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MANGANESE TOXICOKINETICS AT THE BLOOD-BRAIN BARRIER
Impact/Purpose:
Metals comprise a large group of elements. Many of these metals are essential to living systems because they participate in a variety of biological functions, but they can be toxic at concentrations above those needed in the body. Exposure to some metals has been found to cause neurologic damage—for instance, in children exposed to low levels of lead via ingestion and in workers exposed to moderate to high levels of manganese via inhalation. Metals are present as particles or particle components in emissions from vehicles and other sources and have been implicated as one possible reason for the adverse health effects associated with airborne particulate matter exposure.
Dr. Robert Yokel’s objective is to study the mechanisms by which manganese enters and leaves the brain across the blood–brain barrier and, in particular, whether transporter molecules are involved. The blood–brain barrier is a function of the walls of small blood vessels that shield the brain from possibly harmful molecules. Certain molecules may cross the blood–brain barrier via diffusion or via carrier-mediated transport, which includes active transport (a process that uses energy to move molecules against a concentration gradient). The investigators proposed study will be the first direct investigation of whether specific transporter molecules remove manganese from the brain. Evidence for carrier-mediated transport of manganese out of the brain would be particularly interesting in that it would indicate a possible mechanism for preventing manganese accumulation, thereby affecting the likelihood of neurologic damage from chronic low-level exposure.
Description:
Investigators expect to study the mechanisms by which manganese enters and leaves the brain across the blood–brain barrier and, in particular, whether transporter molecules are involved. The investigators plan to use in vivo brain perfusion in rats as well as in vitro tests in several cell lines to assess specific characteristics of manganese transport, such as pH and energy dependence. Manganese transport rates will be compared with those of sucrose and dextran, which do not easily cross the blood–brain barrier. Experiments to identify putative transporters will focus on known transporter molecules, such as a divalent metal transporter, a monocarboxylate transporter, and calcium channels.