• Molecular & Cellular Toxicology
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• v.1 no.1
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• pp.1-6
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• 2005

Toxicology is a multidisciplinary field, and an important science that impacts both environmental health regulation and the development and practice of medicine. The rapid progress in cellular and molecular biology, like many other branches of biomedical research, toxicology is now experiencing a renaissance fueled by the application of "omic" technologies to gain a better understanding of the biological basis of toxicology of drugs and other environmental factors. In this review on current progress on toxicology, the future perspective, concept, approaches and applications of toxicogenomics as next generation promising technology in toxicology field will be described.

• Molecular & Cellular Toxicology
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• v.1 no.1
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• pp.13-16
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• 2005

The current vision of toxicogenomics is the development of methods or platforms to predict toxicity of un characterized chemicals by using '-omics' information in pre-clinical stage. Because each chemical has different ADME (absorption, distribution, mechanism, excretion) and experimental animals have lots of variation, precise prediction of chemical's toxicity based on '-omics' information and toxicity data of known chemicals is very difficult problem. So, the importance of bioinformatics is more emphasized on toxicogenomics than other functional genomics studies because these problems can not be solved only with experiments. Thus, toxicoinformatics covers all information-based analytical methods from gene expression (bioinformatics) to chemical structures (cheminformatics) and it also deals with the integration of wide range of experimental data for further extensive analyses. In this review, the overall strategy to toxicoinformatics is discussed.

• Proceedings of the Korean Society of Toxicology Conference
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• 2005.11a
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• pp.83-87
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• 2005

• Molecular & Cellular Toxicology
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• v.1 no.1
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• pp.17-25
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• 2005

There are some critical drawbacks in the use of biomarkers for a global assessment of the toxicological impacts many chemicals and environmental pollutants have, primarily due to an individual biomarker's specificity for an explicit chemical or toxicant. In other words, the biomarker-based assessment methodology used to analyze toxicological effects lacks a high-throughput capability. Therefore, eco-toxicogenomics, or the study of toxicogenomics with organisms present within a given environmental locale, has recently been introduced with the advent of the so-called "-omics" era, which began with the creation of microarray technologies. Fish are comparable with humans in their toxicological responses and thus data from toxicogenomic studies performed with fish could be applied, with appropriate tools and implementation protocols, to the evaluation of environments where human or animal health is of concern. At present, there have been very active research streams for developing expression sequence tag (EST) databases (DBs) for zebra fish and rainbow trout. Even though few reports involve toxicogenomic studies with fish, a few groups have successfully fabricated and used cDNA microarrays or oligo DNA chips when studying the toxicological impacts of hypoxia or some toxicants with fish. Furthermore, it is strongly believed that this technology can also be implemented with non-model fish. With the standardization of DNA microarray technologies and ample progress in bioinformatics and proteomic technologies, data obtained from DNA microarray technologies offer not only multiple biomarker assays or an analysis of gene expression profiles, but also a means of elucidating gene networking, gene-gene relations, chemical-gene interactions, and chemical-chemical relationships. Accordingly, the ultimate target of eco-toxicogenomics should be to predict and map the pathways of stress propagation within an organism and to analyze stress networking.

• Molecular & Cellular Toxicology
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• v.4 no.3
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• pp.260-266
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• 2008

Recently, there has been scientific discussion on the utility of -omics techniques such as genomics, proteomics, and metabolomics within toxicological research and mechanism-based risk assessment. Toxicogenomics is a novel approach integrating the expression analysis of genes (genomic) or proteins (proteomic) with traditional toxicological methods. Since 1999, the toxicogenomic approach has been extensively applied for regulatory purposes in order to understand the potential toxic mechanisms that result from chemical compound exposures. Therefore, this article's purpose was to consider the utility of toxicogenomic profiles for improved risk assessment, explore the current limitations in applying toxicogenomics to regulation, and finally, to rationalize possible avenues to resolve some of the major challenges. Based on many recent works, the significant impact toxicogenomic techniques would have on human health risk assessment is better identification of toxicity pathways or mode-of-actions (MOAs). In addition, the application of toxicogenomics in risk assessment and regulation has proven to be cost effective in terms of screening unknown toxicants prior to more extensive and costly experimental evaluation. However, to maximize the utility of these techniques in regulation, researchers and regulators must resolve many parallel challenges with regard to data collection, integration, and interpretation. Furthermore, standard guidance has to be prepared for researchers and assessors on the scientifically appropriate use of toxicogenomic profiles in risk assessment. The National Institute of Toxicological Research (NITR) looks forward to an ongoing role as leader in addressing the challenges associated with the scientifically sound use of toxicogenomics data in risk assessment.

• Molecular & Cellular Toxicology
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• v.4 no.4
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• pp.323-330
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• 2008

