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PubMed2006

The comparative toxicogenomics database: a cross-species resource for building chemical-gene interaction networks.

Chemicals in the environment play a critical role in the etiology of many human diseases. Despite their prevalence, the molecular mechanisms of action and the effects of chemicals on susceptibility to disease are not well understood. To promote understanding of these mechanisms, the Comparative Toxicogenomics Database (CTD; http://ctd.mdibl.org/) presents scientifically reviewed and curated information on chemicals, relevant genes and proteins, and their interactions in vertebrates and invertebrates. CTD integrates sequence, reference, species, microarray, and general toxicology information to provide a unique centralized resource for toxicogenomic research. The database also provides visualization capabilities that enable cross-species comparisons of gene and protein sequences. These comparisons will facilitate understanding of structure-function correlations and the genetic basis of susceptibility. Manual curation and integration of cross-species chemical-gene and chemical-protein interactions from the literature are now underway. These data will provide information for building complex interaction networks. New CTD features include (1) cross-species gene, rather than sequence, query and visualization capabilities; (2) integrated cross-links to microarray data from chemicals, genes, and sequences in CTD; (3) a reference set related to chemical-gene and protein interactions identified by an information retrieval system; and (4) a "Chemicals in the News" initiative that provides links from CTD chemicals to environmental health articles from the popular press. Here we describe these new features and our novel cross-species curation of chemical-gene and chemical-protein interactions.

Animals↗

PubMed2006

Comparison of coumarin-induced toxicity between sandwich-cultured primary rat hepatocytes and rats in vivo: a toxicogenomics approach.

Sandwich-cultured primary rat hepatocytes are often used as an in vitro model in toxicology and pharmacology. However, loss of liver-specific functions, in particular, the decline of cytochrome P450 (P450) enzyme activity, limits the value of this model for prediction of in vivo toxicity. In this study, we investigated whether a hepatic in vitro system with improved metabolic competence enhances the predictability for coumarin-induced in vivo toxicity by using a toxicogenomics approach. Therefore, primary rat hepatocytes were cultured in sandwich configuration in medium containing a mixture of low concentrations of P450 inducers, phenobarbital, dexamethasone, and beta-naphthoflavone. The toxicogenomics approach used enabled comparison of similar mechanistic end-points at the molecular level between in vitro and in vivo conditions, namely, compound-induced changes in multiple genes and signaling pathways. Toxicant-induced cytotoxic effects and gene expression profiles observed in hepatocytes cultured in modified medium and hepatocytes cultured in standard medium (without inducers) were compared with results from a rat in vivo study. Coumarin was used as a model compound because its toxicity depends on bioactivation by P450 enzymes. Metabolism of coumarin toward active metabolites, coumarin-induced cytotoxicity, and gene expression modulation were more pronounced in hepatocytes cultured in modified medium compared with hepatocytes cultured in standard medium. In addition, more genes and biological pathways were similarly affected by coumarin in hepatocytes cultured in modified medium and in vivo. In conclusion, these experiments showed that for coumarin-induced toxicity, sandwich-cultured hepatocytes maintained in modified medium better represent the situation in vivo compared with hepatocytes cultured in standard medium.

Alanine Transaminase↗

PubMed2005

EDGE: a centralized resource for the comparison, analysis, and distribution of toxicogenomic information.

Transcriptional profiling via microarrays holds great promise for toxicant classification and hazard prediction. Unfortunately, the use of different microarray platforms, protocols, and informatics often hinders the meaningful comparison of transcriptional profiling data across laboratories. One solution to this problem is to provide a low-cost and centralized resource that enables researchers to share toxicogenomic data that has been generated on a common platform. In an effort to create such a resource, we developed a standardized set of microarray reagents and reproducible protocols to simplify the analysis of liver gene expression in the mouse model. This resource, referred to as EDGE, was then used to generate a training set of 117 publicly accessible transcriptional profiles that can be accessed at http://edge.oncology.wisc.edu/. The Web-accessible database was also linked to an informatics suite that allows on-line clustering and K-means analyses as well as Boolean and sequence-based searches of the data. We propose that EDGE can serve as a prototype resource for the sharing of toxicogenomics information and be used to develop algorithms for efficient chemical classification and hazard prediction.

