Strategies to define and mitigate the placental and fetal alterations caused by maternal oxycodone exposure

项目摘要 仅在美国，1.5%的孕妇自我报告滥用处方阿片类药物，近80 每天都有新生儿被诊断出患有新生儿阿片类药物戒断综合征。子宫内阿片类药物暴露导致 胎儿生长受限，改变胎儿大脑发育，导致认知、运动技能和 受影响儿童的行为。然而，阿片类药物神经发育失调的机制是 目前未知。胎盘是胎儿发育的关键调节器，新的证据表明， 阿片类药物也会损害胎盘发育该项目的首要目标是定义 胎盘和胎儿大脑的发育过程因阿片类药物暴露而失调， 制定战略，以减轻由此产生的病理。羟考酮（oxy）是最常滥用的药物之一， 与吗啡、海洛因、芬太尼和美沙酮相比，阿片类药物更容易通过胎盘。这 一项提案将检验以下假设：在大鼠中，子宫内氧暴露会导致母体循环系统的改变。 因素，胎盘结构和功能，胎儿神经发育和行为，这些变化 可以通过补充褪黑激素来纠正异常的病理生理学来减轻。胎盘和 胎脑超微结构和基因表达将在孕中期（胚胎）进行综合评估 (E)第12.5天，当胎盘完全形成时），和分娩前（E19.5），使用现有技术 这些技术包括单细胞RNA测序和X-BILITY全器官成像。的证据 母体血浆、胎儿和胎盘中的炎症、氧化应激和失调的激素产生 还将评价组织。与此同时，生长因子表达的变化，炎症反应， 暴露于氧的4天和14天大的幼鼠大脑中的分子，免疫细胞和神经递质。 子宫也将被测量，这将与同时进行的行为研究相关 点这些观察结果将首次提供关键结构和功能的综合分析， 异常，激素和神经发育的变化发生在母胎界面， 对氧暴露的反应，并将其与后代行为的改变联系起来。褪黑激素， 天然存在的，抗炎，抗氧化和神经保护激素，以减少程度 还将评估观察到的胎盘和/或胎儿病理生理学。成功完成本 建议，使用预防相关的啮齿动物模型，将提供一个强大的框架，以确定 关键的发育过程容易受到羟化酶的失调。这些研究， 可能在人类中，有可能为第一个生物标志物、胎儿监测和干预性研究提供信息 在人类妊娠中，为受阿片类药物影响的个体提供改进的临床指南和治疗 使用障碍，从而与NICHD，NIDA和NINDS的任务保持一致。

PROJECT SUMMARY In the US alone, 1.5% of pregnant individuals self-report misuse of prescription opioids, and almost 80 newborns a day are diagnosed with neonatal opioid withdrawal syndrome. In utero opioid exposure causes fetal growth restriction, alters fetal brain development and causes deficits in cognition, motor skills and behavior in affected children. However, the mechanisms by which opioids dysregulate neurodevelopment are currently unknown. The placenta is a critical regulator of fetal development, and emerging evidence suggests that opioids also impair placental development. The overarching aim of this project is to define the developmental processes in the placenta and fetal brain that are dysregulated by opioid exposure, and develop strategies to mitigate the resulting pathology. Oxycodone (oxy) is one of the most commonly abused opioids and crosses the placenta to a greater extent than morphine, heroin fentanyl and methadone. This proposal will test the hypotheses that in rats, in utero oxy exposure leads to alterations in maternal circulating factors, placental structure and function, and fetal neurodevelopment and behavior, and that these changes can be mitigated using melatonin supplementation to correct the abnormal pathophysiology. Placental and fetal brain ultrastructure and gene expression will be comprehensively assessed at mid pregnancy (embryonic (E) day 12.5, when the placenta is fully formed), and just before birth (E19.5), using state of the art technologies including single cell RNA sequencing and X-CLARITY whole organ imaging. Evidence of inflammation, oxidative stress and dysregulated hormone production in maternal plasma, fetal and placental tissues will be also be evaluated. In parallel, changes in the expression of growth factors, inflammatory molecules, immune cells and neurotransmitters in the brains of 4- and 14-day old rat pups exposed to oxy in utero will also be measured, which will be correlated with behavioral studies undertaken at the same time points. These observations will provide the first integrated analysis of the key structural and functional abnormalities, hormonal, and neurodevelopmental changes occurring at the maternofetal interface in response to oxy exposure, and link them to alterations in offspring behavior. The ability of melatonin, a naturally occurring, anti-inflammatory, antioxidant and neuroprotective hormone, to reduce the degree of placental and/or fetal pathophysiology observed, will also be assessed. Successful completion of this proposal, using a translationally-relevant rodent model, will provide a robust framework on which to identify key developmental processes that are susceptible to dysregulation by oxy. These studies, which are not possible in humans, have the potential to inform the first biomarker, fetal monitoring and interventional studies in human pregnancy, providing improved clinical guidelines and treatments for individuals affected by opioid use disorder, thereby aligning with the missions of the NICHD, NIDA and NINDS.