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ABSTRACT: Exposing eukaryotic cells to a toxic compound and subsequent gene expression profiling may allow the prediction of selected toxic effects based on changes in gene expression. This objective is complicated by the observation that compounds with different modes of toxicity cause similar changes in gene expression and that a global stress response affects many genes. We developed an elastic network model of global stress response with nodes representing genes which are connected by edges of graded coexpression. The expression of only few genes have to be known to model the global stress response of all but a few atypical responder genes. Those required genes and the atypical response genes are shown to be good biomarker for tox predictions. In total, 138 experiments and 13 different compounds were used to train models for different toxicity classes. The deduced biomarkers were shown to be biologically plausible. A neural network was trained to predict the toxic effects of compounds from profiling experiments. On a validation data set of 189 experiments with 16 different compounds the accuracy of the predictions was assessed: 14 out of 16 compounds have been classified correctly. Derivation of model based biomarkers through the elastic network approach can naturally be extended to other areas beyond toxicology since subtle signals against a broad response background are common in biological studies.
Computational biology and chemistry 06/2010; 34(3):193-202. · 1.37 Impact Factor
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ABSTRACT: Kidneys are the second most frequent site for chemically induced cancers in rats. However, there is still limited information on direct effects of carcinogens on pathways involved in the development of kidney tumors. Since transformed tumor cells have different characteristics than their cell of origin, it was hypothesized that healthy tissue and progressing stages of preneoplastic lesions are differentially influenced by chemical carcinogens. To elucidate this question, TSC2(-/-) Eker rats were gavaged with genotoxic aristolochic acid or nongenotoxic ochratoxin A for 3 and 6 months, respectively. Histopathology and cell proliferation analysis demonstrated a compound- and sex-specific onset of preneoplastic lesions. In contrast, comparable gene expression profiles of laser-microdissected preneoplastic lesions from carcinogen-treated and control rats, including reduced expression of genes involved in carcinogen uptake and metabolism, point to a compound-independent lesion progression. Gene expression profiles and additional immunostaining suggested that clonal expansion of renal lesions appears primarily driven by disturbed mammalian target of rapamycin complex 1 and mammalian target of rapamycin complex 2 pathway regulation. Finally, prolonged carcinogen exposure resulted in only marginal gene expression changes in tubules with normal morphology, indicating that some tubules may have adapted to the treatment. Taken together, these findings indicate that the final outcome of in vivo carcinogenicity studies is primarily determined by time-restricted initial events, while lesion progression may be a compound-independent process, involving deregulated mTOR signaling in the Eker rat model.
American Journal Of Pathology 09/2009; 175(4):1686-98. · 4.89 Impact Factor
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Hans-Jürgen Ahr,
Nathalie Alepée,
Siegfried Breier,
Cornelis Brekelmans,
Ian Cotgreave,
Laura Gribaldo,
Gianni Dal Negro,
Odile De Silva,
Thomas Hartung,
Antonio Lacerda, [......],
Susanna Louhimies,
Irene Manou,
Gavin Maxwell,
Karsten K Müller,
Wolfgang Pape,
Keith Redhead,
Klaus R Schröder,
Dariusz Sladowski,
Katinka van der Jagt,
Phillipe Vanparys
Alternatives to laboratory animals: ATLA 10/2008; 36(4):459-64. · 1.58 Impact Factor
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Mathieu Vinken,
Tatyana Doktorova,
Heidrun Ellinger-Ziegelbauer, Hans-Jürgen Ahr,
Edward Lock,
Paul Carmichael,
Erwin Roggen,
Joost van Delft,
Jos Kleinjans,
José Castell, [......],
Timothy Ebbels,
Toby Athersuch,
Susanna-Assunta Sansone,
Philippe Rocca-Serra,
Rob Stierum,
Paul Jennings,
Walter Pfaller,
Hans Gmuender,
Tamara Vanhaecke,
Vera Rogiers
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ABSTRACT: Recent changes in the European legislation of chemical-related substances have forced the scientific community to speed up the search for alternative methods that could partly or fully replace animal experimentation. The Sixth Framework Program project carcinoGENOMICS was specifically raised to develop omics-based in vitro screens for testing the carcinogenic potential of chemical compounds in a pan-European context. This paper provides an in-depth analysis of the complexity of choosing suitable reference compounds used for creating and fine-tuning the in vitro carcinogenicity assays. First, a number of solid criteria for the selection of the model compounds are defined. Secondly, the strategy followed, including resources consulted, is described and the selected compounds are briefly illustrated. Finally, limitations and problems encountered during the selection procedure are discussed. Since selecting an appropriate set of chemicals is a frequent impediment in the early stages of similar research projects, the information provided in this paper might be extremely valuable.
Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 05/2008; 659(3):202-10. · 2.85 Impact Factor
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Raffaella Corvi, Hans-Jürgen Ahr,
Silvio Albertini,
David H Blakey,
Libero Clerici,
Sandra Coecke,
George R Douglas,
Laura Gribaldo,
John P Groten,
Bernd Haase, [......],
Daniela Maurici,
George Orphanides,
Diana Rembges,
Susanna-Assunta Sansone,
Jason R Snape,
Eisaku Toda,
Weida Tong,
Joost H van Delft,
Brenda Weis,
Leonard M Schechtman
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ABSTRACT: This is the report of the first workshop "Validation of Toxicogenomics-Based Test Systems" held 11-12 December 2003 in Ispra, Italy. The workshop was hosted by the European Centre for the Validation of Alternative Methods (ECVAM) and organized jointly by ECVAM, the U.S. Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM), and the National Toxicology Program (NTP) Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM). The primary aim of the workshop was for participants to discuss and define principles applicable to the validation of toxicogenomics platforms as well as validation of specific toxicologic test methods that incorporate toxicogenomics technologies. The workshop was viewed as an opportunity for initiating a dialogue between technologic experts, regulators, and the principal validation bodies and for identifying those factors to which the validation process would be applicable. It was felt that to do so now, as the technology is evolving and associated challenges are identified, would be a basis for the future validation of the technology when it reaches the appropriate stage. Because of the complexity of the issue, different aspects of the validation of toxicogenomics-based test methods were covered. The three focus areas include a) biologic validation of toxicogenomics-based test methods for regulatory decision making, b) technical and bioinformatics aspects related to validation, and c) validation issues as they relate to regulatory acceptance and use of toxicogenomics-based test methods. In this report we summarize the discussions and describe in detail the recommendations for future direction and priorities.
Environmental Health Perspectives 04/2006; 114(3):420-9. · 7.04 Impact Factor
