Abstract
Background: Some of the biochemical events that lead to necrosis of the liver are well-known. However, the pathogenesis of necrosis of the liver from exposure to hepatotoxicants is a complex biological response to the injury. We hypothesize that gene expression profiles can serve as a signature to predict the level of necrosis elicited by acute exposure of rats to a variety of hepatotoxicants and postulate that the expression profiles of the predictor genes in the signature can provide insight to some of the biological processes and molecular pathways that may be involved in the manifestation of necrosis of the rat liver. Results: Rats were treated individually with one of seven known hepatotoxicants and were analyzed for gene expression by microarray. Liver samples were grouped by the level of necrosis exhibited in the tissue. Analysis of significantly differentially expressed genes between adjacent necrosis levels revealed that inflammation follows programmed cell death in response to the agents. Using a Random Forest classifier with feature selection, 21 informative genes were identified which achieved 90%, 80% and 60% prediction accuracies of necrosis against independent test data derived from the livers of rats exposed to acetaminophen, carbon tetrachloride, and allyl alcohol, respectively. Pathway and gene network analyses of the genes in the signature revealed several gene interactions suggestive of apoptosis as a process possibly involved in the manifestation of necrosis of the liver from exposure to the hepatotoxicants. Cytotoxic effects of TNF-alpha, as well as transcriptional regulation by JUN and TP53, and apoptosis-related genes possibly lead to necrosis. Conclusion: The data analysis, gene selection and prediction approaches permitted grouping of the classes of rat liver samples exhibiting necrosis to improve the accuracy of predicting the level of necrosis as a phenotypic end-point observed from the exposure. The strategy, along with pathway analysis and gene network reconstruction, led to the identification of 1) expression profiles of genes as a signature of necrosis and 2) perturbed regulatory processes that exhibited biological relevance to the manifestation of necrosis from exposure of rat livers to the compendium of hepatotoxicants.