Alcohol increases manganese accumulation in the brain and exacerbates manganese-induced neurotoxicity

• Online Access: http://hdl.handle.net/2047/D20316232

Environmental and occupational exposure to heavy metals remains one of the major concerns in public health. Manganese (Mn) is an essential element for a number of important functions in the body, such as carbohydrates metabolism, antioxidant function, bone development, wound healing and proper brain functions. However, increasing levels of Mn pollution from mining, welding, and alloy production shows profound neurotoxic effects, which is significantly associated with neurobehavioral deficits and disturbances resembling Parkinson's disease. Mn absorption is in part mediated by Fe transporters, such as the DMT1, TfR1 and FPN. Interestingly, recent studies have shown that the levels of these Fe transporters are modified by alcohol treatment and that chronic alcohol consumption increases body Fe stores. However, it is largely unexplored whether or not alcohol exposure influences the transport and neurotoxicity of Mn. My investigation has revealed that alcohol consumption in mice increased Mn uptake into the brain after intranasal instillation of Mn in a dose-dependent manner, due to up-regulation of Fe transporters. In addition, the increased Fe transporters was likely due to down-regulation of hepcidin and increased hypoxia response upon alcohol exposure. Moreover, dopamine and GABA levels were decreased in mice after Mn intranasal instillation, and alcohol further reduced levels of dopamine and GABA in the brain of Mn-instilled mice. The expression of dopaminergic and GABAergic proteins was also modified in Mn-instilled mice, which were exacerbated by alcohol exposure. Finally, I used a model of binge drinking to study the effect of acute alcohol exposure on Mn transport. Like sub-chronic alcohol exposure, binge drinking also increased Mn accumulation in the brain. My study suggests that humans who drink alcohol may have a higher risk of Mn neurotoxicity after inhalation of Mn.