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At least 109 records · Page 6Linked to original sources
PubMed2004

Renal toxicogenomic response to chronic uranyl nitrate insult in mice.

Although the nephrotoxicity of uranium has been established through numerous animal studies, relatively little is known about the effects of long-term environmental uranium exposure. Using a combination of conventional biochemical studies and serial analysis of gene expression (SAGE), we examined the renal responses to uranyl nitrate (UN) chronic exposure. Renal uranium levels were significantly increased 4 months after ingestion of uranium in drinking water. Creatinine levels in serum were slightly but significantly increased compared with those in controls. Although no further significant differences in other parameters were noted, substantial molecular changes were observed in toxicogenomic profiles. UN induced dramatic alterations in expression levels of more than 200 genes, mainly up-regulated, including oxidative-response-related genes, genes encoding for cellular metabolism, ribosomal proteins, signal transduction, and solute transporters. Seven differentially expressed transcripts were confirmed by real-time quantitative polymerase chain reaction. In addition, significantly increased peroxide levels support the implication of oxidative stress in UN toxicant response. This report highlights the potential of SAGE for the discovery of novel toxicant-induced gene expression alterations. Here, we present, for the first time, a comprehensive view of renal molecular events after uranium long-term exposure.

Administration, Oral↗
PubMed2005

Large-scale databases in toxicogenomics.

The use of genomics to improve molecular strategies in safety assessment has immense promise, with increased mechanistic understanding and improved prediction of unknown compounds possible. Several public initiatives in toxicogenomics are now underway, and mechanistic findings are clearly emerging. A number of databases and standards are emerging to support these initiatives. Significant attention to standardization, both for biologic and technical issues, will be necessary for effective community database(s) to be fully operational.

Animals↗
PubMed2006

Toxicogenomics strategies for predicting drug toxicity.

INTRODUCTION: The failure of pharmaceutical drug candidates due to toxicity, especially hepatotoxicity, is an important and continuing problem for drug development. The current manuscript explores new toxicogenomics approaches to better understand the hepatotoxic potential of human pharmaceutical compounds and to assess their toxicity earlier in the drug development process by means of a toxicity screen. RESOURCES: Data consisted of two commercial knowledgebases that employed a hybrid experimental design in which human drug toxicity information was extracted from the literature, dichotomized and merged with rat-based gene expression measures. One knowledgebase used gene expression from rat primary hepatocytes while the other employed whole rats. Approximately 100 compounds were used in each. METHODS: Toxicity classification rules were built using a stochastic gradient boosting machine learner, with classification error estimated using a modified bootstrap estimate of true error. Several types of clustering methods were also applied, some based on sets of compounds and others based on sets of genes. RESULTS: Robust classification rules were constructed for both in vitro (hepatocytes) and in vivo (liver) data, based on a high dose, 24-hour design. There appeared to be little overlap between the two classifiers, at least in terms of their gene lists. Robust classifiers could not be fitted when earlier timepoints and/or low dose data were included, indicating that experimental design is important for these systems. CONCLUSIONS: In light of these findings, a working compound screen based on these toxicity classifiers appears feasible, with classifier operating characteristics used to tune a screen for a specific implementation. To ensure robust and optimal performance, issues such as site variability of microarrays and generalizability of findings should be addressed as indicated.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2002

An overview of toxicogenomics.

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.

Animals↗
PubMed2005

Health and employment practices: ethical, legal, and social implications of advances in toxicogenomics.

Advances in toxicogenomics research may allow the identification of individuals who may be hyper-susceptible to occupational exposures and could create a shift from population to individual-based risk assessment in occupational health. Although many states have passed legislation to prevent the misuse of genetic information in employment, there is no general federal protection from the use of genetic information after a conditional offer of employment. Occupational health professionals have a crucial role in shaping future guidelines governing the use of genetic information in employment.

Confidentiality↗
PubMed2002

Toxicogenomic effects of neonatal exposure to diethylstilbestrol on mouse testicular gene expression in the long term: a study using cDNA microarray analysis.