Animals↗

PubMed2006

Toxicogenomics--a new systems toxicology approach to understanding of gene-environment interactions.

Toxicogenomics is a new interdisciplinary area of research being developed to monitor the expression of multiple genes, proteins, and metabolites simultaneously. It combines new technologies in genomics, proteomics, and metabolomics with traditional tools of pathology and toxicology to study biological response to drugs and other environmental xenobiotics. The biological response to environmental exposure is so complex and involves so many interactive factors that the use of a systems biology analytical approach is required. In my opinion, the development of the field of toxicogenomics will provide powerful and relatively inexpensive tools to identify biomarkers and to relate exposure and biological events during disease progression.

Genomics↗

PubMed2003

ArrayTrack--supporting toxicogenomic research at the U.S. Food and Drug Administration National Center for Toxicological Research.

The mapping of the human genome and the determination of corresponding gene functions, pathways, and biological mechanisms are driving the emergence of the new research fields of toxicogenomics and systems toxicology. Many technological advances such as microarrays are enabling this paradigm shift that indicates an unprecedented advancement in the methods of understanding the expression of toxicity at the molecular level. At the National Center for Toxicological Research (NCTR) of the U.S. Food and Drug Administration, core facilities for genomic, proteomic, and metabonomic technologies have been established that use standardized experimental procedures to support centerwide toxicogenomic research. Collectively, these facilities are continuously producing an unprecedented volume of data. NCTR plans to develop a toxicoinformatics integrated system (TIS) for the purpose of fully integrating genomic, proteomic, and metabonomic data with the data in public repositories as well as conventional (Italic)in vitro(/Italic) and (Italic)in vivo(/Italic) toxicology data. The TIS will enable data curation in accordance with standard ontology and provide or interface a rich collection of tools for data analysis and knowledge mining. In this article the design, practical issues, and functions of the TIS are discussed through presenting its prototype version, ArrayTrack, for the management and analysis of DNA microarray data. ArrayTrack is logically constructed of three linked components: a) a library (LIB) that mirrors critical data in public databases; b) a database (MicroarrayDB) that stores microarray experiment information that is Minimal Information About a Microarray Experiment (MIAME) compliant; and c) tools (TOOL) that operate on experimental and public data for knowledge discovery. Using ArrayTrack, we can select an analysis method from the TOOL and apply the method to selected microarray data stored in the MicroarrayDB; the analysis results can be linked directly to gene information in the LIB.

Databases, Factual↗

PubMed2004

Toxicogenomics in risk assessment: an overview of an HESI collaborative research program.

The value of genomic approaches in hypothesis generation is being realized as a tool for understanding toxicity and consequently contributing to an assessment of drug and chemical safety. In 1999 the membership of the International Life Sciences Institute Health and Environmental Sciences Institute formed a committee to develop a collaborative scientific program to address issues, challenges, and opportunities afforded by the emerging field of toxicogenomics. Experts and advisors from academia and government laboratories participate on the committee, along with approximately 30 corporate member organizations from the pharmaceutical, agrochemical, chemical, and consumer products industries. The committee has designed, conducted, and analyzed numerous toxicogenomic experiments within the broad fields of hepatotoxicity, nephrotoxicity, and genotoxicity. The considerable body of data generated by these programs has been instrumental in increasing understanding of sources of biological and technical variability in the alignment of toxicant-induced transcription changes with the accepted mechanism of action of these agents and the challenges in the consistent analysis and sharing of the voluminous data sets generated by these approaches. Recognizing the importance of standardized microarray data formats and public repository databases as the mechanism by which microarray data can be compared and interpreted by the scientific community, the committee has partnered with the European Bioinformatics Institute to develop a database to house the data generated by its collaborative research.

