Barnette Dustyn, Inselman Amy L, Kaldhone Pravin, Lee Grace S, Davis Kelly, Sarkar Sumit, Malhi Pritpal, Fisher J Edward, Hanig Joseph P, Beger Richard D, Jones E Ellen
National Center for Toxicological Research (FDA), Division of Systems Biology, Jefferson, AR, United States.
Center for Drug Evaluation and Research (CDER), Office of Testing and Research, Silver Spring, MD, United States.
Front Toxicol. 2024 Dec 3;6:1452974. doi: 10.3389/ftox.2024.1452974. eCollection 2024.
In 2015, the FDA released a Drug Safety Communication regarding a possible link between opioid exposure during early pregnancy and an increased risk of fetal neural tube defects (NTDs). At the time, the indications for opioid use during pregnancy were not changed due to incomplete maternal toxicity data and limitations in human and animal studies. To assess these knowledge gaps, largescale animal studies are ongoing; however, state-of-the-art technologies have emerged as promising tools to assess otherwise non-standard endpoints. Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) is a dynamic approach capable of generating 2D ion images to visualize the distribution of an analyte of interest across a tissue section.
Given the importance of lipid metabolism and neurotransmitters in the developing central nervous system, this study incorporates MALDI MSI to assess lipid distributions across mouse gestational day (GD) 18 fetuses, with and without observable NTDs following maternal exposure on GD 8 to morphine (400 mg/kg BW) or the NTD positive control valproic acid (VPA) (500 mg/kg BW).
Analysis of whole-body mouse fetuses revealed differential lipid distributions localized mainly in the brain and spinal cord, which included several phosphatidylcholine (PC) species such as PCs 34:1, 34:0, and 36:2 localized to the cortex or hippocampus and lyso PC 16:0 across all brain regions. Overall, differential lipids increased in with maternal morphine and VPA exposure. Neurotransmitter distributions across the brain using FMP-10 derivatizing agent were also assessed, revealing morphine-specific changes.
The observed differential glycerophospholipid distributions in relation to treatment and NTD development in mouse fetuses provide potential targets for further investigation of molecular mechanisms of opioid-related developmental effects. Overall, these findings support the feasibility of incorporating MALDI MSI to assess non-standard endpoints of opioid exposure during gestation.
2015年，美国食品药品监督管理局（FDA）发布了一份药物安全通讯，内容涉及孕早期接触阿片类药物与胎儿神经管缺陷（NTD）风险增加之间的可能联系。当时，由于母体毒性数据不完整以及人体和动物研究存在局限性，孕期使用阿片类药物的适应症并未改变。为评估这些知识空白，大规模动物研究正在进行；然而，先进技术已成为评估其他非标准终点的有前景的工具。基质辅助激光解吸/电离质谱成像（MALDI MSI）是一种动态方法，能够生成二维离子图像，以可视化感兴趣的分析物在组织切片中的分布。
鉴于脂质代谢和神经递质在发育中的中枢神经系统中的重要性，本研究采用MALDI MSI评估孕18天小鼠胎儿的脂质分布，这些胎儿在孕8天母体接触吗啡（400 mg/kg体重）或NTD阳性对照丙戊酸（VPA）（500 mg/kg体重）后，有无可观察到的NTD。
对全身小鼠胎儿的分析显示，脂质分布差异主要位于脑和脊髓，其中包括几种磷脂酰胆碱（PC）种类，如定位于皮质或海马体的PC 34:1、34:0和36:2，以及遍布所有脑区的溶血PC 16:0。总体而言，母体接触吗啡和VPA后，差异脂质增加。还使用FMP-10衍生剂评估了整个大脑中的神经递质分布，揭示了吗啡特异性变化。
在小鼠胎儿中观察到的与治疗和NTD发育相关的甘油磷脂分布差异，为进一步研究阿片类药物相关发育效应的分子机制提供了潜在靶点。总体而言，这些发现支持了采用MALDI MSI评估孕期阿片类药物暴露非标准终点的可行性。