We examined the effect of neonatal exposure to diethylstilbestrol (DES) on mouse testicular gene expression, using in-house mouse fetus (day 14.5) cDNA microarrays. Newborn male ICR mice were exposed to DES (50 microg/mouse/day) from neonatal day 1 to 5. Differential expression was detected in 14 genes in 4-week-old (day 28) mouse testes by cDNA microarray analysis; 11 genes (AI035263, AU080565, AU080361, AU080678, AI131681, AU080631, AA986882, AI037066, AA986537, AI156816, and AI596237) were up-regulated and three genes (AI131656, AI118968, and AI117606) were down-regulated in DES-treated mouse testes. Higher expression levels of the former eight genes, out of the up-regulated genes picked-up by the microarray, were also confirmed by reverse transcription and real-time polymerase chain reaction (real-time RT-PCR) analysis. However, the differential expression of other genes could not be confirmed. Real-time RT-PCR analysis also revealed that expression levels of the eight genes were still higher in DES-treated testes at 8 and 12 weeks of age. Our results suggest that cDNA microarray analysis is a useful method by which a large number of gene expressions are simultaneously detected and changes in gene expression are screened. In addition, our results suggest that these genes, whose expressions are changed in the testes of adult mice by fetal or neonatal exposure to exogenous chemicals, might be candidates for predictive biological markers.

Animals↗
PubMed2004

Toxicogenomic difference between diethylstilbestrol and 17beta-estradiol in mouse testicular gene expression by neonatal exposure.

In this study, we investigated the effects of neonatal exposure to exogenous estrogen (diethylstilbestrol: DES, 17beta-estradiol: E2) on testicular gene expressions. Male C57BL/6J mice, 1 day after birth, were subcutaneously injected with DES or E2 (3 micrograms/mouse/day) for 5 days, and then they were raised for 8 weeks. In morphological observation of 8-week-old mice testes, spermatozoa were absent from many seminiferous tubules in DES-treated mice testes, but there was no change in E2-treated mice testes. Analysis of in-house cDNA microarray (mouse cDNA 889 genes) revealed that 17 genes were altered in DES-treated mice testes at 8 weeks of age, compared to each control. Real-time reverse transcription-polymerase chain reaction (real-time RT-PCR) analysis of these genes revealed that some genes, which were changed in E2-treated testis, were the same as in DES-treated testis, whereas in other cases there was a difference between DES-treated and E2-treated testis. The present results suggest that each exogenous estrogenic compound has both a common gene expression change pattern and its own testicular gene expression change pattern. Mol. Reprod. Dev. 67: 19-25, 2004.

Animals↗
PubMed2006

[Toxicogenetics and toxicogenomics. Relevance and application in occupational health].

Xenobiotic metabolising enzymes modify most organic compounds into water soluble compounds. Sequence variations of these enzymes can lead to significant interindividual differences in the metabolism of xenobiotics. This review covers important sequence variations of phase I (cytochrome P450) and phase II (glutathion S-transferases, N-acetyltransferases, sulfotransferases, UDP-glucuronosyl transferases) enzymes and elucidates the significance for occupational health. At the present time, the determination of various sequence variations is not suitable for an individual risk assessment in occupational health.

Acetyltransferases↗
PubMed2006

Toxicogenomic analysis of sodium hypochlorite antimicrobial mechanisms in Pseudomonas aeruginosa.

Sodium hypochlorite (bleach) is routinely used in hospitals and health care facilities for surface sterilization; however, the mechanism of action by which this disinfectant kills and the extent to which Pseudomonas aeruginosa is resistant to sodium hypochlorite have not been elucidated. Consequently, nosocomial infections from P. aeruginosa result in considerable casualties and economic hardship. We report the genome-wide transcriptome response of P. aeruginosa to sodium hypochlorite-induced oxidative stress via the use of DNA microarrays. In addition to a general oxidative stress response, our data revealed a downregulation of virtually all genes related to oxidative phosphorylation and electron transport and an upregulation of many organic sulfur transport and metabolism genes.

Bacterial Proteins↗
PubMed2006

Toxicogenomic studies of the rat brain at an early time point following acute sarin exposure.

