Comprehensive Analysis of the Placenta–Cortex Transcriptomic Database Reveals a Neuroactive Ligand–Receptor Dysregulation After Prenatal Alcohol Exposure

Neuroplacentology is an emerging field of research supporting that the placenta actively contributes to the fetal brain development through the release of bioactive molecules. Recent angiogenesis-focused data showed that prenatal alcohol exposure (PAE) disrupts inter-organ gene expression between the placenta and fetal cortex. The present study aimed to perform the first comprehensive and untargeted analysis of a murine placenta-cortex transcriptomic database of PAE. Gene lists from a recently <i>NCBI</i>-deposited PAE Placenta-Cortex transcriptomic database were analyzed using <i>g:Profiler</i> for unbiased functional profiling querying <i>Gene Ontology</i>, <i>KEGG,</i> and <i>Reactome</i> databases. Genes intersecting with cell-cell communication terms were submitted to <i>STRING</i> and <i>ShinyGO</i> analyses to identify enriched protein-protein interactions and pathways. Several ligand or receptor candidates were then validated by Western blot. <i>g:Profiler</i> revealed 21 enriched <i>GO</i> functional maps, seven <i>KEGG</i> pathways, and six <i>Reactome</i> pathways, of which 11 were related to cell-to-cell communication. <i>STRING</i> analysis exhibited substantial protein-protein interaction enrichments supporting that proteins belonging to the functional maps and pathways are biologically connected. Notably, 38 ligands or receptors from endocrine families including angiotensinogen, leptin, somatostatin, or PACAP were identified. Western blot analysis of protein candidates showed different validation patterns. In particular, the PACAP receptor family confirmed transcriptomic findings and revealed sex-dependent PAE-impacted expression profiles. The present study indicates that PAE is associated with alterations in the transcriptomic placenta-cortex expression profile, including changes in the expression ratios of several ligands and/or receptors implicated in key physiological pathways such as energy balance, vascular development, and neurogenesis. These transcriptomic associations suggest that altered placenta-fetal brain signaling at the gene expression level may be involved in alcohol-induced neurodevelopmental disorders, highlighting the need for future functional validation studies.