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TOXICOGENOMIC ANALYSIS INCORPORATING OPERON-TRANSCRIPTIONAL COUPLING AND TOXICANT CONCENTRATRION-EXPRESSION RESPONSE: Analysis of MX-Treated Salmonella
Citation:
WARD, W. O., C. SWARTZ, N. M. HANLEY, G. W. KNAPP, S. H. WARREN, S. PORWOLLIK, M. MCCLELLAND, AND D. M. DEMARINI. TOXICOGENOMIC ANALYSIS INCORPORATING OPERON-TRANSCRIPTIONAL COUPLING AND TOXICANT CONCENTRATRION-EXPRESSION RESPONSE: Analysis of MX-Treated Salmonella. BMC Bioinformatics. BioMed Central Ltd, London, Uk, 8(378):1-12, (2007).
Impact/Purpose:
This study was done to assess whether microarray analysis in a relatively well¬characterized genome (Salmonella) could distinguish between the effects of different, but structurally related toxicants.
Description:
What is the study? This study is the first to use microarray analysis in the Ames strains of Salmonella. The microarray chips were custom-designed for this study and are not commercially available, and we evaluated the well-studied drinking water mutagen, MX. Because much information is available on MX, there was biological data to which to anchor the microarray data. In the course of the analysis, a set of new types of analyses were developed that resulted in a more robust picture of the pathway changes induced by MX. The methods developed could be applicable to toxicogenomic analyses in other systems, including eukaryotic cells.
Why was it done? This study was done to assess whether microarray analysis in a relatively well¬characterized genome (Salmonella) could distinguish between the effects of different, but structurally related toxicants. This initial paper is on the drinking water mutagen MX, but a subsequent paper characterizes the transcriptional profiles of two MX homologues compared to MX. All three MX compounds have distinct mutagenic potencies, mutational spectra, and physical-chemical characteristics. Thus, we have asked if the transcriptional profiles of these three compounds are distinct.
What is the impact to the field and the agency? This study has resulted in the development of a more robust analysis of toxicogenomic data that should be applicable to all cell types, from prokaryotic to eukaryotic. Among these analyses is the use of operon structure to incorporate data from transcriptionally linked genes even though initial analyses (Bayesian t-tests) do not identify all transcriptionally linked genes as being differentially expressed. The analysis also shows the power of including those genes whose expressions change monotonically with the concentration of the toxicant. Finally, the results indicated that MX down-regulated porphyrin metabolism, and we suggest that the structural similarity between MX (a furan) and prophyrin may account for this effect. Thus, we have also included steric coupling in the analysis. Together, these methods may be helpful to the field and to the Agency in the interpreation and analysis of microarray data from toxciogenomic studies.
