Induction of macrophage apoptosis by an organochlorine insecticide acetofenate.
Induction of macrophage apoptosis by an organochlorine insecticide acetofenate.
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DOI：
10.1021/tx800358b
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发表时间：
2009-01
影响因子：
4.1
通讯作者：
Mei-rong Zhao;Ying Zhang;Cui Wang;Z. Fu;Weiping Liu;J. Gan
中科院分区：
文献类型：
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作者：
Mei-rong Zhao;Ying Zhang;Cui Wang;Z. Fu;Weiping Liu;J. Gan
乙氰菊酯(AF)是中国等东南亚地区广泛使用的杀虫剂。先前的一项研究表明，AF会对斑马鱼的发育造成不利影响。巨噬细胞在炎症、宿主防御和对一系列自体和外来入侵者的反应中发挥关键作用，对先天免疫至关重要。然而，有机氯农药(OCPs)对巨噬细胞的细胞毒性和细胞凋亡作用尚未引起足够的重视。本研究以黄曲霉毒素为模型化合物，研究了有机氯农药对小鼠巨噬细胞系RAW264.7的细胞毒作用。细胞存活率和细胞凋亡率检测结果表明，AF可诱导RAW 264.7细胞发生明显的凋亡。此外，AF诱导细胞内ROS生成和DNA损伤，并导致一系列信号分子的改变，包括上调P53和细胞色素c蛋白水平，降低Bcl2/Bax蛋白比值，并通过caspase-9和caspase-3级联激活caspase。这些结果首次揭示了OCP诱导巨噬细胞凋亡的内源性ROS和DNA损伤的增加可能是通过线粒体和P53信号通路实现的。我们的结果提示巨噬细胞参与了房颤诱导的不良免疫效应。考虑到有机氯农药在环境中的普遍存在，这项研究为长期接触有机氯农药可能产生的生理和免疫影响提供了新的信息。
Acetofenate (AF) is a widely used insecticide in China and other regions of southeastern Asia. A previous study showed that AF caused adverse developmental effects in zebrafish. Macrophages, which play a key role in inflammation, host defense, and reactions against a spectrum of autologous and foreign invaders, are crucial for innate immunity. However, cytotoxicity and apoptosis of macrophages caused by organochlorine pesticides (OCPs) have so far received little attention. In this study, we used AF as a model chemical to investigate the cytotoxic effects of OCPs on mouse macrophage cell line RAW264.7. Results from cell viability and apoptosis assays showed that AF induced apparent apoptosis in RAW 264.7 cells. Furthermore, AF induced intracellular reactive oxygen species (ROS) generation and DNA damage and resulted in the alteration of a series of signaling molecules including up-regulation of p53 and cytochrome c protein levels, decline of the Bcl-2/Bax protein ratio, and activation of the caspases cascade through caspase-9 and caspase-3. These results, for the first time, revealed that the increase of endogenous ROS and DNA damage comediating OCP-induced apoptosis in macrophages may be by the mitochondria and p53 signal pathway. Our results suggested that macrophages are involved in AF-induced adverse immune effects. Considering the ubiquitous environmental presence of OCPs, this study provided new information on the potential long-term physiological and immunological effects due to chronic exposures to OCPs.