Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL, USA.
Neurotoxicology. 2010 Mar;31(2):215-22. doi: 10.1016/j.neuro.2009.12.007. Epub 2009 Dec 29.
Elevated environmental exposure to pesticides has been implicated as a contributing factor in the pathogenesis of Parkinson's disease (PD), a progressive movement disorder resulted from degeneration of the nigrostriatal dopaminergic (DA) pathway. Organochlorine pesticides (OCPs) including dieldrin and lindane remain ubiquitous in the environment and food supply due to their resistance to degradation and bioaccumulation along the food chain. While prior studies have gained insight into the neurotoxic effects of individual OCPs such as dieldrin, the effect of combinations of coexisting OCPs is lacking. In this study, we determined the combined effect of dieldrin and lindane on DA neurons and potential mechanism of action. Combinations of dieldrin and lindane (5-25 microM) were more effective in causing toxicity in immortalized rat N27 DA neurons than when used alone. Mechanistically, dieldrin and lindane combination induced a rapid increase in the levels of intracellular reactive oxygen species, a decrease in mitochondrial membrane potential and activation of caspase 3/7. Pretreatment with antioxidant N-acetyl cysteine blocked the effect of dieldrin and lindane on ROS generation and mitochondrial membrane potential and protected against dieldrin- and lindane-induced neurotoxicity. These results demonstrate that dieldrin and lindane work cooperatively to induce DA neurotoxicity through the induction of oxidative stress and mitochondrial dysfunction. These findings may advance understanding of the role of pesticides in the multi-factorial etiology of PD.
环境中有机氯农药（OCPs）暴露水平升高与帕金森病（PD）的发病机制有关，PD 是一种由黑质纹状体多巴胺能（DA）通路变性引起的进行性运动障碍。由于其在食物链中难以降解和生物蓄积，滴滴涕和林丹等有机氯农药（OCPs）仍然广泛存在于环境和食物供应中。尽管先前的研究已经深入了解了滴滴涕等个别 OCP 的神经毒性作用，但对于共存 OCP 组合的影响仍缺乏研究。在这项研究中，我们确定了滴滴涕和林丹联合对 DA 神经元的影响及其潜在的作用机制。与单独使用相比，滴滴涕和林丹（5-25 μM）联合使用更有效地导致永生化大鼠 N27 DA 神经元毒性。从机制上讲，滴滴涕和林丹联合使用会迅速增加细胞内活性氧（ROS）的水平，降低线粒体膜电位并激活 caspase 3/7。抗氧化剂 N-乙酰半胱氨酸预处理可阻断滴滴涕和林丹对 ROS 生成和线粒体膜电位的影响，并防止滴滴涕和林丹引起的神经毒性。这些结果表明，滴滴涕和林丹通过诱导氧化应激和线粒体功能障碍协同作用诱导 DA 神经毒性。这些发现可能有助于理解农药在 PD 的多因素病因学中的作用。
