Discovery in toxicology: Mediation by gene expression array technology

Hamadeh, Hisham K.; Bushel, Pierre R.; Paules, Richard S.; Afshari, Cynthia A.

doi:10.1002/jbt.10006

Cited by 57 publications

(12 citation statements)

References 75 publications

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“…Such observations derived through the application of microarrays to toxicology will broaden our understanding of mechanisms and our ability to identify compounds with similar mechanisms of toxicity. The authors also confirmed toxicity in the animals using conventional methods such as histopathology, modulations in liver enzymes and bilirubin levels and related these effects to gene expression changes; however, it would have been advantageous to utilize gene expression data to map relevant pathways depicting mechanism(s) associated with the hepatotoxicity of each compound (Hamadeh et al, 2001). Collectively, in the future, researchers may attempt to build "transcriptome" or "effector maps" that will help to visualize pathway activation (Tennant, 2001).…”

Section: Mechanistic Inference From Toxicant Profilingmentioning

confidence: 86%

“…These technological advances have led to the development of the field of "toxicogenomics", which proposes to apply global mRNA, protein and metabolite analysis relatedtechnologies to study the effects of hazards on organisms Farr, 1999;Henry, 1999;Nuwaysir, et al, 1999;Rockett and Dix, 1999;Hamadeh and Afshari, 2000;Pennie, et al, 2000;Rockett and Dix, 2000;Hooker, 2001;Iannaccone, 2001;Olden, 2001;Smith, 2001;Tennant, 2001;Hamadeh et al, 2001;Hamadeh et al, 2002d). These collective approaches will allow the development of a knowledge base of compound effects that will aid in improving the efficiency of safety and risk assessment of drugs and chemicals by facilitating better understanding of the mechanisms by which chemical-or stressor-induced injury occurs.…”

Section: Background and Definition Of Toxicogenomicsmentioning

confidence: 99%

“…This method, however, is labor intensive and is practical for examining expression changes for a limited number of genes. Alternate technologies, including DNA microarrays, can measure the expression of tens of thousands of genes in an equivalent amount of time (DeRisi, et al, 1996;Duggan, et al, 1999;Hamadeh and Afshari, 2000;Hamadeh et al, 2001). DNA microarrays provide a revolutionary platform to compare genome-wide gene expression patterns in dose and time contexts.…”

Section: Gene Expression Profilingmentioning

confidence: 99%

See 2 more Smart Citations

An Overview of Toxicogenomics

Hamadeh

Amin²,

Paules³

et al. 2002

Current Issues in Molecular Biology

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Toxicogenomics is a rapidly developing discipline that promises to aid scientists in understanding the molecular and cellular effects of chemicals in biological systems. This field encompasses global assessment of biological effects using technologies such as DNA microarrays or high throughput NMR and protein expression analysis. This review provides an overview of advancing multiple approaches (genomic, proteomic, metabonomic) that may extend our understanding of toxicology and highlights the importance of coupling such approaches with classical toxicity studies. Background and Definition of Toxicogenomics

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Section: Mechanistic Inference From Toxicant Profilingmentioning

confidence: 86%

Section: Background and Definition Of Toxicogenomicsmentioning

confidence: 99%

Section: Gene Expression Profilingmentioning

confidence: 99%

See 1 more Smart Citation

An Overview of Toxicogenomics

Hamadeh

Amin²,

Paules³

et al. 2002

Current Issues in Molecular Biology

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“…It has been argued before that relatively toxic doses of chemicals must be administered to obtain significant changes in gene expression (Bartosiewicz et al, 2001), and that compounds affect different genes and pathways depending on the dose administered (Steiner et al, 2004). If this is true, gene expression analysis was not more sensitive in detection of the primary effect of TBTO in rats than the traditional toxicological endpoints, even though that has often been suggested to be an advantage of toxicogenomics (Hamadeh et al, 2001;Roberts, 2002;de Longueville et al, 2004). Alternatively, although organotin compounds have immunosuppressive effects in both mouse and rat lymphocytes, the molecular mechanisms of action may differ between these species, which may cause differences in gene expression profiles.…”

Section: Discussionmentioning

confidence: 99%

Gene Expression Profiling of Bis(tri-n-butyltin)oxide (TBTO)-Induced Immunotoxicity in Mice and Rats

