Superfund Research Program

Metal-Metal Interactions in the Kidney

Project Leader: A. Jay Gandolfi
Grant Number: P42ES004940
Funding Period: 1995 - 2000

Project-Specific Links

Final Progress Reports

Year:   1999 

Over the past year, these studies focused on the molecular effects of low-level arsenic (10-100 ppb) exposure on renal cortical slices. Since the kidney is the major route of excretion for cumulative arsenic and is susceptible to metal-induced toxicity, researchers continue to utilize an in vitro renal system (renal slices) as the model. Using this system, a gene screen analysis has been utilized as a sensitive monitor for the effects of low-level arsenic exposure. Low-level exposure to arsenite, arsenate, and DNA produced some common gene changes as well as specific gene changes unique to the chemical species of arsenic. Selected genes were then further evaluated for their specific alterations, effects on protein expression, and their potential as a biomarker of arsenic exposure or toxicity. For example, low-level arsenic concentrations were found to affect several genes in the ubiquitin-dependent proteolytic pathway in our renal cortical slices. Furthermore, alterations in the ubiquitin gene production by arsenite have been shown to affect the ubiquitin-dependent proteolytic pathway as evidenced by alterations in the amount of ubiquinated proteins. Altering the ubiquitin-dependent proteolytic pathway could be responsible for a host of biochemical, molecular, and cellular malfunctions due to abnormal turnover of critical cellular proteins. Efforts are underway to see if changes in ubiquinated proteins can be used as a biomarker for arsenic exposure or toxicity.