Takahashi Tsutomu, Kim Min-Seok, Iwai-Shimada Miyuki, Fujimura Masatake, Toyama Takashi, Naganuma Akira, Hwang Gi-Wook
Laboratory of Molecular and Biochemical Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba-ku, Sendai 980-8578, Japan.
Department of Environmental Health, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan.
Toxics. 2018 Jul 7;6(3):36. doi: 10.3390/toxics6030036.
Methylmercury (MeHg) is selectively toxic to the central nervous system, but mechanisms related to its toxicity are poorly understood. In the present study, we identified the chemokine, C-C motif Chemokine Ligand 4 (CCL4), to be selectively upregulated in the brain of MeHg-administered mice. We then investigated the relationship between CCL4 expression and MeHg toxicity using in vivo and in vitro approaches. We confirmed that in C17.2 cells (a mouse neural stem cell line) and the mouse brain, induction of CCL4 expression occurs prior to cytotoxicity caused by MeHg. We also show that the addition of recombinant CCL4 to the culture medium of mouse xprimary neurons attenuated MeHg toxicity, while knockdown of CCL4 in C17.2 cells resulted in higher MeHg sensitivity compared with control cells. These results suggest that CCL4 is a protective factor against MeHg toxicity and that induction of CCL4 expression is not a result of cytotoxicity by MeHg but is a protective response against MeHg exposure.
甲基汞（MeHg）对中枢神经系统具有选择性毒性，但其毒性相关机制仍知之甚少。在本研究中，我们鉴定出趋化因子C-C基序趋化因子配体4（CCL4）在给予甲基汞的小鼠脑中选择性上调。然后，我们使用体内和体外方法研究了CCL4表达与甲基汞毒性之间的关系。我们证实，在C17.2细胞（一种小鼠神经干细胞系）和小鼠脑中，CCL4表达的诱导发生在甲基汞引起的细胞毒性之前。我们还表明，向小鼠原代神经元培养基中添加重组CCL4可减轻甲基汞毒性，而在C17.2细胞中敲低CCL4会导致与对照细胞相比对甲基汞的敏感性更高。这些结果表明，CCL4是抵抗甲基汞毒性的保护因子，并且CCL4表达的诱导不是甲基汞细胞毒性的结果，而是针对甲基汞暴露的一种保护反应。
