PubMed Health⌕ Search

SEARCH · PubMed Health

Results for “toxicogenomics”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 145 records · Page 8Linked to original sources
PubMed2002

Differential toxicogenomic responses to 2,3,7,8-tetrachlorodibenzo-p-dioxin in malignant and nonmalignant human airway epithelial cells.

In humans, exposure to high levels of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is associated with chronic obstructive pulmonary disease and lung cancer. While several studies have shown that the lung is a target organ for TCDD toxicity, little is known on the specific biological pathways altered by TCDD. Studies have shown that the transcriptional response of TCDD (in vivo and in vitro) is complex, and exhibits cell type and tissue specificity. Thus, the purpose of this study was to look at global and concentration-dependent effects of TCDD on gene expression in human lung cells. Gene expression profiling of both a nontumorigenic (HPL1A) and a malignant, tumorigenic lung cell line (A549) was performed by microarray dual fluorescence hybridizations in cells treated with increasing concentrations of TCDD (0, 0.1, 1, 10 nM) for 24 h. Real time RT-PCR was used to verify alterations in specific genes. Results showed that 68 out of 2091 genes were changed in each cell line, and 15 of those genes were found altered in both cell lines. Common gene responses altered by TCDD were identified and included known xenobiotic metabolizing genes, genes known to alter cell cycle, as well as genes that are involved with cell signaling and that mediate cell motility or communication. Cell line specific differences in gene expression were found that indicate the nonmalignant HPL1A cells are retinoic acid responsive. In addition, TCDD altered specific immunomodulatory genes in the HPL1A cells. These data show that TCDD alters multiple integrated networks of signaling pathways associated with pulmonary disease, particularly that of lung cancer.

Algorithms↗
PubMed2004

A toxicogenomic approach to drug-induced phospholipidosis: analysis of its induction mechanism and establishment of a novel in vitro screening system.

Phospholipidosis is a lipid storage disorder in which excess phospholipids accumulate within cells. Some cationic amphiphilic compounds are known to have the potential to induce phospholipidosis. This study was undertaken to examine the molecular mechanisms that contribute to the development of phospholipidosis and to identify specific markers that might form the basis of an in vitro screening test. Specifically, we performed a large-scale gene expression analysis using DNA microarrays on human hepatoma HepG2 cells after they were treated with each of 12 compounds known to induce phospholipidosis. In electron microscopy, HepG2 cells developed lamellar myelin-like bodies in their lysosomes, the characteristic change of phospholipidosis, after treatment with these compounds for 72 h. DNA microarray analysis performed 6 and 24 h after treatment showed alterations in gene expression reflecting the inhibition of lysosomal phospholipase activity and lysosomal enzyme transport, and the induction of phospholipid and cholesterol biosynthesis. Seventeen genes that showed a similar expression profile following treatment were selected as candidate markers. Real-time PCR analysis confirmed that 12 gene markers showed significant concordance with lamellar myelin-like body formation. Furthermore, the average fold change values of these markers correlated well with the magnitude of this pathological change. In conclusion, microarray analysis revealed that factors such as alterations in lysosomal function and cholesterol metabolism were involved in the induction of phospholipidosis. Furthermore, comprehensive gene expression analysis enabled us to identify biomarkers of this condition that we then used to develop a rapid and sensitive in vitro screening test for drug-induced phospholipidosis.

Carcinoma, Hepatocellular↗
PubMed2005

Toxicogenomic profile of 2,3,7,8-tetrachlorodibenzo-p-dioxin in the murine fetal heart: modulation of cell cycle and extracellular matrix genes.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and similar environmental contaminants have been demonstrated to be potent cardiovascular teratogens in developing piscine and avian species. In the present study, we investigated the effects of TCDD on gene expression during murine cardiovascular development. C57Bl6N pregnant mice were dosed with 1.5, 3.0, or 6.0 microg TCDD/kg on gestational day (GD) 14.5, and microarray analysis was used to characterize the global changes in fetal cardiac gene expression on GD 17.5. TCDD significantly altered expression of a number of genes involved in xenobiotic metabolism, cardiac homeostasis, extracellular matrix production/remodeling, and cell cycle regulation. Interestingly, while the AhR-responsive genes Cyp1A1, Cyp1B1, Ugt1a6, and Ahrr, were all induced by TCDD in the fetal murine heart, other AhR-responsive genes, Cyp1a2, Nqo1, and Gsta1, were not. Quantitative real-time polymerase chain reactions confirmed the changes in expression of several G1/S-type cyclins and extracellular matrix-related genes. These results demonstrate the global changes in cardiac gene expression that result from TCDD exposure of the fetal murine heart and implicate genes involved in cell cycle and extracellular matrix regulation in TCDD-induced cardiac teratogenicity and functional deficits.

