Department of Sciences, John Jay College of Criminal Justice, City University of New York, 524 West 59th Street, 5.61.09NB, New York, NY 10019, USA.
Cell Mol Neurobiol. 2013 Aug;33(6):815-23. doi: 10.1007/s10571-013-9948-1. Epub 2013 Jun 7.
Humans are exposed to various chemical mixtures daily. The toxic response to a mixture of chemicals could be potentiated or suppressed. This study demonstrates that non-toxic doses of pesticides can induce cellular changes that increase cell sensitivity to other toxins or stress. Pesticide exposure is an environmental risk factor for Parkinson's disease. Manganese (Mn) is essential but high dose exposure may results in neurological dysfunction. Mn-containing dithiocarbamates, maneb (MB) and mancozeb (MZ), are primarily used as pesticides. Studies have shown that MB can augment dopaminergic damage triggered by sub-toxic doses of Parkinsonian mimetic MPTP. However, the mechanism underlying this effect is not clear. Activation of nuclear factor kappa B (NF-κB) has been implicated in MPTP toxicity. Mn stimulates the activation of NF-κB and subsequently induces neuronal injury via an NF-κB dependent mechanism. We speculate that MB and MZ enhance MPTP active metabolite (methyl-4-phenylpyridine ion, MPP(+)) toxicity by activating NF-κB. The activation of NF-κB was observed using Western blot analysis and NF-κB response element driven Luciferase reporter assay. Western blot data demonstrated the nuclear translocation of NF-κB p65 and the degradation of IkBα after MB and MZ 4-h treatments. Results of NF-κB response element luciferase reporter assay confirmed that MB and MZ activated NF-κB. The NF-κB inhibitor (SN50) was also shown to alleviate cytotoxicity induced by co-treatment of MB or MZ and MPP(+). This study demonstrates that activation of NF-κB is responsible for the potentiated toxic effect of MB and MZ on MPP(+) induced cytotoxicity.
人类每天都会接触到各种化学混合物。化学混合物的毒性反应可能会增强或抑制。本研究表明，非毒性剂量的农药会诱导细胞发生变化，从而增加细胞对其他毒素或应激的敏感性。农药暴露是帕金森病的环境风险因素。锰（Mn）是必需的，但高剂量暴露可能导致神经功能障碍。含锰的二硫代氨基甲酸盐，代森锰（MB）和代森锰锌（MZ），主要用作农药。研究表明，MB 可以增强亚毒性剂量的帕金森病模拟物 MPTP 引发的多巴胺能损伤。然而，这种效应的机制尚不清楚。核因子 kappa B（NF-κB）的激活与 MPTP 毒性有关。Mn 刺激 NF-κB 的激活，并通过 NF-κB 依赖性机制随后诱导神经元损伤。我们推测 MB 和 MZ 通过激活 NF-κB 增强 MPTP 活性代谢物（甲基-4-苯基吡啶离子，MPP(+))毒性。使用 Western blot 分析和 NF-κB 反应元件驱动的荧光素酶报告基因检测观察到 NF-κB 的激活。Western blot 数据表明，MB 和 MZ 处理 4 小时后 NF-κB p65 的核转位和 IkBα 的降解。NF-κB 反应元件荧光素酶报告基因检测结果证实 MB 和 MZ 激活了 NF-κB。NF-κB 抑制剂（SN50）也显示出减轻 MB 或 MZ 与 MPP(+)共同处理引起的细胞毒性。本研究表明，NF-κB 的激活是 MB 和 MZ 对 MPP(+)诱导的细胞毒性增强毒性作用的原因。
