Microarray analysis of hepatotoxins in vitro reveals a correlation between gene expression profiles and mechanisms of toxicity

Waring, Jeffrey F.; Ciurlionis, Rita; Jolly, Robert A.; Heindel, Matthew; Ulrich, Roger G.

doi:10.1016/s0378-4274(01)00267-3

Cited by 302 publications

(136 citation statements)

References 28 publications

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“…[7][8][9] The application of gene expression analysis to models of chemically induced hepatotoxicity has been successfully used to monitor genes for altered expression during toxic injury and gain insight into the mechanism of action of hepatotoxins. [10][11][12] Currently, there are two major platforms of nucleic acid microarrays. The first, commonly referred to as the complementary deoxyribonucleic acid (cDNA) microarray, consists of probes (usually amplified cDNAs or PCR products) attached to a surface such as a nylon membrane or glass substrate.…”

Section: Introductionmentioning

confidence: 99%

Analysis of gene expression in carbon tetrachloride-treated rat livers using a novel bioarray technology

et al. 2003

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The present study successfully utilizes a new ADME Rat Expression Bioarray, containing 1040 metabolism-and toxicology-linked genes, to monitor gene expression from the livers of rats treated with carbon tetrachloride (CCl 4 ). Histopathological analysis, hierarchical clustering methods, and gene expression profiling are compared between the control and CCl 4 -treated animals. A total of 44 transcripts were found to be altered in response to the hepatotoxin, 19 of which were upregulated and 25 were downregulated. Some of these gene expression changes were expected and concurred with previously published data while others were novel findings.

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Section: Introductionmentioning

confidence: 99%

Analysis of gene expression in carbon tetrachloride-treated rat livers using a novel bioarray technology

et al. 2003

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“…Recent application of microarray-based gene profiling has provided some unique insights into compound-specific and toxicity-related gene expression changes in the liver (Hamadeh et al 2002a(Hamadeh et al , 2002bWaring et al 2001aWaring et al , 2001b, and several laboratories have applied similar techniques to identify gene expression changes related to nephrotoxicity (Huang et al 2001;Nagasawa et al 2001;Yoshida et al 2002).…”

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confidence: 99%

Identification of Putative Gene Based Markers of Renal Toxicity

Amin¹,

Vickers²,

Sistare³

et al. 2004

Environ. Health Perspect.

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This study, designed and conducted as part of the International Life Sciences Institute working group on the Application of Genomics and Proteomics, examined the changes in the expression profile of genes associated with the administration of three different nephrotoxicants-cisplatin, gentamicin, and puromycin-to assess the usefulness of microarrays in the understanding of mechanism(s) of nephrotoxicity. Male Sprague-Dawley rats were treated with daily doses of puromycin (5-20 mg/kg/day for 21 days), gentamicin (2-240 mg/kg/day for 7 days), or a single dose of cisplatin (0.1-5 mg/kg). Groups of rats were sacrificed at various times after administration of these compounds for standard clinical chemistry, urine analysis, and histological evaluation of the kidney. RNA was extracted from the kidney for microarray analysis. Principal component analysis and gene expression-based clustering of compound effects confirmed sample separation based on dose, time, and degree of renal toxicity. In addition, analysis of the profile components revealed some novel changes in the expression of genes that appeared to be associated with injury in specific portions of the nephron and reflected the mechanism of action of these various nephrotoxicants. For example, although puromycin is thought to specifically promote injury of the podocytes in the glomerulus, the changes in gene expression after chronic exposure of this compound suggested a pattern similar to the known proximal tubular nephrotoxicants cisplatin and gentamicin; this prediction was confirmed histologically. We conclude that renal gene expression profiling coupled with analysis of classical end points affords promising opportunities to reveal potential new mechanistic markers of renal toxicity.

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“…Within the pharmaceutical industry and elsewhere there is widespread interest in applying this technology to facilitate toxicity testing, in both research models for mechanistic investigations and in diagnostic modes to screen for expression patterns associated with established toxicity. (6,11,37,38) In the present study using microarray technology, we evaluated whether it was possible to use MH1C1 hepatoma cells for prediction of chemical carcinogenicity in a short period of time. The 39 genes selected for analysis 1 were limited compared to the 207 for analysis 2.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, use of this approach for predictive toxicology using gene expression profiles has been reported by several groups. (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17) In the present study, we aimed to provide a basis for a rapid and easy method to predict carcinogenicity of chemicals based on microarray technology with cultured MH1C1 rat hepatoma cells, selected as a model system to minimize complicating factors such as cell type heterogeneity and interindividual differences of animals. For this purpose, 39 chemicals that have been well characterized for carcinogenicity were first tested for cytotoxicity in cells using reductase activity at 3 days and non-toxic doses were determined for measurement of gene expression.…”

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confidence: 99%

Prediction of carcinogenic potential by a toxicogenomic approach using rat hepatoma cells

et al. 2006

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The long-term rodent bioassay is the standard method to predict the carcinogenic hazard of chemicals for humans. However, this assay is costly, and the results take at least two years to produce. In the present study, we conducted gene expression profiling of cultured cells exposed to carcinogenic chemicals with the aim of providing a basis for rapid and reliable prediction of carcinogenicity using microarray technology. We selected 39 chemicals, including 17 rat hepatocarcinogens and eight compounds demonstrating carcinogenicity in organs other than the liver. The remaining 14 were non-carcinogens. When rat hepatoma cells (MH1C1) were treated with the chemicals for 3 days at a non-toxic dose, analysis of gene expression changes with our in-house microarray allowed a set of genes to be identified differentiating hepatocarcinogens from non-carcinogens, and all carcinogens from non-carcinogens, by statistical methods. N umerous studies have investigated relationships among chemical exposure, toxicity, and disease states. The long-term rodent bioassay, the standard method to predict carcinogenic hazard of chemicals to humans, is costly in terms of time and material resources, therefore interest has concentrated on shortor medium-term bioassays.(1-5) One approach is to study change in gene expression in biological models in response to chemical exposure. Signatures of genetic alteration cannot be defined using classical methods for investigation of individual genes but with the advent of toxicogenomics, and the use of cDNA microarrays, the potential roles of multiple genes in concert can now be readily investigated in high throughput assays that are more sensitive and predictive than, for example, cell death assays. Recently, use of this approach for predictive toxicology using gene expression profiles has been reported by several groups. (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17) In the present study, we aimed to provide a basis for a rapid and easy method to predict carcinogenicity of chemicals based on microarray technology with cultured MH1C1 rat hepatoma cells, selected as a model system to minimize complicating factors such as cell type heterogeneity and interindividual differences of animals. For this purpose, 39 chemicals that have been well characterized for carcinogenicity were first tested for cytotoxicity in cells using reductase activity at 3 days and non-toxic doses were determined for measurement of gene expression. Genes for prediction for carcinogen and non-carcinogen groups were selected with statistical methods and analyzed by clustering analysis and an SVM. Additionally, cross-validation using individual external data was carried out for confirmation. For some selected genes, semiquantitative RT-PCR analyses were used to confirm the microarray results. Materials and Methods

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Microarray analysis of hepatotoxins in vitro reveals a correlation between gene expression profiles and mechanisms of toxicity

Cited by 302 publications

References 28 publications

Analysis of gene expression in carbon tetrachloride-treated rat livers using a novel bioarray technology

Analysis of gene expression in carbon tetrachloride-treated rat livers using a novel bioarray technology

Identification of Putative Gene Based Markers of Renal Toxicity

Prediction of carcinogenic potential by a toxicogenomic approach using rat hepatoma cells

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