Radhakrishna Uppala, Radhakrishnan Rupa, Uppala Lavanya V, Muvvala Srinivas B, Prajapati Jignesh, Rawal Rakesh M, Bahado-Singh Ray O, Sadhasivam Senthilkumar
Department of Anesthesiology and Perioperative Medicine, University of Pittsburgh, Pittsburgh, PA, United States.
Department of Obstetrics and Gynecology, Corewell Health William Beaumont University Hospital, Royal Oak, MI, United States.
Front Neurosci. 2024 Aug 19;18:1442915. doi: 10.3389/fnins.2024.1442915. eCollection 2024.
Neonatal Opioid Withdrawal Syndrome (NOWS) is a consequence of in-utero exposure to prenatal maternal opioids, resulting in the manifestation of symptoms like irritability, feeding problems, tremors, and withdrawal signs. Opioid use disorder (OUD) during pregnancy can profoundly impact both mother and fetus, disrupting fetal brain neurotransmission and potentially leading to long-term neurological, behavioral, and vision issues, and increased infant mortality. Drug resistance complicates OUD and NOWS treatment, with protein kinase regulation of drug transporters not fully understood.
DNA methylation levels of ATP-binding cassette (ABC) and solute carrier (SLC) drug transporters, along with protein kinase C (PKC) genes, were assessed in 96 placental samples using the Illumina Infinium MethylationEPIC array (850K). Samples were collected from three distinct groups: 32 mothers with infants prenatally exposed to opioids who needed pharmacological intervention for NOWS, 32 mothers with prenatally opioid-exposed infants who did not necessitate NOWS treatment, and 32 mothers who were not exposed to opioids during pregnancy.
We identified 69 significantly differentially methylated SLCs, with 24 hypermethylated and 34 hypomethylated, and 11 exhibiting both types of methylation changes including , and . We identified methylation changes in 11 ABC drug transporters ): 3 showed hypermethylation, 3 hypomethylation, and 5 exhibited both. Additionally, 7 PKC family genes (, and ) showed methylation changes. These genes are associated with 13 pathways involved in NOWS, including ABC transporters, bile secretion, pancreatic secretion, insulin resistance, glutamatergic synapse, and gastric acid secretion.
We report epigenetic changes in PKC-related regulation of drug transporters, which could improve our understanding of clinical outcomes like drug resistance, pharmacokinetics, drug-drug interactions, and drug toxicity, leading to maternal relapse and severe NOWS. Novel drugs targeting PKC pathways and transporters may improve treatment outcomes for OUD in pregnancy and NOWS.
新生儿阿片类药物戒断综合征（NOWS）是胎儿在子宫内接触产前母体阿片类药物的结果，导致出现易怒、喂养问题、震颤和戒断症状等。孕期阿片类药物使用障碍（OUD）会对母亲和胎儿产生深远影响，扰乱胎儿大脑神经传递，并可能导致长期的神经、行为和视力问题，以及婴儿死亡率增加。耐药性使OUD和NOWS的治疗变得复杂，药物转运蛋白的蛋白激酶调节尚未完全了解。
使用Illumina Infinium MethylationEPIC阵列（850K）对96份胎盘样本中的ATP结合盒（ABC）和溶质载体（SLC）药物转运蛋白以及蛋白激酶C（PKC）基因的DNA甲基化水平进行评估。样本来自三个不同的组：32名母亲，其婴儿在产前接触过阿片类药物，需要对NOWS进行药物干预；32名母亲，其产前接触过阿片类药物的婴儿不需要NOWS治疗；32名母亲在孕期未接触过阿片类药物。
我们鉴定出69个显著差异甲基化的SLC，其中24个高甲基化，34个低甲基化，11个表现出两种类型的甲基化变化，包括 ，以及 。我们在11个ABC药物转运蛋白中鉴定出甲基化变化（ ）：3个显示高甲基化，3个显示低甲基化，5个表现出两种情况。此外，7个PKC家族基因（ ，以及 ）显示出甲基化变化。这些基因与NOWS涉及的13条途径相关，包括ABC转运蛋白、胆汁分泌、胰腺分泌、胰岛素抵抗、谷氨酸能突触和胃酸分泌。
我们报告了PKC相关的药物转运蛋白调节中的表观遗传变化，这可能增进我们对耐药性、药代动力学、药物 - 药物相互作用和药物毒性等临床结果的理解，这些结果会导致母亲复发和严重的NOWS。针对PKC途径和转运蛋白的新型药物可能会改善孕期OUD和NOWS的治疗效果。
