Print Email Facebook Twitter Transcriptomics analysis of interactive effects of benzene, trichloroethylene and methyl mercury within binary and ternary mixtures on the liver and kidney following subchronic exposure in the rat Title Transcriptomics analysis of interactive effects of benzene, trichloroethylene and methyl mercury within binary and ternary mixtures on the liver and kidney following subchronic exposure in the rat Author Hendriksen, P.J.M. Freidig, A.P. Jonker, D. Thissen, U. Bogaards, J.J.P. Mumtaz, M.M. Groten, J.P. Stierum, R.H. TNO Kwaliteit van Leven Publication year 2007 Abstract The present research aimed to study the interaction of three chemicals, methyl mercury, benzene and trichloroethylene, on mRNA expression alterations in rat liver and kidney measured by microarray analysis. These compounds were selected based on presumed different modes of action. The chemicals were administered daily for 14 days at the Lowest-Observed-Adverse-Effect-Level (LOAEL) or at a two- or threefold lower concentration individually or in binary or ternary mixtures. The compounds had strong antagonistic effects on each other's gene expression changes, which included several genes encoding Phase I and II metabolizing enzymes. On the other hand, the mixtures affected the expression of "novel" genes that were not or little affected by the individual compounds. The three compounds exhibited a synergistic interaction on gene expression changes at the LOAEL in the liver and both at the sub-LOAEL and LOAEL in the kidney. Many of the genes induced by mixtures but not by single compounds, such as Id2, Nr2f6, Tnfrsf1a, Ccng1, Mdm2 and Nfkb1 in the liver, are known to affect cellular proliferation, apoptosis and tissue-specific function. This indicates a shift from compound specific response on exposure to individual compounds to a more generic stress response to mixtures. Most of the effects on cell viability as concluded from transcriptomics were not detected by classical toxicological endpoints illustrating the benefit of increased sensitivity of assessing gene expression profiling. These results emphasize the benefit of applying toxicogenomics in mixture interaction studies, which yields biomarkers for joint toxicity and eventually can result in an interaction model for most known toxicants. © 2007 Elsevier Inc. All rights reserved. Subject BiologyAnalytical researchBiomedical researchBenzeneMercuryMicroarraysMixturesToxicogenomicsTrichloroethylenebenzenebiological markermessenger RNAmethylmercurytrichloroethyleneanimal experimentanimal tissueapoptosisarticleCcng1 genecell proliferationcell viabilitycontrolled studygenegene expression profilinggene inductionid2 geneliver toxicitylong term exposuremaleMDM2 genemicroarray analysisnephrotoxicityNFKB1 genenonhumanNr2f6 generatstresstissue specificitytnfrsf1a genetoxicogeneticstranscriptomicsAnimalsBenzeneCell SurvivalDrug InteractionsDrug SynergismEnvironmental PollutantsGene Expression ProfilingGene Expression RegulationKidneyLiverMaleMethylmercury CompoundsNo-Observed-Adverse-Effect LevelOligonucleotide Array Sequence AnalysisRatsRats, Inbred F344RNA, MessengerToxicity TestsTrichloroethyleneRattus To reference this document use: http://resolver.tudelft.nl/uuid:3f05455a-9265-43c2-bf67-a75043001d56 DOI https://doi.org/10.1016/j.taap.2007.08.017 TNO identifier 240386 ISSN 0041-008X Source Toxicology and Applied Pharmacology, 225 (2), 171-188 Document type article Files To receive the publication files, please send an e-mail request to TNO Library.