Brain copper clearance by the blood-cerebrospinal fluid-barrier: Effects of lead exposure

Lead (Pb) is a heavy metal commonly found in the environment and is known to have neurotoxic, hematological, and other toxic effects. It has been reported that Pb exposure can disturb metal regulation in the blood-cerebrospinal fluid-barrier (BCB). Copper (Cu) plays a key role in maintaining normal brain function and can accumulate in the brain after Pb exposure. However, the mechanism by which Pb affects Cu levels in the brain is still unknown. This study investigated Cu clearance by the BCB in the central nervous system (CNS) of Sprague-Dawley rats after Pb exposure by focusing on the Cu transporter protein CTR1/ATP7A. Inductively coupled plasma mass spectrometry (ICP-MS) was used to examine how heavy metal levels change in the hippocampus, cortex, and cerebrospinal fluid (CSF) after Pb exposure. Ventriculo-cisternal perfusion measurements suggested that the ability of the BCB to deliver Cu from the CSF to the blood decreased after Pb exposure. The presence of excess Cu in the choroid plexus led to CTR1/ATP7A shifting toward the apical microvilli facing the CSF after Pb exposure. We further evaluated microstructure of the choroid plexus by transmission electron microscopy, revealing altered mitochondrial morphology with decreased microvilli after Pb exposure. Conclusively, exposure to Pb alters the cellular structure of the BCB and its Cu clearance function, which can cause further brain damage.