Department of Pharmacology, College of Medicine, Hanyang University, Republic of Korea.
Neurotoxicology. 2011 Dec;32(6):702-10. doi: 10.1016/j.neuro.2011.08.004. Epub 2011 Sep 3.
A number of epidemiological studies have demonstrated a strong association between the incidence of neurodegenerative disease and pesticide exposure. Fluazinam (FZN) is a preventative fungicide from the pyridinamine group that was introduced in the 1990 s and that quickly established itself as a new standard for the control of blight caused by Phytophthora infestans in potatoes. We used human neuroblastoma SH-SY5Y cells to investigate mechanisms of neuronal cell death in response to FZN and showed that FZN was cytotoxic to SH-SY5Y cells in a concentration- and time-dependent manner. Additionally, we showed that FZN treatment significantly decreased the neuron numbers including dopaminergic neurons and mitochondrial complex I activity. The cytotoxic effects of FZN were associated with an increase in reactive oxygen species (ROS) generation because pretreatment with N-acetyl cysteine, an anti-oxidant, reduced cell death. We showed that neuronal cell death in response to FZN was due to apoptosis because FZN increased cytochrome C release into the cytosol and activated caspase-3 through the accumulation of p53. FZN also reduced the levels of Bcl-2 protein but increased the levels of Bax. Our results provide insight into the molecular mechanisms of FZN-induced apoptosis in neuronal cells.
许多流行病学研究表明，神经退行性疾病的发病率与农药暴露之间存在很强的关联。氟唑菌胺（FZN）是一种 20 世纪 90 年代引入的吡啶酰胺类预防性杀菌剂，它很快成为防治马铃薯晚疫病菌引起的疫病的新标准。我们使用人神经母细胞瘤 SH-SY5Y 细胞研究了 FZN 诱导神经元细胞死亡的机制，并表明 FZN 以浓度和时间依赖的方式对 SH-SY5Y 细胞具有细胞毒性。此外，我们还表明，FZN 处理显著减少了神经元数量，包括多巴胺能神经元和线粒体复合物 I 活性。FZN 的细胞毒性作用与活性氧（ROS）生成的增加有关，因为抗氧化剂 N-乙酰半胱氨酸的预处理减少了细胞死亡。我们表明，FZN 诱导的神经元细胞死亡是由于细胞凋亡，因为 FZN 增加了细胞色素 C 向细胞质中的释放，并通过 p53 的积累激活了 caspase-3。FZN 还降低了 Bcl-2 蛋白的水平，但增加了 Bax 的水平。我们的结果提供了对 FZN 诱导神经元细胞凋亡的分子机制的深入了解。
