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USE OF GENE EXPRESSION ANALYSIS INCORPORATING OPERON-TRANSCRIPTIONAL COUPLING AND TOXICANT DOSE RESPONSE TO DISTINGUISH AMONG STRUCTURAL HOMOLOGUES OF MX
Citation:
WARD, W. O., C. SWARTZ, N. M. HANLEY, S. H. WARREN, AND D. M. DEMARINI. USE OF GENE EXPRESSION ANALYSIS INCORPORATING OPERON-TRANSCRIPTIONAL COUPLING AND TOXICANT DOSE RESPONSE TO DISTINGUISH AMONG STRUCTURAL HOMOLOGUES OF MX. Presented at 38th Annual Meeting Environmental Mutagen Society, Atlanta, GA, October 20 - 24, 2007.
Impact/Purpose:
To describe a general method that can improve microarray analysis of toxicant-exposed cells.
Description:
We recently described a general method that can improve microarray analysis of toxicant-exposed cells that uses the intrinsic power of transcriptional coupling and toxicant concentration-expression response data. In this analysis, we characterized changes in global gene expression induced in Salmonella typhimurium TA100 by 3¬chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX), the primary mutagen in chlorinated drinking water. We used the co-expression of genes within an operon and the monotonic increases or decreases in gene expression relative to increasing toxicant concentration to augment our identification of differentially expressed genes beyond Bayesian-t analysis. A functional analysis of the resulting 448 differentially expressed genes yielded functional changes beyond what would be expected from only the mutagenic properties of MX. In addition to gene-expression changes in DNA-damage response, MX induced changes in expression of genes involved in membrane transport and porphyrin metabolism, among other biological processes. The disruption of porphyrin metabolism might be attributable to the structural similarity of MX, which is a chlorinated furanone, to ligands indigenous to the porphyrin metabolism pathway. A previous analysis by us of structural homologues of MX showed that structural properties influenced relative mutagenic potency and could be used to classify these compounds as weak or potent mutagens. A significant correlation was found between pKa and mutagenic potency and between a measure of bioavailability and mutagenic potency. These results illustrated the potential value of structural analyses for revealing a relationship between chemical structure and mutational mechanisms. To determine if structural properties that influence mutagenic potency also influence gene expression, we are examining global gene expression for two homologues of MX. We will apply the same operon and monotonic analyses to improve the identification of differentially expressed genes for MX homologues and determine whether differences in structural properties and mutagenic potencies among the compounds are also reflected in gene expression patterns.