Animals↗
PubMed2005

Toxicogenomic profiling of the hepatic tumor promoters indole-3-carbinol, 17beta-estradiol and beta-naphthoflavone in rainbow trout.

Indole-3-carbinol (I3C), from cruciferous vegetables, has been found to suppress or enhance tumors in several animal models. We previously reported that dietary I3C promotes hepatocarcinogenesis in rainbow trout (Oncorhynchus mykiss) at concentrations that differentially activated estrogen receptor (ER) or aryl hydrocarbon receptor (AhR)-mediated responses based on individual protein biomarkers. In this study, we evaluated the relative importance of these pathways as potential mechanisms for I3C on a global scale. Hepatic gene expression profiles were examined in trout after dietary exposure to 500 and 1500 ppm I3C and 3,3'-diindolylmethane (DIM), a major in vivo component of I3C, and were compared to the transcriptional signatures of two model hepatic tumor promoters: 17beta-estradiol (E2), an ER agonist, and beta-naphthoflavone, an AhR agonist. We demonstrate that I3C and DIM acted similar to E2 at the transcriptional level based on correlation analysis of expression profiles and clustering of gene responses. Of the genes regulated by E2 (fold change >or =2.0 or < or =0.50), most genes were regulated similarly by DIM (87-92%) and I3C (71%), suggesting a common mechanism of action. Of interest were upregulated genes associated with signaling pathways for cell growth and proliferation, vitellogenesis, and protein folding, stability, and transport. Other genes downregulated by E2, including those involved in acute-phase immune response, were also downregulated by DIM and I3C. Gene regulation was confirmed by qRT-PCR and Western blot. These data indicate I3C promotes hepatocarcinogenesis through estrogenic mechanisms in trout liver and suggest DIM may be an even more potent hepatic tumor promoter in this model.

Animals↗
PubMed2006

Comparative toxicogenomic analysis of the hepatotoxic effects of TCDD in Sprague Dawley rats and C57BL/6 mice.

In an effort to further characterize conserved and species-specific mechanisms of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-mediated toxicity, comparative temporal and dose-response microarray analyses were performed on hepatic tissue from immature, ovariectomized Sprague Dawley rats and C57BL/6 mice. For temporal studies, rats and mice were gavaged with 10 or 30 microg/kg of TCDD, respectively, and sacrificed after 2, 4, 8, 12, 18, 24, 72, or 168 h while dose-response studies were performed at 24 h. Hepatic gene expression profiles were monitored using custom cDNA microarrays containing 8567 (rat) or 13,361 (mouse) cDNA clones. Affymetrix data from male rats treated with 40 microg/kg TCDD were also included to expand the species comparison. In total, 3087 orthologous genes were represented in the cross-species comparison. Comparative analysis identified 33 orthologous genes that were commonly regulated by TCDD as well as 185 rat-specific and 225 mouse-specific responses. Functional annotation using Gene Ontology identified conserved gene responses associated with xenobiotic/chemical stress and amino acid and lipid metabolism. Rat-specific gene expression responses were associated with cellular growth and lipid metabolism while mouse-specific responses were associated with lipid uptake/metabolism and immune responses. The common and species-specific gene expression responses were also consistent with complementary histopathology, clinical chemistry, hepatic lipid analyses, and reports in the literature. These data expand our understanding of TCDD-mediated gene expression responses and indicate that species-specific toxicity may be mediated by differences in gene expression which may help explain the wide range of species sensitivities and will have important implications in risk assessment strategies.

Animals↗
PubMed2006

A toxicogenomic approach revealed hepatic gene expression changes mechanistically linked to drug-induced hemolytic anemia.