We have studied sarin-induced global gene expression patterns at an early time point (2 h: 0.5 x LD50) using Affymetrix Rat Neurobiology U34 chips and male Sprague-Dawley rats. A total of 46 genes showed statistically significant alterations from control levels. Three gene categories contained more of the altered genes than any other groups: ion channel (8 genes) and calcium channel and binding proteins (6 genes). Alterations were also found in the following gene groups: ATPases and ATP-based transporters (4), growth factors (4), G-protein-coupled receptor pathway-related molecules (3), neurotransmission and neurotransmitter transporters (3), cytoskeletal and cell adhesion molecules (2), hormones (2), mitochondria-associated proteins (2), myelin proteins (2), stress-activated molecules (2), cytokine (1), caspase (1), GABAnergic (1), glutamergic (1), immediate early gene (1), prostaglandin (1), transcription factor (1), and tyrosine phosphorylation molecule (1). Persistent alteration of the following genes also were noted: Arrb1, CaMKIIa, CaMKIId, Clcn5, IL-10, c-Kit, and Plp1, suggesting altered GPCR, kinase, channel, and cytokine pathways. Selected genes from the microarray data were further validated using relative RT-PCR. Some of those genes (GFAP, NF-H, CaMKIIa, Calm, and MBP) have been shown by other laboratories and ours, to be involved in the pathogenesis of sarin-induced pathology and organophosphate-induced delayed neurotoxicity (OPIDN). Induction of both proapoptotic (Bcl2l11, Casp6) and antiapoptotic (Bcl-X) genes, besides suppression of p21, suggest complex cell death/protection-related mechanisms operating early on. Principal component analysis (PCA) of the expression data confirmed that the changes in gene expression are a function of sarin exposure, since the control and treatment groups separated clearly. Our model (based on current and previous studies) indicates that both degenerative and regenerative pathways are activated early and contribute to the level of neurodegeneration at a later time, leading to neuro-pathological alterations.

Animals↗
PubMed2006

Toxicogenomics of A375 human malignant melanoma cells treated with arbutin.

Although arbutin is a natural product and widely used as an ingredient in skin care products, its effect on the gene expression level of human skin with malignant melanoma cells is rarely reported. We aim to investigate the genotoxic effect of arbutin on the differential gene expression profiling in A375 human malignant melanoma cells through its effect on tumorigenesis and related side-effect. The DNA microarray analysis provided the differential gene expression pattern of arbutin-treated A375 cells with the significant changes of 324 differentially expressed genes, containing 88 up-regulated genes and 236 down-regulated genes. The gene ontology of differentially expressed genes was classified as belonging to cellular component, molecular function and biological process. In addition, four down-regulated genes of AKT1, CLECSF7, FGFR3, and LRP6 served as candidate genes and correlated to suppress the biological processes in the cell cycle of cancer progression and in the downstream signaling pathways of malignancy of melanocytic tumorigenesis.

Arbutin↗
PubMed2005

Toxicogenomics of resveratrol in rat liver.

Resveratrol, a polyphenolic compound found in grape skin and peanuts has been shown to prevent many diseases including cardiovascular diseases and cancer. To better understand resveratrol's potential in vivo toxicity, we studied the dose response using cDNA stress arrays coupled with drug metabolizing enzymatic (DME) assays to investigate the expression of stress-responsive genes and Phase I and II detoxifying enzymes in rat livers. Male and female CD rats were treated with high doses of resveratrol (0.3, 1.0 and 3.0 gm/kg/day) for a period of 28 days. Total RNA from rat liver was reverse-transcribed using gene-specific primers and hybridized to stress-related cDNA arrays. Among female rats, Phase I DME genes were repressed at 0.3 and 1.0 gm/kg/day doses, while genes such as manganese superoxide dismutase, cytochrome P450 reductase, quinone oxidoreductase and thiosulfate sulfurtransferase demonstrated a dose-dependent increase in gene expression. The modulation of these liver genes may implicate the potential toxicity as observed among the rats at the highest dose level of resveratrol. Real-Time PCR was conducted on some of the Phase II DME genes and anti-oxidant genes to validate the cDNA array data. The gene expression from real-time PCR demonstrated good correlation with the cDNA array data. UGT1A genes were amongst the most robustly induced especially at the high doses of resveratrol. We next performed Phase I and Phase II enzymatic assays on cytochrome P450 2E1 (CYP2E1), cytochrome P450 1A1 (CYP1A1), NAD(P)H:quinone oxidoreductase (NQO1), glutathione S-transferase (GST) and UDP-glucuronosyl transferase (UGT). Induction of Phase II detoxifying enzymes was most pronounced at the highest dose of resveratrol. CYP1A1 activity demonstrated a decreasing trend among the 3 dose groups and CYP2E1 activity increased marginally among female rats over controls. In summary, at lower doses of resveratrol there are few significant changes in gene expression whereas the modulation of liver genes at the high dose of resveratrol may implicate the potential toxicity observed.

Animals↗
PubMed2004

Mechanistic toxicogenomic analysis of WAY-144122 administration in Sprague-Dawley rats.