Surrogate tissue analysis incorporating -omics technologies has emerged as a potential alternative method for evaluating toxic effect of the tissues which are not accessible for sampling. Among the recent applications, blood including whole blood, peripheral blood lymphocytes and peripheral blood mononuclear cells (PBMCs) was suggested as a suitable surrogate tissue in determining toxicant exposure and effect at the pre- or early clinical stage. In this application, we investigated transcriptomic profiles in astemizole treated Cynomolgus monkey's PBMCs. PBMCs were isolated from 4-6 years old male monkeys at 24 hr after administration45 Helvetica Light (10 mg/kg, 30 mg/kg). Gene expression profiles of astemizole treated monkey's PBMCs were determined using Affymetrix $GeneChip^{(R)}$ Human Genome U133 plus 2.0 arrays. The expression levels of 724 probe sets were significantly altered in PBMCs at 10 or 30 mg/kg after astemizole administration following determination of paired t-test using statistical criteria of ${\geq}$$1.5-fold changes at P<0.05. Gene expression patterns in PBMCs showed a considerable difference between astemizole 10 and 30 mg/kg administration groups in spite of an administration of the same chemical. However, close examination using Ingenuity Pathway Analysis (IPA) software revealed that several gene sets related to cardiotoxicity were deregulated at astemizole 10 and 30 mg/kg administration groups. The deregulation of cardiac hypertrophy related genes such as TXN, GNAQ, and MAP3K5 was observed at 10 mg/kg group. In astemizole 30 mg/kg group, genes involved in cardiotoxicity including cardiac necrosis/cell death, dilation, fibrosis, and hypertrophy were also identified. These results suggest that toxicogenomic approach using PBMCs as surrogate tissues will contribute to assess toxicant exposures and identify biomarkers at the pre-clinical stage.

• Molecular & Cellular Toxicology
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• v.3 no.2
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• pp.119-126
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• 2007

1, 1-dichloroethylene (DCE) is well known hepatotoxicant as a model acute hepatotoxicity and selectively injure the bile canalicular membrane of centrilobular hepatocytes. In this study, we investigated hepatic gene expression and histopathological changes in response to DCE treatment. DCE was administered once daily at 20 mg/kg up to 14 days via intraperitoneal injection. Five mice were used in each test group and were sacrificed at 1, 7, and 14 days. Serum biochemical and histopathological analysis were performed for evaluation of hepatotoxicity level. Direct bilirubin and total bilirubin activities were slightly elevated in treated group at 7 days. DCE treatment for 7 days resulted in centrilobular hepatocyte hypertrophy and hepatocyte vacuolation, and mild hepatocyte vacuolation and high hepatocyte basophilia were observed in 14 days treated group. One hundred twenty three up-regulated genes and 445 down-regulated genes with over 2-fold changes between treated and control group at each time point were used for pathway analysis. These data may contribute in understanding the molecular mechanism DCE-induced hepatotoxicity.

• Molecular & Cellular Toxicology
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• v.3 no.3
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• pp.208-213
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• 2007

With the help of a development and popularization of microarray technology that enable to us to simultaneously investigate the expression pattern of thousands of genes, the toxicogenomics experimenters can interpret the genome-scale interaction between genes exposed in toxicant or toxicant-related environment. The ultimate and primary goal of toxicogenomics identifies functional context among the group of genes that are differentially or similarly coexpressed under the specific toxic substance. On the other side, public reference databases with transcriptom, proteom, and biological pathway information are needed for the analysis of these complex omics data. However, due to the heterogeneous and independent nature of these databases, it is hard to individually analyze a large omics annotations and their pathway information. Fortunately, several web sites of the public database provide information linked to other. Nevertheless it involves not only approriate information but also unnecessary information to users. Therefore, the systematically integrated database that is suitable to a demand of experimenters is needed. For these reasons, we propose SOP (Search of Omics Pathway) database system which is constructed as the integrated biological database converting heterogeneous feature of public databases into combined feature. In addition, SOP offers user-friendly web interfaces which enable users to submit gene queries for biological interpretation of gene lists derived from omics experiments. Outputs of SOP web interface are supported as the omics annotation table and the visualized pathway maps of KEGG PATHWAY database. We believe that SOP will appear as a helpful tool to perform biological interpretation of genes or proteins traced to omics experiments, lead to new discoveries from their pathway analysis, and design new hypothesis for a next toxicogenomics experiments.

• Molecular & Cellular Toxicology
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• v.3 no.2
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• pp.137-144
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• 2007

The mechanism of cytotoxicity of doxifluridine, a prodrug fluorouracil (5-FU), has been ascribed to the misincorporation of fluoropyrimidine into RNA and DNA and to the inhibition of the nucleotide synthetic enzyme thymidylate synthase. Increased understanding of the mechanism of 5-FU has led to the development of strategies that increases its anticancer activity or predicts its sensitivity to patients. Using GeneChip?? Rhesus Macaque Genome arrays, we analyzed gene expression profiles of doxifluridine after two weeks repeated administration in cynomolgus monkey. Kegg pathway analysis suggested that cytoskeletal rearrangement and cell adhesion remodeling were commonly occurred in colon, jejunum, and liver. However, expression of genes encoding extracellular matrix was distinguished colon from others. In colon, COL6A2, COL18A1, ELN, and LAMA5 were over-expressed. In contrast, genes included in same category were down-regulated in jejunum and liver. Interestingly, MMP7 and TIMP1, the key enzymes responsible for ECM regulation, were overexpressed in colon. Several studies were reported that both gene reduced cell sensitivity to chemotherapy-induced apoptosis. Therefore, we suggest they have potential as target for modulation of 5-FU action. In addition, the expression of genes which have been previously known to involve in 5-FU pathway, were examined in three organs. Particularly, there were more remarkable changes in colon than in others. In colon, ECGF1, DYPD, TYMS, DHFR, FPGS, DUT, BCL2, BAX, and BAK1 except CAD were expressed in the direction that was good response to doxifluridine. These results may provide that colon is a prominent target of doxifluridine and transcriptional profiling is useful to find new targets affecting the response to the drug.

• 대한생식의학회:학술대회논문집
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• 2005.06a
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• pp.131-132
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• 2005