Gene Expression Profiling↗

PubMed2005

Ushering in the new toxicology: toxicogenomics and the public interest.

New scientific tools spawned by the genomics revolution promise to improve our ability to identify causative factors in human diseases. But as these new tools elucidate the complex interactions between chemical toxins and biologic systems, the strain on traditional ways of understanding toxic effects grows. Despite major advances in the science and technology of these new toxicogenomics tools, scientific and political complexities threaten to delay the use of toxicogenomics to further the public interest or--worse--to advance its use initially to weaken the regulation and safety of widely used chemicals. To gain further insight into the scientific and political landscape of the new toxicology, we interviewed 27 experts from a variety of disciplines and sectors. Interviewees expressed widespread agreement that the new toxicology promises a significant increase in the amount of information available on toxic effects of chemicals. But the interviews show that the promise of the new toxicology will be realized only if technical and political obstacles can be overcome. Although scientific rigor is necessary for the new toxicology to move forward, the scientific and public-interest communities must ensure that inappropriate definitions of rigor, as well as proprietary interests, do not create unnecessary barriers to more effective public health protection.

Gene Expression↗

PubMed2006

Cross-species comparative toxicogenomics as an aid to safety assessment.

Cross-species comparative toxicogenomics has the potential for improving the understanding of the different responses of animal models to toxicants at a molecular level. This understanding could then lead to a more accurate extrapolation of the risk posed by these toxicants to humans. Cross-species comparative studies have been carried out at the genomic sequence level and using microarrays to examine changes in global mRNA profiles. However, these studies face considerable bioinformatic challenges in terms of identifying which genes are truly orthologous across species. The resources to analyse such studies, in the context of such orthologues, beg improvement. Finally, the experimental design of such studies needs to be carefully considered to make their results fully interpretable. These issues are discussed, along with the current state-of-the-art cross-species comparative toxicogenomics in this review.

Animals↗

PubMed2006

Utilization of a one-dimensional score for surveying chemical-induced changes in expression levels of multiple biomarker gene sets using a large-scale toxicogenomics database.

A large-scale toxicogenomcis database has now been constructed in the Toxicogenomics Project in Japan (TGP). To facilitate the analytical procedures for such large-scale microarray data, we developed a simple one-dimensional score, named TGP1 which expresses the trend of the changes in expression of biomarker genes as a whole. To evaluate the usefulness of the TGP1 score, microarray data of rat liver and rat hepatocytes deposited in the TGP database were scored for three biomarker gene sets, i.e., carcinogenesis-related, PPARalpha-regulated and glutathione depletion-related gene sets. The TGP1 scoring system gave reasonable results, i.e., the scores for carcinogenesis-related genes were high in omeprazole-, chlorpromazine-, hexachlorobenzene-, sulfasalazine- and Wy-14,643-treated rat livers, that for PPARalpha-regulated genes were high in clofibrate-, Wy-14,643-, gemfibrozil-, benzbromarone- and aspirin-treated rat livers as well as rat hepatocytes, and for glutathione deficiency-related genes were high in omeprazole-, bromobenzene-, acetaminophen- and coumarin-treated rat liver. We concluded that the TGP1 score is useful for surveying the expression changes in multiple biomarker gene sets for a large-scale toxicogenomics database, which would reduce the time of doing conventional multivariate statistical analysis. In addition, the TGP1 score can be applied to screening of compatible biomarker gene sets between rat liver and rat hepatocytes, like PPARalpha-regulated gene sets, which will allow us to develop an appropriate in vitro system for drug safety assessment in vivo.

Animals↗

PubMed2006

Development of a toxicogenomics in vitro assay for the efficient characterization of compounds.

