a common carcinogen benzo[a]pyrene causes neuronal death in mouse via microglial activation常见的致癌物苯并[a]芘通过小胶质激活导致小鼠神经元死亡.pdfVIP

A Common Carcinogen Benzo[a]pyrene Causes Neuronal Death in Mouse via Microglial Activation . .¤ Kallol Dutta , Debapriya Ghosh , Arshed Nazmi, Kanhaiya Lal Kumawat, Anirban Basu* National Brain Research Centre, Manesar, Haryana, India Abstract Background: 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. Methodology/Principal Findings: 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 subsequen