Abstract
INTRODUCTION: Opioid exposure during pregnancy may significantly alter gene expression in the placenta, potentially disrupting its function and influencing fetal brain development. These alterations may contribute to adverse outcomes such as neonatal opioid withdrawal syndrome (NOWS). In this study, we aim to systematically investigate the changes in placental gene expression associated with maternal opioid exposure to better understand the underlying molecular mechanisms and their implications for fetal health. METHODS: Fresh placental tissue samples were collected from 18 opioid-exposed pregnancies and 26 non-opioid-exposed control pregnancies. Transcriptomic changes related to opioid exposure were assessed using RNA sequencing (RNA-seq). RESULTS: Among the 16,172 genes detected, 55 showed differential expression (P(adjusted) < 0.25 or P(unadjusted) < 0.001) in opioid-exposed placentas. Gene Set Enrichment Analysis (GSEA) revealed that the differentially expressed genes were primarily associated with immune responses, neuronal development and function, as well as cell replication and division. Computational deconvolution using the PlacentaCellEnrich program identified significant enrichment of upregulated genes in decidual NK cells. Furthermore, integrative analysis of DNA methylation and gene expression showed an enrichment of differentially methylated genes among downregulated genes in opioid-exposed placentas. DISCUSSION: Our findings suggest that opioid exposure during pregnancy may disrupt critical placental pathways, particularly those involved in immune responses. Future studies focusing on transcriptomic changes in specific placental cell types will be essential for fully understanding the structural and functional alterations in the placenta due to opioid exposure during pregnancy.