Lead toxicity was identified as the most important environmental health hazard affecting children in the United States. Consequently, understanding mechanisms whereby lead enters cells can aid in determining factors that increase the risk of lead exposure. Certain tissues are known to accumulate large concentrations of lead and these include erythrocytes, bone, kidney and choroid plexus. Surprisingly, only one study, to our knowledge, addressed the mechanism responsible for lead uptake into erythrocytes, and pharmacological evidence was presented suggesting that uptake was mediated by anion exchange. Since, similar to erythrocytes, kidney and choroid plexus epithelial cells also display high levels of the protein that mediates anion exchange, it is hypothesized that the uptake of lead into epithelial cells is mediated by anion exchange. This hypothesis is addressed through two specific aims. First, the role of anion exchange in lead uptake in cultures of renal epithelium and choroid plexus epithelium and brain endothelium will be assessed. If anion exchange mediates the uptake of lead, then drugs and antisense oligonucleotides that inhibit anion exchange should also block uptake of lead. Second, lead uptake will be examined in a human fibroblast cell line that is engineered to overexpress anion exchanger. Since these cells display very little anion exchange activity, overexpression of anion exchange should greatly increase the uptake of lead. Anion exchange may be affected by ailments that are common in children who are exposed to lead. Anion exchange is also sensitive to drugs that are used to treat these disorders. Thus, the results from this proposal may in the future be formulated into a toxicokinetic model to predict risk factors for lead toxicity.
