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Mutagen Structure and Transcriptional Response: Induction of Distinct Transcriptional Profiles in Salmonella TA100 by the Drinking-Water Mutagen MX and Its Homologues
Citation:
WARD, W. O., C. SWARTZ, N. M. HANLEY, J. W. WHITAKER, AND R. Franzen. Mutagen Structure and Transcriptional Response: Induction of Distinct Transcriptional Profiles in Salmonella TA100 by the Drinking-Water Mutagen MX and Its Homologues. ENVIRONMENTAL AND MOLECULAR MUTAGENESIS. John Wiley & Sons, Inc, Hoboken, NJ, 51(1):69-79, (2010).
Impact/Purpose:
MX is a disinfection by-product that surveys have shown occurs at ng/L levels in typical U.S. drinking water. Although this is a low concentration, MX is also the most potent in vitro mutagen and the most potent in vivo carcinogen of all disinfection by-products. It also causes tumors at more tumor sites (7) than any other disinfection by-product. It might eventually be considered for regulation given its occurrence levels and carcinogenic effects, and understanding more about its mode of action for its potent in vitro mutagenic activity, provides additional data to help in any regulatory decisions or risk assessments regarding MX and drinking water in general. This study does that, and it also shows that our current knowledge would not have permitted us to predict the global gene expression induced by homologous compounds. This is also important for risk assessors to know, and it indicates that predictions of gene-expression and biological effects can not yet be predicted based on structural similarity of compounds.
Description:
The relationship between chemical structure and biological activity has been examined for various compounds and endpoints for decades. To explore this question relative to global gene expression, we performed microarray analysis of Salmonella TA100 after treatment under conditions of mutagenesis by the drinking-water mutagen MX and two of its structural homologues, BA-1 and BA-4. Approximately 50% of the genes expressed differentially by MX treatment were unique to MX; the corresponding percentages for BA-1 and BA-4 were 91 and 80, respectively. Among these mutagens, there was no overlap of altered Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways or RegulonDB regulons. Among the 25 Comprehensive Microbial Resource (CMR) functions altered by these mutagens, only 4 were altered by more than one mutagen. Thus, subtle changes in the structure of a mutagen can result in the induction of dramatically different transcriptional profiles. We also examined if structural similarity between a xenobiotic and endogenous cellular metabolites could explain transcriptional changes. For the 830 intracellular metabolites present in Salmonella that we examined, BA-1 had a high degree of structural similarity to 2-isopropylmaleate, which is the substrate for isopropylmalate isomerase. The transcription of the gene for this enzyme was suppressed 2-fold in BA-1-treated cells. Although a novel and potentially useful observation, this similarity between a xenobiotic and an intracellular metabolite explained only a small portion of the transcriptional response. Ultimately, explanations for varying transcriptional responses induced by compounds with similar structures await an improved understanding of the interactions between small molecules and the cellular machinery.
