of monoamine oxidase-A (MAO-A), the primary degrading enzyme, was significantly lower in the impaired group. Interestingly, 5-HT levels and the expression of 5-HT1E and 5-HTR5A receptors were similar between groups. These findings suggest that dysregulation of the placental serotonergic system, independent of total 5-HT levels, could be associated with early neurodevelopmental impairments, highlighting the importance of placental serotonin signaling in fetal brain development.