Baken

Pennings

Breit

et al. 2006

Journal of Immunotoxicology

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Bis(tri-n-butyltin)oxide (TBTO) is one of the organotin compounds that have been used as biocides and occur as persistent environmental pollutants. Human exposure to these compounds occurs through consumption of meat and fish products in which they accumulate. The most sensitive endpoint of TBTO exposure is immunotoxicity. TBTO causes thymus atrophy and thereby interferes with T-lymphocyte-mediated immune responses. Tributyltin compounds have been found to adversely affect a wide range of cellular components and processes in many species, organ systems, and cell types. Both inhibition of proliferation and induction of apoptosis have been observed in thymocytes. We conducted microarray experiments in mice and rats in order to investigate if the immunosuppressive actions of TBTO could be detected by gene expression profiling, and if so, to elucidate the mechanisms of action. Gene expression changes that were detected in mouse thymuses after exposure to a maximum tolerable dose of TBTO correlated to previously observed effects. Most notably, reduction of expression of cell surface determinants and T-cell receptor chains, suppression of cell proliferation, and a possible involvement of nuclear receptors in interference with lipid metabolism by TBTO were observed. The TBTO-induced thymus involution may therefore primarily be caused by inhibition of thymocyte proliferation. In contrast, in rats only limited effects of a lower dose of TBTO were found at the gene expression level in the thymus, even though thymus involution was observed. Here, most gene expression regulation by TBTO was detected in the liver. These preliminary results indicate that gene expression analysis is able to reveal effects of TBTO and to gain insight into its molecular mechanism of action. It may even be a suitable tool to investigate immunotoxicology in general. However, dose and inter-species differences are apparently clearly reflected in the gene expression profiles.

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“…Since the initial publications (47,65,69,83), DNA microarrays have found widespread interest in drug research. The tremendous potential for the application of DNA microarrays in drug development and in particular in toxicology is just going to be realized (7,33,40,51,64). This review will provide an overview of mRNA and protein expression array technologies used in the field of toxicogenomics, and their application to facilitate discovery of mechanistic pathways associated with drug related effects, outlining both the strengths and challenges of this approach.…”

Section: Introductionmentioning

confidence: 99%

Toxicogenomics in Drug Development

et al. 2003

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Toxicogenomics represents the merging of toxicology with technologies that have been developed, together with bioinformatics, to identify and quantify global gene expression changes. It represents a new paradigm in drug development and risk assessment, which promises to generate a wealth of information towards an increased understanding of the molecular mechanisms that lead to drug toxicity and efficacy, and of DNA polymorphisms responsible for individual susceptibility to toxicity. Gene expression profiling, through the use of DNA microarray and proteomic technologies will aid in establishing links between expression profiles, mode of action and traditional toxic endpoints. Such patterns of gene expression, or 'molecular fingerprints' could be used as diagnostic or predictive markers of exposure, that is characteristic of a specific mechanism of induction of that toxic or efficacious effect. It is anticipated that toxicogenomics will be increasingly integrated into all phases of the drug development process particularly in mechanistic and predictive toxicology, and biomarker discovery. This review provides an overview of the expression profiling technologies applied in toxicogenomics, and discusses the promises as well as the future challenges of applying this discipline to the drug development process.Keywords. DNA microarrays; PCR; bioinformatics; gene expression profiling; genomics; proteomics; biomarkers; toxicology. INTRODUCTIONThe evolution of new innovative technologies in parallel with recent dramatic increases in genomic knowledge is anticipated to revolutionize toxicological studies by providing significant advances in the understanding and prediction of the toxicity and efficacy of new drugs (38, 39, 52). In classic toxicology, potential adverse effects resulting from drug exposure are evaluated using endpoints such as body and organ weight changes, biochemical and histopathological observations. Such observations, however, do not provide information about a drug's mode of action. To better evaluate the adverse effects associated with drug exposure, one needs to understand the drug's specific mode of action. Drugs are expected to induce a multitude of complex molecular perturbations in a wide variety of pathways, involving differential gene expression at the transcript and functional protein level, leading to efficacious and/or pathological outcomes. These changes in gene expression are often more sensitive and characteristic of the toxic response or process than currently employed endpoints of pathology, and have the potential to indicate toxicity already at lower doses or at earlier time points.Technological advances derived from genomic research have made it possible to follow transcriptional and translational events of genes and even the entire genome. The application of genome-wide expression profiling technologies to toxicology has created a new subdiscipline coined 'toxicogenomics,' which has the potential to provide a more comprehensive understanding of the mechanisms of pharmacology ...

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Discovery in toxicology: Mediation by gene expression array technology

Cited by 57 publications

References 75 publications

An Overview of Toxicogenomics

An Overview of Toxicogenomics

Gene Expression Profiling of Bis(tri-n-butyltin)oxide (TBTO)-Induced Immunotoxicity in Mice and Rats

Toxicogenomics in Drug Development

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