Jin J, Lao A J, Katsura M, Caputo A, Schweizer F E, Sokolow S
UCLA School of Nursing, Los Angeles, CA 90095, USA; Department of Neurobiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, PR China.
UCLA School of Nursing, Los Angeles, CA 90095, USA.
Neurotoxicology. 2014 Dec;45:56-66. doi: 10.1016/j.neuro.2014.09.004. Epub 2014 Oct 2.
Ziram is a dimethyldithiocarbamate fungicide which can cause intraneuronal calcium (Ca(2+)) dysregulation and subsequently neuronal death. The signaling mechanisms underlying ziram-induced Ca(2+) dyshomeostasis and neurotoxicity are not fully understood. NCX3 is the third isoform of the sodium-calcium exchanger (NCX) family and plays an important role in regulating Ca(2+) homeostasis in excitable cells. We previously generated a mouse model deficient for the sodium-calcium exchanger 3 and showed that NCX3 is protective against ischemic damage. In the present study, we aim to examine whether NCX3 exerts a similar role against toxicological injury caused by the pesticide ziram. Our data show baby hamster kidney (BHK) cells stably transfected with NCX3 (BHK-NCX3) are more susceptible to ziram toxicity than cells transfected with the empty vector (BHK-WT). Increased toxicity in BHK-NCX3 was associated with a rapid rise in cytosolic Ca(2+) concentration [Ca(2+)]i induced by ziram. Profound mitochondrial dysfunction and ATP depletion were also observed in BHK-NCX3 cells following treatment with ziram. Lastly, primary dopaminergic neurons lacking NCX3 (NCX3(-/-)) were less sensitive to ziram neurotoxicity than wildtype control dopaminergic neurons. These results demonstrate that NCX3 genetic deletion protects against ziram-induced neurotoxicity and suggest NCX3 and its downstream molecular pathways as key factors involved in ziram toxicity. Our study identifies new molecular events through which pesticides (e.g. ziram) can lead to pathological features of degenerative diseases such as Parkinson's disease and indicates new targets to slow down neuronal degeneration.
福美锌是一种二甲基二硫代氨基甲酸盐类杀菌剂，可导致神经元内钙（Ca(2+)）调节异常，进而引起神经元死亡。福美锌诱导的Ca(2+)稳态失衡和神经毒性的信号传导机制尚未完全明确。钠钙交换体（NCX）家族的第三个亚型NCX3在调节可兴奋细胞的Ca(2+)稳态中起重要作用。我们之前构建了一个钠钙交换体3基因缺失的小鼠模型，并表明NCX3对缺血性损伤具有保护作用。在本研究中，我们旨在探究NCX3对农药福美锌所致毒理学损伤是否发挥类似作用。我们的数据显示，稳定转染NCX3的幼仓鼠肾（BHK）细胞（BHK-NCX3）比转染空载体的细胞（BHK-WT）对福美锌毒性更敏感。BHK-NCX3细胞毒性增加与福美锌诱导的胞质Ca(2+)浓度[Ca(2+)]i迅速升高有关。在用福美锌处理后的BHK-NCX3细胞中还观察到严重的线粒体功能障碍和ATP耗竭。最后，缺乏NCX3的原代多巴胺能神经元（NCX3(-/-)）对福美锌神经毒性的敏感性低于野生型对照多巴胺能神经元。这些结果表明，NCX3基因缺失可保护机体免受福美锌诱导的神经毒性，并提示NCX3及其下游分子途径是福美锌毒性的关键因素。我们的研究确定了农药（如福美锌）可导致帕金森病等退行性疾病病理特征的新分子事件，并指出了减缓神经元变性的新靶点。
