This project of the Environmental Stress and Cancer Group investigates the molecular mechanisms of responses to environmental stresses involved in the etiology and progression of injury and disease processes. The overall goal of these studies is to provide a better understanding of the regulatory networks that control critical cellular responses to environmental stresses. Our approach utilizes advances in genomics and bioinformatics to address critical threats to human health as a consequence of environmental exposures. Specifically, the group is designing, executing, and analyzing studies that integrate global "omics" approaches with conventional studies of environmental stress, toxicity and disease processes. Core to these toxicogenomic efforts is the concept of phenotypic anchoring, in which studies are designed to relate alterations in gene expression to adverse effects defined by conventional parameters of toxicity and pathology. Studies are designed to provide insight into mechanisms of injury and disease as well as to establish signatures of adverse effects to develop putative biomarkers. These studies have utilized agents at multiple doses and times of treatment to fully explore ranges of biological responses to those agents. Analyses that implicate a critical role of a particular biological process or of a particular gene in an adverse response are followed up with additional experiments designed to test hypotheses concerning these roles. Studies have focused on the injury to the liver caused by exposures to a variety of hepatotoxic agents, including acetaminophen, and examined global gene expression changes in both the liver and circulating blood cells from rodents as well as blood cells from exposed humans for early indicators of the mechanism of injury as well as putative biomarkers.

Project Start
Project End
Budget Start
Budget End
Support Year
15
Fiscal Year
2013
Total Cost
$140,611
Indirect Cost
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State
Country
Zip Code
Fannin, Rick D; Russo, Mark; O'Connell, Thomas M et al. (2010) Acetaminophen dosing of humans results in blood transcriptome and metabolome changes consistent with impaired oxidative phosphorylation. Hepatology 51:227-36
Kienhuis, Anne S; van de Poll, Marcel C G; Wortelboer, Heleen et al. (2009) Parallelogram approach using rat-human in vitro and rat in vivo toxicogenomics predicts acetaminophen-induced hepatotoxicity in humans. Toxicol Sci 107:544-52
Waters, Michael; Stasiewicz, Stanley; Merrick, B Alex et al. (2008) CEBS--Chemical Effects in Biological Systems: a public data repository integrating study design and toxicity data with microarray and proteomics data. Nucleic Acids Res 36:D892-900
Huang, Lingkang; Heinloth, Alexandra N; Zeng, Zhao-Bang et al. (2008) Genes related to apoptosis predict necrosis of the liver as a phenotype observed in rats exposed to a compendium of hepatotoxicants. BMC Genomics 9:288