Methylmercury-induced developmental toxicity is associated with oxidative stress and cofilin phosphorylation. Cellular and human studies
Methylmercury-induced developmental toxicity is associated with oxidative stress and cofilin phosphorylation. Cellular and human studies
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DOI：
10.1016/j.neuro.2016.05.018
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发表时间：
2017-03-01
期刊：
影响因子：
3.4
通讯作者：
Sunol, Cristina
中科院分区：
文献类型：
--
作者：
Caballero, Beatriz;Olguin, Nair;Sunol, Cristina
在发育过程中环境中接触甲基汞是一个令人关注的问题，因为它很容易在出生前后进入儿童体内，它作用于神经通路的几个层面（线粒体、细胞骨架、神经传递），并导致儿童行为障碍。我们评估了长期暴露于10-600 nM甲基汞对小鼠皮质（CCN）和小脑颗粒细胞（CGC）在其分化期的原代培养物的影响。此外，还研究了出生前接触甲基汞是否与来自INMA队列（西班牙）的人类胎盘（n=12）中抗氧化防御和cofilin磷酸化的改变相关，在体外接触甲基汞9天（DIV）分别导致蛋白质羰基化和细胞死亡，浓度分别为>= 200 nM和>= 300 nM。暴露CCN和CGC的非细胞毒性甲基汞浓度为5 DIV诱导的早期浓度依赖性减少cofilin磷酸化。此外，在这两种细胞类型的肌动蛋白易位从胞质到线粒体，而cofilin易位只发现在CGC。从30 nM甲基汞开始，CGC中的cofilin和肌动蛋白易位到线粒体。我们还发现CGC中corneum和LIMK 1 mRNA的表达增加，而CCN中没有。抗氧化剂普罗布考可阻止所有这些作用。与低剂量组相比，高剂量组（20-40 μ g/L）暴露于甲基汞的胎儿侧胎盘样本中，Cofilin磷酸化显著降低，谷胱甘肽还原酶和谷胱甘肽过氧化物酶活性有降低的趋势。
Environmental exposure to methylmercury (MeHg) during development is of concern because it is easily incorporated in children's body both pre- and post-natal, it acts at several levels of neural pathways (mitochondria, cytoskeleton, neurotransmission) and it causes behavioral impairment in child. We evaluated the effects of prolonged exposure to 10-600 nM MeHg on primary cultures of mouse cortical (CCN) and of cerebellar granule cells (CGC) during their differentiation period. In addition, it was studied if prenatal MeHg exposure correlated with altered antioxidant defenses and cofilin phosphorylation in human placentas (n=12) from the INMA cohort (Spain).Exposure to MeHg for 9 days in vitro (DIV) resulted in protein carbonylation and in cell death at concentrations >= 200 nM and >= 300 nM, respectively. Exposure of CCN and CGC to non-cytotoxic MeHg concentrations for 5 DIV induced an early concentration-dependent decrease in cofilin phosphorylation. Furthermore, in both cell types actin was translocated from the cytosol to the mitochondria whereas cofilin translocation was found only in CGC. Translocation of cofilin and actin to mitochondria in CGC occurred from 30 nM MeHg onwards. We also found an increased expression of cortactin and LIMK1 mRNA in CGC but not in CCN. All these effects were prevented by the antioxidant probucol.Cofilin phosphorylation was significantly decreased and a trend for decreased activity of glutathione reductase and glutathione peroxidase was found in the fetal side of human placental samples from the highest (20-40 mu g/L) MeHg-exposed group when compared with the low (