Meijer Mandy, Konwar Chaini, Asiimwe Rebecca, Maclsaac Julia, Ramadori Katia, Lin David, Garland Eric L, Ostlund Brendan, Kobor Michael S, Crowell Sheila E, Conradt Elisabeth
Department of Medical Genetics, Faculty of Medicine, University of British Columbia, Vancouver, BC V5Z 4H4, Canada.
British Columbia Children's Hospital Research Institute, University of British Columbia, Vancouver, BC V5Z 4H4, Canada.
Environ Epigenet. 2025 Sep 4;11(1):dvaf021. doi: 10.1093/eep/dvaf021. eCollection 2025.
The increasing incidence of opioid use during pregnancy has led to a rise in the number of infants exposed to opioids in utero. Prenatal opioid exposure may have consequences for health and (neuro)development, including neonatal opioid withdrawal syndrome (NOWS). It is unknown which infants are at greatest risk for NOWS. DNA methylation (DNAm) is an epigenetic mark reflecting both allelic variation and environmental exposures, which may provide biomarkers for prenatal opioid exposure and infant NOWS. The placenta is an accessible, biologically relevant tissue in which to directly investigate the epigenetic effects of prenatal opioid exposure. Therefore, the aims of this study were to examine whether prenatal opioid exposure is associated with differential DNAm, including epigenetic age acceleration (EAA) in the placenta. We performed an epigenome-wide association study based on co-methylated regions and single CpG sites in placental samples from in utero opioid-exposed ( 19) and nonexposed infants ( = 143), correcting for potential confounders. We did not identify statistically significant differential DNAm profiles, but the strongest associations were found for cg06621211; cg18688392 (, adjusted = .068) and cg04460738 (, adjusted = .068), although effect sizes were very small. One of these DNAm patterns (cg06621211) was in part under control of genetic variants through methylation quantitative trait loci. The involved single nucleotide polymorphism did not show significant associations in recent genome-wide association studies for phenotypes related to substance use, and the finding was not driven by potential co-occurring substance use based on sensitivity analyses. There was also no association between placental EAA and in utero opioid exposure. In conclusion, placental DNAm showed limited associations with in utero opioid exposure and NOWS diagnosis.
孕期阿片类药物使用的发生率不断上升，导致子宫内接触阿片类药物的婴儿数量增加。产前阿片类药物暴露可能对健康和（神经）发育产生影响，包括新生儿阿片类药物戒断综合征（NOWS）。尚不清楚哪些婴儿患NOWS的风险最大。DNA甲基化（DNAm）是一种表观遗传标记，反映等位基因变异和环境暴露，可为产前阿片类药物暴露和婴儿NOWS提供生物标志物。胎盘是一种可获取的、具有生物学相关性的组织，可直接研究产前阿片类药物暴露的表观遗传效应。因此，本研究的目的是检查产前阿片类药物暴露是否与差异DNAm相关，包括胎盘中的表观遗传年龄加速（EAA）。我们基于子宫内阿片类药物暴露婴儿（n = 19）和未暴露婴儿（n = 143）胎盘样本中的共甲基化区域和单个CpG位点进行了全表观基因组关联研究，并对潜在混杂因素进行了校正。我们未发现具有统计学意义的差异DNAm谱，但发现与cg06621211、cg18688392（p，校正后p = 0.068）和cg04460738（p，校正后p = 0.068）的关联最强，尽管效应大小非常小。这些DNAm模式之一（cg06621211）部分受甲基化数量性状位点的遗传变异控制。所涉及的单核苷酸多态性在最近关于物质使用相关表型的全基因组关联研究中未显示出显著关联，且基于敏感性分析，该发现并非由潜在的同时使用物质所驱动。胎盘EAA与子宫内阿片类药物暴露之间也无关联。总之，胎盘DNAm与子宫内阿片类药物暴露和NOWS诊断的关联有限。
