Perinatal opioid exposure and outcomes of exposed offspring in early adolescence

The opioid epidemic has received considerable attention, but the impact on perinatal opioid-exposed (POE) offspring remains underexplored. This study addresses the emerging public health challenge of understanding and treating POE children. We examine two scenarios using preclinical models: offspring exposed to oxycodone (OXY) in utero (IUO) and postnatally (PNO). We hypothesized exposure to OXY during pregnancy primes offspring for neurodevelopmental deficits and severity of deficits is dependent on timing of exposure. Notable findings include reduced head size and brain weight in offspring. Molecular analyses revealed significantly lower levels of inflammasome-specific genes in the prefrontal cortex (PFC). Gene Set Enrichment Analysis (GSEA) and Ingenuity Pathway Analysis (IPA) highlighted the enrichment of genes associated with mitochondrial and synapse dysfunction in POE offspring. Western blot analysis validated IPA predictions of mitochondrial dysfunction in PFC-derived synaptosomes. Behavioral studies identified significant social deficits in POE offspring. This study presents the first comparative analysis of PNO- and IUO-offspring during early adolescence finding PNO-offspring have considerably greater deficits. The striking difference in deficit severity in PNO-offspring suggests that exposure to opioids in late pregnancy pose the greatest risk for offspring well-being.阿片类药物流行问题已受到广泛关注，但围产期阿片类药物暴露（perinatal opioid-exposed, POE）子代所受影响仍未得到充分探索。本研究针对当前亟需厘清并治疗POE子代的新兴公共卫生挑战展开探索。我们借助临床前模型开展两类场景的研究：宫内暴露于羟考酮（oxycodone, OXY）的子代（in utero, IUO）与产后暴露于羟考酮的子代（postnatal, PNO）。本研究提出假设：妊娠期间暴露于羟考酮会使子代易出现神经发育缺陷，且缺陷严重程度取决于暴露时机。值得关注的研究结果包括子代头围减小、脑重量降低。分子分析显示，前额叶皮层（prefrontal cortex, PFC）内的炎性小体特异性基因表达水平显著下调。基因集富集分析（Gene Set Enrichment Analysis, GSEA）与Ingenuity通路分析（Ingenuity Pathway Analysis, IPA）结果表明，POE子代中与线粒体功能异常及突触功能异常相关的基因呈现富集特征。蛋白质印迹分析验证了IPA关于PFC来源突触体中线粒体功能异常的预测结论。行为学研究发现POE子代存在显著的社交缺陷。本研究首次针对青春期早期的PNO子代与IUO子代开展对比分析，结果显示PNO子代的神经发育缺陷程度显著更严重。两组子代缺陷严重程度的显著差异提示，妊娠晚期暴露于阿片类药物对子代健康构成的风险最高。