Investigation of potential adverse central nervous system effects after long term oral administration of gadolinium in mice
Investigation of potential adverse central nervous system effects after long term oral administration of gadolinium in mice
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DOI：
10.1371/journal.pone.0231495
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发表时间：
2020-04-23
期刊：
影响因子：
3.7
通讯作者：
Levin, Johannes
中科院分区：
文献类型：
--
作者：
Noerenberg, Dominik;Schmidt, Felix;Levin, Johannes
目的 检测长期口服含钆颗粒食物后健康小鼠大脑中钆 (Gd) 的潜在积累，并研究钆 (Gd) 是否会导致中枢神经系统 (CNS) 不良影响，特别关注与对照动物相比，暴露于钆 (Gd) 的小鼠的运动障碍。材料和方法当地动物实验伦理委员会批准了所有程序和应用。 15 只雌性 C57Bl/6 小鼠从 4 周龄开始，在 90 周的时间内每天经口摄入 0.57 mmol Gd 氯化物/kg 体重。对照组 (N = 13) 接受无 Gd 但其他方面相当的实验饮食。动物饲养员每天监测动物是否有任何明显的痛苦迹象，并在前 60 周每四周进行一次临床评估，之后每两周进行一次临床评估，以便更好地解决有关运动性能受损和体重减轻的潜在长期影响。使用质谱法测量 N = 6 只小鼠的子队列中的个体 Gd 含量。结果 与对照小鼠相比，Gd 暴露小鼠的绝对脑 Gd 水平显着增加（0.033 +/- 0.009 vs. 0.006 +/- 0.002 nmol Gd/g 脑组织）。在整个研究期间，健康小鼠几乎在整个生命周期中长期口服 Gd 暴露不会导致不良 CNS 影响，包括运动变化（旋转性能，p = 0.1467）。在研究期间，与对照小鼠相比，暴露于 Gd 的小鼠体重增加较少 (p = 0.0423)。两组的外周器官均发现组织病理学改变，例如肝脏脂肪变化导致的肝细胞空泡化和脾红髓中有核细胞的丢失。结论在小鼠的几乎整个生命周期中，由于长期口服Gd而导致的脑内Gd水平较低，并没有导致健康小鼠在整个正常衰老过程中运动能力的改变。
ObjectivesTo examine potential gadolinium (Gd) accumulation in the brain of healthy mice after long-term oral administration of Gd-containing food pellets and to investigate whether Gd leads to adverse central nervous system (CNS) effects, specifically focussing on locomotor impairment in Gd exposed compared to control animals.Materials and methodsThe local Animal Experimental Ethics Committee approved all procedures and applications. Fifteen female C57Bl/6 mice were orally exposed to a daily intake of 0.57 mmol Gd chloride/kg body weight over a period of 90 weeks from the age of 4 weeks on. Gd-free, but otherwise equivalent experimental diets were given to the control group (N = 13). The animals were monitored daily by animal caretakers regarding any visible signs of distress and evaluated clinically every four weeks for the first 60 weeks and afterwards every two weeks for a better temporal resolution of potential long-term effects regarding impairment of motor performance and loss of body weight. The individual Gd content was measured using mass spectrometry in a sub-cohort of N = 6 mice.ResultsThe absolute brain Gd levels of the Gd-exposed mice were significantly increased compared to control mice (0.033 +/- 0.009 vs. 0.006 +/- 0.002 nmol Gd/g brain tissue). Long-term oral Gd exposure over almost the entire life-span did not lead to adverse CNS effects including locomotor changes (rotarod performance, p = 0.1467) in healthy mice throughout the study period. Gd-exposed mice showed less increased body weight compared to control mice during the study period (p = 0.0423). Histopathological alterations, such as hepatocellular vacuolization due to fatty change in the liver and a loss of nucleated cells in the red pulp of the spleen, were found in peripheral organs of both groups.ConclusionsLow levels of intracerebral Gd caused by chronic oral exposure over almost the entire life span of mice did not lead to alterations in locomotor abilities in healthy mice throughout the normal aging process.