A Common Carcinogen Benzo[a]pyrene Causes Neuronal Death in Mouse via Microglial Activation

Background

Benzoa]pyrene (Ba]P) belongs to a class of polycyclic aromatic hydrocarbons that serve as micropollutants in the environment. Ba]P has been reported as a probable carcinogen in humans. Exposure to Ba]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 Ba]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 Ba]P has no direct neurotoxic effect. We utilized both in vivo and in vitro systems to demonstrate that Ba]P causes microglial activation. Using microglial cell line and primary microglial culture, we showed for the first time that Ba]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, Ba]P was found to cause microglial activation and astrogliosis in the brain with subsequent increase in proinflammatory cytokine levels.

Conclusions/Significance

Contrary to earlier published reports we found that Ba]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 Ba]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.