title: Analysis of common and specific mechanisms of liver function affected by nitrotoluene compounds.
abstract: BACKGROUND
  Nitrotoluenes are widely used chemical manufacturing and munitions applications. This group of chemicals has been shown to cause a range of effects from anemia and hypercholesterolemia to testicular atrophy. We have examined the molecular and functional effects of five different, but structurally related, nitrotoluenes on using an integrative systems biology approach to gain insight into common and disparate mechanisms underlying effects caused by these chemicals.
  
  
  RESULTS
  Sprague-Dawley female rats were exposed via gavage to one of five concentrations of one of five nitrotoluenes [2,4,6-trinitrotoluene (TNT), 2-amino-4,6-dinitrotoluene (2ADNT) 4-amino-2,6-dinitrotoulene (4ADNT), 2,4-dinitrotoluene (2,4DNT) and 2,6-dinitrotoluene (2,6DNT)] with necropsy and tissue collection at 24 or 48 h. Gene expression profile results correlated well with clinical data and liver histopathology that lead to the concept that hematotoxicity was followed by hepatotoxicity. Overall, 2,4DNT, 2,6DNT and TNT had stronger effects than 2ADNT and 4ADNT. Common functional terms, gene expression patterns, pathways and networks were regulated across all nitrotoluenes. These pathways included NRF2-mediated oxidative stress response, aryl hydrocarbon receptor signaling, LPS/IL-1 mediated inhibition of RXR function, xenobiotic metabolism signaling and metabolism of xenobiotics by cytochrome P450. One biological process common to all compounds, lipid metabolism, was found to be impacted both at the transcriptional and lipid production level.
  
  
  CONCLUSIONS
  A systems biology strategy was used to identify biochemical pathways affected by five nitroaromatic compounds and to integrate data that tie biochemical alterations to pathological changes. An integrative graphical network model was constructed by combining genomic, gene pathway, lipidomic, and physiological endpoint results to better understand mechanisms of liver toxicity and physiological endpoints affected by these compounds.
authors.affiliation: Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, United States of America. youping_deng@rush.edu
authors.forename: Youping
authors.initials: Y
authors.lastname: Deng
authors.forename: Sharon A
authors.initials: SA
authors.lastname: Meyer
authors.forename: Xin
authors.initials: X
authors.lastname: Guan
authors.forename: Barbara Lynn
authors.initials: BL
authors.lastname: Escalon
authors.forename: Junmei
authors.initials: J
authors.lastname: Ai
authors.forename: Mitchell S
authors.initials: MS
authors.lastname: Wilbanks
authors.forename: Ruth
authors.initials: R
authors.lastname: Welti
authors.forename: Natàlia
authors.initials: N
authors.lastname: Garcia-Reyero
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Perkins
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D004785:Environmental Pollutants / Q000633:toxicity*; D005260:Female; D053263:Gene Regulatory Networks / Q000187:drug effects; D050356:Lipid Metabolism / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results; D013997:Time Factors; D014050:Toluene / Q000032:analysis / Q000633:toxicity*; D018675:Toxicity Tests / Q000379:methods*; D059467:Transcriptome / Q000187:drug effects
chemical_list: D004785:Environmental Pollutants; D014050:Toluene