In vitro gene regulatory networks predict in vivo function of liver

Here we use the nitroaromatic 2,4,6-trinitrotoluene (TNT) as a model chemical to compare and determine how we might extrapolate from in vitro data to in vivo effects. We found 341 transcripts differentially expressed in common among in vitro and in vivo assays in response to TNT. The major functional term corresponding to these transcripts was cell cycle. Similarly modulated common pathways were identified between in vitro and in vivo. Furthermore, we uncovered the conserved common transcriptional gene regulatory networks between in vitro and in vivo cellular liver systems that responded to TNT exposure, which mainly contain 2 subnetwork modules: PTTG1 and PIR centered networks. Interestingly, all 7 genes in the PTTG1 module were involved in cell cycle and downregulated by TNT both in vitro and in vivo.The results of our investigation of TNT effects on gene expression in liver suggest that gene regulatory networks obtained from an in vitro system can predict in vivo function and mechanisms. Inhibiting PTTG1 and its targeted cell cyle related genes could be key machanism for TNT induced liver toxicity.High-throughput toxicity testing is predicated upon using in vitro cell based systems to rapidly screen and predict how a chemical might cause toxicity to an organ in vivo [1]. Recent microarray studies have shown that the in vitro gene expression profiles in liver slices treated with various compounds could predict the toxicity and pathology observed in vivo [2]. However, the degree to which in vitro results can be extended to in vivo activity and possible mechanisms of action remains to be fully addressed.Compared with animal models, primary cell cultures have advantages for investigating mechanisms of chemical toxicity. Primary cultured cells, such as hepatocytes, can offer a convenient system that is easily genetically manipulated and can be used to test various throughput screens using different molecular and biochemical methods. Use of primary cell cultures can al