INSERM UMRS 968, Institut de la Vision, Université Pierre et Marie Curie Paris 6, 75012 Paris, France.
Toxicol Sci. 2012 Jan;125(1):209-18. doi: 10.1093/toxsci/kfr252. Epub 2011 Oct 5.
Industrial pollution due to heavy metals such as mercury is a major concern for the environment and public health. Mercury, in particular methylmercury (MeHg), primarily affects brain development and neuronal activity, resulting in neurotoxic effects. Because chemokines can modulate brain functions and are involved in neuroinflammatory and neurodegenerative diseases, we tested the possibility that the neurotoxic effect of MeHg may interfere with the chemokine CCL2. We have used an original protocol in young mice using a MeHg-contaminated fish-based diet for 3 months relevant to human MeHg contamination. We observed that MeHg induced in the mice cortex a decrease in CCL2 concentrations, neuronal cell death, and microglial activation. Knock-out (KO) CCL2 mice fed with a vegetal control food already presented a decrease in cortical neuronal cell density in comparison with wild-type animals under similar diet conditions, suggesting that the presence of CCL2 is required for normal neuronal survival. Moreover, KO CCL2 mice showed a pronounced neuronal cell death in response to MeHg. Using in vitro experiments on pure rat cortical neurons in culture, we observed by blockade of the CCL2/CCR2 neurotransmission an increased neuronal cell death in response to MeHg neurotoxicity. Furthermore, we showed that sod genes are upregulated in brain of wild-type mice fed with MeHg in contrast to KO CCL2 mice and that CCL2 can blunt in vitro the decrease in glutathione levels induced by MeHg. These original findings demonstrate that CCL2 may act as a neuroprotective alarm system in brain deficits due to MeHg intoxication.
工业污染导致的重金属，如汞，是环境和公共健康的主要关注点。汞，特别是甲基汞（MeHg），主要影响大脑发育和神经元活动，导致神经毒性作用。由于趋化因子可以调节大脑功能，并且涉及神经炎症和神经退行性疾病，我们测试了 MeHg 的神经毒性作用可能干扰趋化因子 CCL2 的可能性。我们使用了一个原始方案，在年轻小鼠中使用了含有 MeHg 的鱼基饮食，这与人类的 MeHg 污染有关，为期 3 个月。我们观察到 MeHg 诱导小鼠皮质中 CCL2 浓度降低、神经元细胞死亡和小胶质细胞激活。用植物性对照食物喂养的 CCL2 敲除（KO）小鼠与在类似饮食条件下的野生型动物相比，皮质神经元细胞密度已经降低，这表明 CCL2 的存在对于正常神经元存活是必需的。此外，KO CCL2 小鼠在 MeHg 作用下表现出明显的神经元细胞死亡。通过在体外培养的纯大鼠皮质神经元上进行实验，我们观察到通过阻断 CCL2/CCR2 神经传递，对 MeHg 神经毒性的神经元细胞死亡增加。此外，我们表明，在给予 MeHg 的野生型小鼠的大脑中 sod 基因上调，而在 KO CCL2 小鼠中则没有，并且 CCL2 可以在体外减轻 MeHg 诱导的谷胱甘肽水平降低。这些原始发现表明，CCL2 可能在由于 MeHg 中毒导致的大脑缺陷中作为一种神经保护报警系统发挥作用。
