A common carcinogen benzo[a]pyrene causes neuronal death in mouse via microglial activation.
A common carcinogen benzo[a]pyrene causes neuronal death in mouse via microglial activation.
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DOI：
10.1371/journal.pone.0009984
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发表时间：
2010-04-01
期刊：
影响因子：
3.7
通讯作者：
Basu A
中科院分区：
文献类型：
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作者：
Dutta K;Ghosh D;Nazmi A;Kumawat KL;Basu A
苯并[a]芘(B[a]P)属于一类多环芳烃，是环境中的微污染物。B[a]P已被报道为人类可能的致癌物。接触苯并[a]磷可通过摄入受污染(尤其是烧烤、烘烤或烟熏)的食物或水，或吸入受污染的空气而发生。现有的报告也表明，苯并[a]磷暴露会造成神经毒性，但确切的作用机制尚不清楚。利用神经母细胞瘤细胞系和原代培养的皮层神经元，我们证明了苯并[a]P没有直接的神经毒性作用。我们利用体内和体外系统来证明B[a]P引起小胶质细胞的激活。利用小胶质细胞系和原代小胶质细胞培养，我们首次表明，苯并[a]P可导致小胶质细胞内活性氧物种的增加，从而导致抗氧化蛋白水平的降低；诱导型一氧化氮合酶的表达增强，从而导致细胞产生NO的增加。促炎症细胞因子的合成和分泌也在小胶质细胞内增加，可能是通过p38MAP激酶途径。在体外，所有这些因素都导致了神经元的旁观者死亡。当给动物服用时，B[a]P被发现在大脑中引起小胶质细胞激活和星形胶质细胞增生，随后促炎细胞因子水平增加。与早先发表的报告相反，我们发现B[a]P没有直接的神经毒性活性。然而，它通过激活大脑的免疫细胞，即小胶质细胞，以旁观者机制杀死神经元。我们首次提供了关于微污染物B[a]P实际上可能对中枢神经系统造成损害的机制的确凿证据。在当今，全球不断上升的污染水平是一个令人严重关切的问题，我们的研究揭示了此类污染物可能造成的其他健康危害。
Benzo[a]pyrene (B[a]P) belongs to a class of polycyclic aromatic hydrocarbons that serve as micropollutants in the environment. B[a]P has been reported as a probable carcinogen in humans. Exposure to B[a]P can take place by ingestion of contaminated (especially grilled, roasted or smoked) food or water, or inhalation of polluted air. There are reports available that also suggests neurotoxicity as a result of B[a]P exposure, but the exact mechanism of action is unknown. Using neuroblastoma cell line and primary cortical neuron culture, we demonstrated that B[a]P has no direct neurotoxic effect. We utilized both in vivo and in vitro systems to demonstrate that B[a]P causes microglial activation. Using microglial cell line and primary microglial culture, we showed for the first time that B[a]P administration results in elevation of reactive oxygen species within the microglia thereby causing depression of antioxidant protein levels; enhanced expression of inducible nitric oxide synthase, that results in increased production of NO from the cells. Synthesis and secretion of proinflammatory cytokines were also elevated within the microglia, possibly via the p38MAP kinase pathway. All these factors contributed to bystander death of neurons, in vitro. When administered to animals, B[a]P was found to cause microglial activation and astrogliosis in the brain with subsequent increase in proinflammatory cytokine levels. Contrary to earlier published reports we found that B[a]P has no direct neurotoxic activity. However, it kills neurons in a bystander mechanism by activating the immune cells of the brain viz the microglia. For the first time, we have provided conclusive evidence regarding the mechanism by which the micropollutant B[a]P may actually cause damage to the central nervous system. In today's perspective, where rising pollution levels globally are a matter of grave concern, our study throws light on other health hazards that such pollutants may exert.