Wang Chuanbing, Tang Yuxia, Tang Jiajia, Zhang Jie, Wang Siqi, Wu Feiyun, Wang Shouju
Laboratory of Molecular Imaging, Department of Radiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
Eur Radiol Exp. 2025 Jan 10;9(1):3. doi: 10.1186/s41747-024-00546-x.
BACKGROUND: We examined chronic gadolinium retention impact on gene expression in the mouse central nervous system (CNS) after injection of linear or macrocyclic gadolinium-based contrast agents (GBCAs). METHODS: From 05/2022 to 07/2023, 36 female mice underwent weekly intraperitoneal injections of gadodiamide (2.5 mmol/kg, linear), gadobutrol (2.5 mmol/kg, macrocyclic), or saline. Mice were sacrificed on day 29 or 391 after a 1-year washout. Assessments included magnetic resonance imaging (MRI), mechanical hyperalgesia tests, and inductively coupled plasma mass spectrometry to measure gadolinium levels. Ribonucleic acid (RNA) sequencing and bioinformatic analyses identified differentially expressed genes (DEGs), with validation by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blot (WB). RESULTS: Post-gadodiamide, MRI showed increased signal intensity in the deep cerebellar nuclei (pre, 0.997 ± 0.006 versus post, 1.086 ± 0.013, p < 0.001). Mechanical hyperalgesia tests indicated transient sensory changes. After 1-year, gadolinium retention was noted in the brain (5.92 ± 0.32 nmol/kg) and spinal cord (1.23 ± 0.66 nmol/kg) with gadodiamide, compared to saline controls (0.06 ± 0.02 nmol/kg in brains and 0.28 ± 0.06 nmol/kg in spinal cords). RNA sequencing identified 17 shared DEGs between brain and spinal cord in the gadodiamide group on day 391, with altered Hmgb2 and Sgk1 expression confirmed by qRT-PCR and WB. Reactome pathway analysis showed enrichment in neuroinflammation pathways. No DEGs were detected in brains on day 29. CONCLUSION: Chronic gadolinium deposition from repeated linear GBCA but not macrocyclic administration causes significant gene expression alterations in the mouse CNS, particularly affecting neuroinflammation pathways. RELEVANCE STATEMENT: This study examined the long-term impact of chronic gadolinium retention on gene expression in the mouse CNS, uncovering significant changes associated with neuroinflammation pathways after repeated administration of linear GBCA, but not with macrocyclic GBCA. These findings highlight the importance of further research on the long-term safety of linear GBCA in medical imaging. KEY POINTS: Chronic gadolinium retention alters gene expression in the mouse central nervous system. Significant neuroinflammatory pathway changes were observed after linear gadodiamide exposure. MRI showed increased signal intensity in deep cerebellar nuclei after gadodiamide injection.
背景：我们研究了注射线性或大环钆基造影剂（GBCAs）后，慢性钆潴留对小鼠中枢神经系统（CNS）基因表达的影响。 方法：从2022年5月至2023年7月，36只雌性小鼠每周接受一次腹腔注射钆双胺（2.5 mmol/kg，线性）、钆布醇（2.5 mmol/kg，大环）或生理盐水。在1年洗脱期后的第29天或391天处死小鼠。评估包括磁共振成像（MRI）、机械性痛觉过敏测试以及电感耦合等离子体质谱法测量钆水平。核糖核酸（RNA）测序和生物信息学分析鉴定出差异表达基因（DEGs），并通过定量逆转录聚合酶链反应（qRT-PCR）和蛋白质免疫印迹（WB）进行验证。 结果：注射钆双胺后，MRI显示小脑深部核团信号强度增加（注射前，0.997±0.006对比注射后，1.086±0.013，p<0.001）。机械性痛觉过敏测试表明存在短暂的感觉变化。1年后，与生理盐水对照组相比（脑内0.06±0.02 nmol/kg，脊髓内0.28±0.06 nmol/kg），注射钆双胺的小鼠脑内（5.92±0.32 nmol/kg）和脊髓内（1.23±0.66 nmol/kg）存在钆潴留。RNA测序在第391天钆双胺组的脑和脊髓中鉴定出17个共享的差异表达基因，qRT-PCR和WB证实了Hmgb2和Sgk1表达的改变。Reactome通路分析显示神经炎症通路富集。在第29天脑内未检测到差异表达基因。 结论：重复注射线性GBCA而非大环GBCA导致的慢性钆沉积会引起小鼠中枢神经系统显著的基因表达改变，尤其影响神经炎症通路。 相关性声明：本研究考察了慢性钆潴留对小鼠中枢神经系统基因表达的长期影响，发现重复注射线性GBCA而非大环GBCA后，与神经炎症通路相关的显著变化。这些发现凸显了进一步研究线性GBCA在医学成像中长期安全性的重要性。 关键点：慢性钆潴留会改变小鼠中枢神经系统的基因表达。线性钆双胺暴露后观察到显著的神经炎症通路变化。注射钆双胺后MRI显示小脑深部核团信号强度增加。
Magn Reson Imaging Clin N Am. 2020-11
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