Application of global gene expression analysis in the study of mechanisms of toxicity could provide a more comprehensive interpretation of the molecular basis of drug action. WAY-144122 has pharmacological activity against several targets improving insulin responsiveness and favorably altering lipid profiles. Normal rats treated with suprapharmacological doses of WAY-144122 for 28 days exhibited drug-related effects in the liver and ovary. To determine the molecular mechanism underlying these effects, we employed global gene expression profiling to measure RNA levels in these target organs obtained from WAY-144122-treated rats administered test article for 1, 3, 7, and 14 days. Genes altered in expression by WAY-144122 were functionally categorized and related to their biological activity. In the liver, WAY-144122 caused a widespread up-regulation of genes involved in lipid mobilization, peroxisomal proliferation, and fatty acid beta-oxidation. In the ovary, we observed reduced expression of genes encoding luteinizing hormone receptor, follistatin, and enzymes in the estradiol synthesis pathway. Transcriptional changes in both organs precede histopathological effects. Profiling analysis allowed us to formulate hypotheses for molecular mechanisms underlying the physiological observations. In the liver, transcriptional changes suggest that WAY-144122 induced increased metabolic activity and peroxisomal proliferation resulting in increased liver weight and hepatocellular hypertrophy. We propose decreased estradiol synthesis as the underlying mechanism for the observed follicular atrophy in the ovary. Importantly, in this study, we have identified potential molecular mechanisms of drug effect in expression profiles before observation of physiological changes.

Administration, Oral↗
PubMed2005

Use of toxicogenomics for identifying genetic markers of pulmonary oedema.

This study was undertaken primarily to identify genetic markers of oedema and inflammation. Mild pulmonary injury was induced following the instillation of the oedema-producing agent, bleomycin (0.5 units). Oedema was then confirmed by conventional toxicology (lavage protein levels, free cell counts and lung/body weight ratios) and histology 3 days post-bleomycin instillation. The expression profile of 1176 mRNA species was determined for bleomycin-exposed lung (Clontech Atlas macroarray, n=9). To obtain pertinent results from these data, it was necessary to develop a simple, effective method for bioinformatic analysis of altered gene expression. Data were log10 transformed followed by global normalisation. Differential gene expression was accepted if: (a) genes were statistically significant (P < or = 0.05) from a two-tailed t test; (b) genes were consistently outside a two standard deviation (SD) range from control levels. A combination of these techniques identified 31 mRNA transcripts (approximately 3%) which were significantly altered in bleomycin treated tissue. Of these genes, 26 were down-regulated whilst only five were up-regulated. Two distinct clusters were identified, with 17 genes classified as encoding hormone receptors, and nine as encoding ion channels. Both these clusters were consistently down-regulated. The magnitude of the changes in gene expression were quantified and confirmed by Q-PCR (n = 6), validating the macroarray data and the bioinformatic analysis employed. In conclusion, this study has developed a suitable macroarray analysis procedure and provides the basis for a better understanding of the gene expression changes occurring during the early phase of drug-induced pulmonary oedema. This work has been presented orally, in part at the British Association for Lung Research Summer Meeting, University of Brighton, 3-5 September, 2003 and in full at the British Toxicology Society Annual Congress, Heriot Watt University, Edinburgh, 21-24 April 2004.

Animals↗
PubMed2005

Complementary gene and protein expression studies and integrative approaches in toxicogenomics.

Parallel transcript and protein profiling is a strategy to gain further insight into the mechanisms of toxicity and disease. The technologies used to measure expression at the transcript and protein levels each convey different information and have different technical capabilities that can complement each other when combined. In this review, over twenty studies are considered for the use of -Omics platform, the chemical or disease being profiled, tissues, the number of genes and proteins found by each platform and common expression products. A strategy is suggested for toxicant expression profiling that combines the transcriptomics and proteomics of both the target tissue and blood/serum that could provide a more complete characterization of toxicity as well as synergize expression technologies toward biomarker discovery.

Animals↗
PubMed2005

Drug-induced oxidative stress in rat liver from a toxicogenomics perspective.

Macrophage activators (MA), peroxisome proliferators (PP), and oxidative stressors/reactive metabolites (OS/RM) all produce oxidative stress and hepatotoxicity in rats. However, these three classes of hepatotoxicants give three distinct gene transcriptional profiles on cDNA microarrays, an indication that rat hepatocytes respond/adapt quite differently to these three classes of oxidative stressors. The differential gene responses largely reflect differential activation of transcription factors: MA activate Stat-3 and NFkB, PP activate PPARa, and OS/RM activate Nrf2. We have used gene signature profiles for each of these three classes of hepatotoxicants to categorize over 100 paradigm (and 50+ in-house proprietary) compounds as to their oxidative stress potential in rat liver. In addition to a role for microarrays in predictive toxicology, analyses of small subsets of these signature profiles, genes within a specific pathway, or even single genes often provide important insights into possible mechanisms involved in the toxicities of these compounds.

Animals↗