A variety of pharmaceutical compounds causes hemolytic anemia as a significant adverse effect and this toxicity restricts the clinical utility of these drugs. In this study, we applied microarray technology to investigate hepatic gene expression changes associated with drug-induced hemolytic anemia and to identify potential biomarker genes for this hematotoxicity. We treated female Sprague-Dawley rats with two hemolytic anemia-inducing compounds: phenylhydrazine and phenacetin. Hepatic gene expression profiles were obtained using a whole-genome oligonucleotide microarray with pooled RNA samples from individual rats within each dose group and analyzed in comparison with hepatic histopathology, hematology, and blood chemistry data. We identified a small subset of genes that were commonly deregulated in all the severe hemolytic conditions, some of which were considered to be involved in hepatic events characteristic of hemolytic anemia, such as hemoglobin biosynthesis, heme metabolism, and phagocytosis. Among them, we selected six upregulated genes as putative biomarkers, and their expression changes from microarray measurements were confirmed by quantitative real-time PCR using RNAs from individual animals. They were Alas2, beta-glo, Eraf, Hmox1, Lgals3, and Rhced. Expression patterns of all these genes showed high negative and positive correlation against erythrocyte counts and total bilirubin levels in circulation, respectively, suggesting that these genes may be the potential biomarkers for hemolytic anemia. These findings indicate that drug-induced hemolytic anemia may be detected based on hepatic changes in the expression of a subset of genes that are mechanistically linked to the hematotoxicity.

Anemia, Hemolytic↗
PubMed2006

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

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. Moreover, optimization of the two gene sets for classification with an SVM and LOO-CV resulted in selection of 39 genes. The highest predictivity was achieved with 207 genes for differentiation between non-hepatocarcinogens and non-carcinogens. The overlap between the two selected gene sets encompassed 26 genes. This gene set contained significant genes for prediction of carcinogenicity, with a concordance of 84.6% by LOO-CV SVM. Using nine external samples, correct prediction of carcinogenicity by SVM was 88.9%. These results indicate that short-term bioassay systems for carcinogenicity using gene expression profiling in hepatoma cells have great promise.

Animals↗
PubMed2006

In vivo-in vitro toxicogenomic comparison of TCDD-elicited gene expression in Hepa1c1c7 mouse hepatoma cells and C57BL/6 hepatic tissue.

BACKGROUND: In vitro systems have inherent limitations in their ability to model whole organism gene responses, which must be identified and appropriately considered when developing predictive biomarkers of in vivo toxicity. Systematic comparison of in vitro and in vivo temporal gene expression profiles were conducted to assess the ability of Hepa1c1c7 mouse hepatoma cells to model hepatic responses in C57BL/6 mice following treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). RESULTS: Gene expression analysis and functional gene annotation indicate that Hepa1c1c7 cells appropriately modeled the induction of xenobiotic metabolism genes in vivo. However, responses associated with cell cycle progression and proliferation were unique to Hepa1c1c7 cells, consistent with the cell cycle arrest effects of TCDD on rapidly dividing cells. In contrast, lipid metabolism and immune responses, representative of whole organism effects in vivo, were not replicated in Hepa1c1c7 cells. CONCLUSION: These results identified inherent differences in TCDD-mediated gene expression responses between these models and highlighted the limitations of in vitro systems in modeling whole organism responses, and additionally identified potential predictive biomarkers of toxicity.

Animals↗
PubMed2006

Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells.

Kojic acid is a natural product and normally used as a food additive and preservative, a skin-whitening agent in cosmetics, a plant growth regulator and a chemical intermediate. Using DNA microarray technology, the overall biological effects of kojic acid on the gene expression profiling of a human skin A375 malignant melanoma cells were examined. After treatment with kojic acid, a total of 361 differentially expressed genes were distinctively changed with 136 up-regulated genes and 225 down-regulated genes. We used the bioinformatics tool to search the gene ontology and category classification of differentially expressed genes that provided the useful information of expressed genes belonging to cellular component, molecular function and biological process in regulation of melanogenesis. Seven down-regulated genes of APOBEC1, ARHGEF16, CD22, FGFR3, GALNT1, UNC5C and ZNF146 that were typically validated by the real-time quantitative PCR (RT-qPCR) analysis technology showed to be the tumor suppressor genes in melanoma cancer cells. Thus, microarray technology coupled with RT-qPCR offered a high throughput method to explore the number of differentially expressed genes responding to kojic acid and their biological functions, and led to more understanding of kojic acid effects on skin cancer therapy and related side effects. Moreover, the differentially expressed genes may become useful markers of skin malignant melanoma for further diagnostic and therapeutic applications.

Antioxidants↗