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Abstract：
Background: Neonatal opioid withdrawal syndrome (NOWS), arises due to increased opioid use during pregnancy. Cytochrome P450 (CYP) enzymes play a pivotal role in metabolizing a wide range of substances in the human body, including opioids, other drugs, toxins, and endogenous compounds. The association between CYP gene methylation and opioid effects is unexplored and it could offer promising insights. Objective: To investigate the impact of prenatal opioid exposure on disrupted CYPs in infants and their anticipated long-term clinical implications. Study Design: DNA methylation levels of CYP genes were analyzed in a cohort of 96 placental tissues using Illumina Infinium MethylationEPIC (850 k) BeadChips. This involved three groups of placental tissues: 32 from mothers with infants exposed to opioids prenatally requiring pharmacologic treatment for NOWS, 32 from mothers with prenatally opioid-exposed infants not needing NOWS treatment, and 32 from unexposed control mothers. Results: The study identified 20 significantly differentially methylated CpG sites associated with 17 distinct CYP genes, with 14 CpGs showing reduced methylation across 14 genes (CYP19A1, CYP1A2, CYP4V2, CYP1B1, CYP24A1, CYP26B1, CYP26C1, CYP2C18, CYP2C9, CYP2U1, CYP39A1, CYP2R1, CYP4Z1, CYP2D7P1 and), while 8 exhibited hypermethylation (CYP51A1, CYP26B1, CYP2R1, CYP2U1, CYP4X1, CYP1A2, CYP2W1, and CYP4V2). Genes such as CYP1A2, CYP26B1, CYP2R1, CYP2U1, and CYP4V2 exhibited both increased and decreased methylation. These genes are crucial for metabolizing eicosanoids, fatty acids, drugs, and diverse substances. Conclusion: The study identified profound methylation changes in multiple CYP genes in the placental tissues relevant to NOWS. This suggests that disruption of DNA methylation patterns in CYP transcripts might play a role in NOWS and may serve as valuable biomarkers, suggesting a future pathway for personalized treatment. Further research is needed to confirm these findings and explore their potential for diagnosis and treatment.
摘要：
背景：新生儿阿片类药物戒断综合征（NOWS），由于怀孕期间阿片类药物的使用增加。细胞色素P450（CYP）酶在人体代谢多种物质中起着关键作用，包括阿片类药物,其他药物,毒素,和内源性化合物。CYP基因甲基化与阿片效应之间的关联尚未被探索，它可以提供有希望的见解。目的：探讨产前阿片类药物暴露对婴儿CYP破坏的影响及其预期的长期临床意义。研究设计:使用IlluminaInfinium甲基化EPIC(850k)BeadChips在一组96个胎盘组织中分析CYP基因的DNA甲基化水平。这涉及三组胎盘组织：32名来自母亲，其婴儿在产前暴露于阿片类药物，需要对NOWS进行药物治疗，32来自产前阿片类药物暴露婴儿不需要NOWS治疗的母亲，32名来自未暴露的对照母亲。结果：该研究确定了20个与17个不同CYP基因相关的显著差异甲基化CpG位点，14个CpG在14个基因（CYP19A1，CYP1A2，CYP4V2，CYP1B1，CYP24A1，CYP26B1，CYP26C1，CYP2C18，CYP2C9，CYP2U1，CYP39A1，CYP2R1，CYP4Z1，CYP2D7P1和）中显示甲基化减少，而8位表现出超甲基化（CYP51A1，CYP26B1，CYP2R1，CYP2U1，CYP4X1，CYP1A2，CYP2W1和CYP4V2）。CYP1A2，CYP26B1，CYP2R1，CYP2U1和CYP4V2等基因均表现出甲基化增加和减少。这些基因对代谢类花生酸至关重要，脂肪酸，毒品,和不同的物质。结论：该研究发现与NOWS相关的胎盘组织中多个CYP基因的甲基化变化。这表明CYP转录本中DNA甲基化模式的破坏可能在NOWS中起作用，并可能作为有价值的生物标志物。建议个性化治疗的未来途径。需要进一步的研究来证实这些发现并探索其诊断和治疗的潜力。
