oa Environmental Toxicogenomics: How Genomic Technologies are Impacting the Science of Toxicology

Decision-makers in safety assessment of exposures to environmental stressors and health care providers need improved biomarkers of toxic exposures and biomarkers of adverse events that precede the development of overt injury or disease. Two toxicogenomic studies will be presented that demonstrate the utility of genomic approaches for developing potential biomarkers of toxicity for both nephrotoxicity and hepatotoxicity. The use of calcineurin inhibitor (CI) immunosuppressants has revolutionized the clinical practice of organ transplantation. However, chronic nephrotoxicity limits their long-term utility. In order to understand the pathophysiology that underlies the development of CI-associated nephrotoxicity and to develop CI-specific biomarkers of toxicity, rats were dosed with cyclosporine A (CsA) or FK506, or rapamycin, and gene expression profiling was performed on RNA isolated from kidneys 24 hours after one, seven, 14 or 28 daily doses. A gene expression signature was identified that was correlated with CI-specific kidney damage and responded with an earlier onset than the more general kidney injury biomarkers Kim-1 and Clusterin, and is CI-specific. We have been interested in gene expression patterns derived from peripheral blood cells as they would provide useful early indicators of acute toxicity. With respect to hepatotoxicity, the case of acetaminophen (APAP) intoxication is particularly important, as this is the leading cause of liver failure in the United States. We generated a blood gene expression data set from rats exposed to APAP to train genomic classifiers of toxicity. Prediction accuracy was tested on a blinded, independent rat blood test data set and ranged from 88.9% to 95.8%. Genomic markers outperformed predictions based on traditional clinical parameters. We are currently testing the hypothesis that gene expression data from peripheral blood cells can provide valuable information about hepatotoxicity to humans, well before liver damage is detected by classical parameters. Our results support the potential use of genomic markers in the blood as surrogates for clinical markers of potential acute liver damage.