Environmental, biochemical and molecular factors regulating manganese-induced neurological injury

摘要

Manganese intoxication is most often regarded as an occupational disorder in which abnormally high atmospheric concentrations prevail, such as in welding and mining. The syndrome known as manganism is characterized by cognitive, behavioral, intellectual and minor neurological disturbances in the initial stages of the disorder and by more prominent and irreversible extrapyramidal dysfunction resembling Parkinson's disease upon prolonged exposure. Recent evidence further reveals that individuals with liver dysfunction and those receiving parenteral nutrition exhibit many of the same symptoms as occupationally exposed workers. Common homeostatic processes are normally capable of preventing Mn overload for a typical dietary intake but in environmental settings in which occupational exposures are both chronic and excessive, these regulatory processes are inadequate to maintain tolerable levels of the metal, as demonstrated by significant increases in both blood and brain levels of Mn. Based on T1-weighted MRI scans, Mn is preferentially deposited in the globus pallidus and substantia nigra, two areas of the brain normally associated with the highest metal concentrations. Neurons within the globus pallidus appear to be more sensitive to the deposited Mn, as they are preferentially damaged, whereas the neurons in the substantia nigra are initially spared. Uptake of inspired Mn into the circulation from particulates deposited in the pulmonary airway may be the rate-limiting process regulating central nervous system (CNS) toxicity as brain levels often parallel those found in blood, implying that the blood-brain barrier is not a viable obstacle preventing Mn transport into the CNS. Accordingly, this review attempts to present an overview of the initial findings linking Mn to this neurological disorder as well as presenting an updated perspective as to the causes and potential biological mechanisms responsible for Mn toxicity.