In vitro toxicogenomics represents a useful approach for evaluating the toxic properties of new drug candidates early in the drug discovery process using minimal amounts of compounds. The aim of this study was to develop in vitro-based gene expression assays for two prototypical toxicological classes: aryl hydrocarbon receptor (AhR) agonists and peroxisome proliferator activated receptor alpha (PPAR alpha) agonists. Primary rat hepatocytes were exposed to a number of class-specific compounds, including 3-methylcholanthrene, aroclor, and beta-napthoflavone as AhR agonists, bezafibrate, clofibrate, and Wy-14643 as peroxisome proliferators, and chlorpheniramine, penicillin and spectinomycin as negative controls. Global gene expression profiles were generated with microarrays for each class of compounds. Using linear discriminant analysis coupled with permutation-based t-test, gene signatures were established to classify compounds according to a discriminant score. The final gene signatures consist of eight genes for AhR agonism and 11 genes for PPAR alpha agonism, and were further validated using additional compounds. The assay was initially developed using a microarray platform. The authors then evaluated whether it could be transferred to a more cost-effective platform with higher throughput. The results indicate that a small set of genes can be used to quantitatively assess the degree to which a compound falls into a certain mechanistic toxicological class. While this study only focused on two classes, it could be expanded to encompass other toxicological mechanistic classes as well. Furthermore, by adapting this type of assay to a higher throughput platform, in vitro toxicogenomics can represent an effective approach to generate robust toxicological data early in the drug discovery process.

Animals↗

PubMed2006

Toxicogenomics in drug discovery and development: mechanistic analysis of compound/class-dependent effects using the DrugMatrix database.

A range of genomics technologies are increasingly becoming integrated with existing scientific disciplines to broaden and strengthen existing capabilities and open new avenues of research in drug discovery and development. Examples of these new research fields are proteomics, pharmacogenomics, metabolomics and toxicogenomics. Here we review the application of toxicogenomics to improve the evaluation of drug safety, mechanism of action and toxicity in the drug discovery and development process.

Databases, Genetic↗

PubMed2002

The promise of toxicogenomics.

As human genetics and genomics have progressed, culminating in the completion of the rough draft of the human genome in February 2001, new tools and technologies have been developed to identify and quantify global gene expression changes occurring in the cell. These new technologies are allowing researchers to gain an increased understanding of the function and regulation of genes at the systems level, and are transforming virtually all areas of biological research. In the field of toxicology, a new subdiscipline termed toxicogenomics has emerged which promises to identify and characterize the molecular mechanisms that lead to toxicity. Gene expression profiling, through the use of microarray technology, is rapidly becoming a standard analysis in toxicology studies, and has the potential to play a pivotal role in all stages of drug safety evaluation. This review focuses on recent studies in toxicogenomics, and discusses the promises and future challenges in this field.

Animals↗

PubMed2001

[Prospects on the application of toxicogenomics in assessing the safety of chemical compounds].

Toxicogenomics has been developing with the rapid advances in Human Genome Project in recent two years. The categories and specialty of tox-gene; the application of tox-gene microarray in safety assessment, analysis of gene mutation and gene polymorphism, extrapolation of animal tests results, clarification of mechanism and safety assessment of mixtures; some problems of toxicogenomics need to be solved in spite of its great prospective application.

Safety↗

PubMed2003

Toxicogenomics takes center stage.

The Society of Toxicology held a meeting on March 9-13, 2003, in Salt Lake City, U.S.A. to discuss all aspects of toxicology with an emphasis on toxicogenomics, including the current state of high-throughput gene expression screens. The meeting gave the most up-to-date overview of current progress in this field, and gave experts to opportunity to discuss their work on in vitro toxicogenomics, proteomics, immunosuppressive drugs, toxicology and magnetic resonance spectroscopy, the environmental impact of pharmaceuticals, antioxidant-responsive element, and estrogens. Speakers from various companies and institutions were present.

