title: In vitro gene regulatory networks predict in vivo function of liver.
abstract: BACKGROUND
  Evolution of 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. However, the degree to which we can extend in vitro results to in vivo activity and possible mechanisms of action remains to be fully addressed.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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 cycle related genes could be key mechanism for TNT induced liver toxicity.
authors.affiliation: Rush University Medical Center, Chicago, IL 60612, USA. youping_deng@rush.edu
authors.forename: Youping
authors.initials: Y
authors.lastname: Deng
authors.forename: David R
authors.initials: DR
authors.lastname: Johnson
authors.forename: Xin
authors.initials: X
authors.lastname: Guan
authors.forename: Choo Y
authors.initials: CY
authors.lastname: Ang
authors.forename: Junmei
authors.initials: J
authors.lastname: Ai
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Perkins
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks / Q000187:drug effects*; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008658:Inactivation, Metabolic / Q000235:genetics; D050356:Lipid Metabolism / Q000187:drug effects / Q000235:genetics; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism* / Q000502:physiology; D020411:Oligonucleotide Array Sequence Analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D049490:Systems Biology / Q000379:methods*; D013997:Time Factors; D018675:Toxicity Tests; D014303:Trinitrotoluene / Q000493:pharmacokinetics / Q000633:toxicity
chemical_list: D014303:Trinitrotoluene