title: Application of computational systems biology to explore environmental toxicity hazards.
abstract: BACKGROUND
  Computer-based modeling is part of a new approach to predictive toxicology.
  
  
  OBJECTIVE
  We investigated the usefulness of an integrated computational systems biology approach in a case study involving the isomers and metabolites of the pesticide dichlorodiphenyltrichloroethane (DDT) to ascertain their possible links to relevant adverse effects.
  
  
  METHODS
  We extracted chemical-protein association networks for each DDT isomer and its metabolites using ChemProt, a disease chemical biology database that includes both binding and gene expression data, and we explored protein-protein interactions using a human interactome network. To identify associated dysfunctions and diseases, we integrated protein-disease annotations into the protein complexes using the Online Mendelian Inheritance in Man database and the Comparative Toxicogenomics Database.
  
  
  RESULTS
  We found 175 human proteins linked to p,p'-DDT, and 187 to o,p'-DDT.Dichlorodiphenyldichloroethylene (p,p'-DDE) was the metabolite with the highest number of links, with 52. We grouped proteins for each compound based on their disease annotations. Although the two data sources differed in linkage to diseases, integrated results predicted that most diseases were linked to the two DDT isomers. Asthma was uniquely linked with p,p'-DDT, and autism with o,p'-DDT. Several reproductive and neurobehavioral outcomes and cancer types were linked to all three compounds.
  
  
  CONCLUSIONS
  Computer-based modeling relies on available information. Although differences in linkages to proteins may be due to incomplete data, our results appear meaningful and suggest that the parent DDT compounds may be responsible for more disease connections than the metabolites. The findings illustrate the potential use of computational approaches to toxicology.
authors.affiliation: Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark. karine@cbs.dtu.dk
authors.forename: Karine
authors.initials: K
authors.lastname: Audouze
authors.forename: Philippe
authors.initials: P
authors.lastname: Grandjean
mesh_terms: D019295:Computational Biology / Q000379:methods*; D003634:DDT / Q000009:adverse effects / Q000378:metabolism*; D030541:Databases, Genetic; D003633:Dichlorodiphenyl Dichloroethylene / Q000009:adverse effects / Q000378:metabolism*; D015386:Hazardous Substances / Q000009:adverse effects / Q000378:metabolism*; D006801:Humans; D008962:Models, Theoretical; D011506:Proteins / Q000378:metabolism*; D018570:Risk Assessment; D049490:Systems Biology / Q000379:methods*
chemical_list: D015386:Hazardous Substances; D011506:Proteins; D003633:Dichlorodiphenyl Dichloroethylene; D003634:DDT