Drug Design↗

PubMed2003

[Toxicogenomics--the research of environment and health at gene expression level].

Toxicogenomics is a new scientific field that elucidates how the entire genome is involved in biological responses of organisms exposed to environmental stressors and provides profound understanding of the roles of gene-environment interactions in pathogenesis of disease using high throughput technologies. In this paper, the research progress on the toxicogenomics and its application in both improving environmental health and preventing environmentally related disease were reviewed.

Environmental Health↗

PubMed1999

Microarrays and toxicology: the advent of toxicogenomics.

The availability of genome-scale DNA sequence information and reagents has radically altered life-science research. This revolution has led to the development of a new scientific subdiscipline derived from a combination of the fields of toxicology and genomics. This subdiscipline, termed toxicogenomics, is concerned with the identification of potential human and environmental toxicants, and their putative mechanisms of action, through the use of genomics resources. One such resource is DNA microarrays or "chips," which allow the monitoring of the expression levels of thousands of genes simultaneously. Here we propose a general method by which gene expression, as measured by cDNA microarrays, can be used as a highly sensitive and informative marker for toxicity. Our purpose is to acquaint the reader with the development and current state of microarray technology and to present our view of the usefulness of microarrays to the field of toxicology.

Animal Testing Alternatives↗

PubMed2006

The Comparative Toxicogenomics Database (CTD): a resource for comparative toxicological studies.

The etiology of most chronic diseases involves interactions between environmental factors and genes that modulate important biological processes (Olden and Wilson, 2000. Nat Rev Genet 1(2):149-153). We are developing the publicly available Comparative Toxicogenomics Database (CTD) to promote understanding about the effects of environmental chemicals on human health. CTD identifies interactions between chemicals and genes and facilitates cross-species comparative studies of these genes. The use of diverse animal models and cross-species comparative sequence studies has been critical for understanding basic physiological mechanisms and gene and protein functions. Similarly, these approaches will be valuable for exploring the molecular mechanisms of action of environmental chemicals and the genetic basis of differential susceptibility.

Animals↗

PubMed2006

Predictive toxicogenomics approaches reveal underlying molecular mechanisms of nongenotoxic carcinogenicity.

Toxicogenomics technology defines toxicity gene expression signatures for early predictions and hypotheses generation for mechanistic studies, which are important approaches for evaluating toxicity of drug candidate compounds. A large gene expression database built using cDNA microarrays and liver samples treated with over one hundred paradigm compounds was mined to determine gene expression signatures for nongenotoxic carcinogens (NGTCs). Data were obtained from male rats treated for 24 h. Training/testing sets of 24 NGTCs and 28 noncarcinogens were used to select genes. A semiexhaustive, nonredundant gene selection algorithm yielded six genes (nuclear transport factor 2, NUTF2; progesterone receptor membrane component 1, Pgrmc1; liver uridine diphosphate glucuronyltransferase, phenobarbital-inducible form, UDPGTr2; metallothionein 1A, MT1A; suppressor of lin-12 homolog, Sel1h; and methionine adenosyltransferase 1, alpha, Mat1a), which identified NGTCs with 88.5% prediction accuracy estimated by cross-validation. This six genes signature set also predicted NGTCs with 84% accuracy when samples were hybridized to commercially available CodeLink oligo-based microarrays. To unveil molecular mechanisms of nongenotoxic carcinogenesis, 125 differentially expressed genes (P<0.01) were selected by Student's t-test. These genes appear biologically relevant, of 71 well-annotated genes from these 125 genes, 62 were overrepresented in five biochemical pathway networks (most linked to cancer), and all of these networks were linked by one gene, c-myc. Gene expression profiling at early time points accurately predicts NGTC potential of compounds, and the same data can be mined effectively for other toxicity signatures. Predictive genes confirm prior work and suggest pathways critical for early stages of carcinogenesis.

Animals↗