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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
1R01ES007980-01A1
Application #
2018633
Study Section
Special Emphasis Panel (ZRG4-ALTX-4 (01))
Program Officer
Kitt, Cheryl A
Project Start
1997-02-01
Project End
2000-01-31
Budget Start
1997-02-01
Budget End
1998-01-31
Support Year
1
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Hugo W. Moser Research Institute Kennedy Krieger
Department
Type
DUNS #
167202410
City
Baltimore
State
MD
Country
United States
Zip Code
21205
Glenn, Barbara S; Stewart, Walter F; Links, Jonathan M et al. (2003) The longitudinal association of lead with blood pressure. Epidemiology 14:30-6
Hwang, Kyu-Yoon; Lee, Byung-Kook; Bressler, Joseph P et al. (2002) Protein kinase C activity and the relations between blood lead and neurobehavioral function in lead workers. Environ Health Perspect 110:133-8
I Bannon, Desmond; Portnoy, Matthew E; Olivi, Luisa et al. (2002) Uptake of lead and iron by divalent metal transporter 1 in yeast and mammalian cells. Biochem Biophys Res Commun 295:978-84
Glenn, B S; Stewart, W F; Schwartz, B S et al. (2001) Relation of alleles of the sodium-potassium adenosine triphosphatase alpha 2 gene with blood pressure and lead exposure. Am J Epidemiol 153:537-45
Olivi, L; Sisk, J; Bressler, J (2001) Involvement of DMT1 in uptake of Cd in MDCK cells: role of protein kinase C. Am J Physiol Cell Physiol 281:C793-800
Olivi, L; Bressler, J (2000) Maitotoxin stimulates Cd influx in Madin-Darby kidney cells by activating Ca-permeable cation channels. Cell Calcium 27:187-93
Bannon, D I; Olivi, L; Bressler, J (2000) The role of anion exchange in the uptake of Pb by human erythrocytes and Madin-Darby canine kidney cells. Toxicology 147:101-7
Kim, K A; Chakraborti, T; Goldstein, G W et al. (2000) Immediate early gene expression in PC12 cells exposed to lead: requirement for protein kinase C. J Neurochem 74:1140-6
Williams, K; Wilson, M A; Bressler, J (2000) Regulation and developmental expression of the divalent metal-ion transporter in the rat brain. Cell Mol Biol (Noisy-le-grand) 46:563-71
Bressler, J; Kim, K A; Chakraborti, T et al. (1999) Molecular mechanisms of lead neurotoxicity. Neurochem Res 24:595-600