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At least 91 records · Page 5Linked to original sources
PubMed2003

On the safety of a new generation of DSM Aspergillus niger enzyme production strains.

Consumers safety of enzyme preparations is determined by three variables: the producing organism, the raw materials used in the production, and the production process itself. The latter one is embedded in current Good Manufacturing Practice (cGMP) and Hazard Analysis of Critical Control Points (HACCP); therefore the safety focus can be directed to raw materials and the producing organism. In this paper, we describe the use of novel genetically modified strains of Aspergillus niger-made by a design and build strategy-from a lineage of classically improved strains with a history of safe use in enzyme production. The specifics of the host strain allow for integration and over-expression of any gene of interest at a targeted integration site implying that the rest of the host genome is not affected by this integration. Furthermore due to the fact that the newly integrated gene copies are put under the genetic regulation of the host's own glucoamylase promoter, the recipe of the production process of any new production strain can be kept constant with respect to the raw materials composition. Consequently the safety of a new enzyme product from these novel genetically modified strains is determined by the background of the production organism. The use of a strain with a history of safe use and targeted integration according to the concept described above has consequences for the safety studies on the final product. If a known enzymatic activity is over-expressed the safety of a new enzyme preparation is covered by the results of the safety studies performed for other strains from this specific Aspergillus niger strain lineage. In this paper an overview is given on the available toxicity tests with these strains. We conclude that for new enzyme products produced with strains from this lineage using the design and build technology no new sub-acute/chronic oral toxicity studies are needed. This also has the benefit that no longer test animals are needed to demonstrate the safety of products produced by these strains.

Animals↗
PubMed2004

Toxicology investigations with cell culture systems: 20 years after.

From almost 20 years the "in vitro" model has gained a wide ground in toxicological investigation, providing advanced tools, reliable protocols, mechanistic information. These advancements have been done thanks to different approaches, addressed at improving chemical testing and validating procedures, at exploring the cellular and molecular basis of toxicity, at studying the modifications that xenobiotics undergo in the cellular environment. In this review the most advanced cellular models, the mechanisms of cell death, the techniques to monitor gene activation, following chemical exposure, is highlighted. Moreover the more recent in vitro models to approach the biotransformation issue will be presented.

Animals↗
PubMed2003

Toxicogenomic effects of marine brevetoxins in liver and brain of mouse.

Although the polyether brevetoxins (PbTx's) produced by Karenia brevis (the organism responsible for blooms of the Florida red tide) are known to exert their acute toxic effects through ion-channel mediated pathways in neural tissue, prior studies have also demonstrated that at least one form of the toxin (PbTx-6) is bound avidly by the aryl hydrocarbon receptor (AhR). Since AhR binding of a prototypical ligand such as dioxin is the first step in a cascade pathway producing major changes in gene expression, we reasoned that PbTx-6 might produce similar genomic-wide changes in expression. Mice were injected i.p. with sub-lethal doses of PbTx's (either 1.5 or 3 mg/g body weight of PbTx-6; or 0.15 mg/g body weight of PbTx-2, a toxin not avidly bound by the AhR), and liver and brain tissues were sampled at 8, 24 and 72 h and RNA was isolated. Changes in gene-specific RNA levels were assessed using commercially available mouse cDNA arrays (Incyte) containing >9600 array elements, including many elements from AhR-mediated genes. Histopathology of the two organs was also assessed. We observed minor histopathological effects and a total of only 29 significant (>2.0-fold) changes in gene expression, most of which occurred in the liver, and most of which could be attributable to an 'acute phase' inflammatory response. These results argue against the hypothesis that PbTx-6 acts via a classic AhR-mediated mechanism to evoke gene expression changes. However, given the avidity with which PbTx-6 binds to the AhR, these findings have important implications for how PbTx's may act in concert with other toxicants that are sensed by the AhR.

Animals↗
PubMed2003

The toxicogenomics of nuclear receptor agonists.

Toxicogenomics is the study of the structure and output of the genome as it responds to adverse xenobiotic exposure. Large-scale transcriptional analysis, made possible through microarray technologies, enables us to study and understand the complexity of the biological effects of drugs and chemicals, with the ultimate goal of separating wanted effects from adverse effects. Nuclear receptors are attractive targets for drug discovery because, as ligand-activated transcription factors, they coordinately regulate the expression of at least hundreds of genes that, in turn, control much of cellular metabolism. Through toxicogenomics, it is becoming possible to understand the therapeutic effects of agonists within the context of toxic effects, classify new chemicals as to their complete effects on biological systems, and identify environmental factors that may influence safety or efficacy of new and existing drugs.

Animals↗
PubMed2005

Microarray analysis of toxicogenomic effects of peracetic acid on Pseudomonas aeruginosa.

Hospital-acquired (nosocomial) infection (HAI) represents a serious threat to public health, both in terms of human casualty and in terms of economic impact. On an annual basis, 2 million individuals require prolonged hospitalization, and an estimated 90 000 patients die due to HAI. Economic damages are reported to exceed $4.5 billion, annually. While many disinfectants, including peracetic acid, have been employed to eradicate infectious bacteria, a lack of understanding their mode of action and the corresponding defense mechanisms hinders successful antimicrobial application. We report here the first transcriptome analysis of the response of Pseudomonas aeruginosa, a pathogen infecting those with cystic fibrosis, upon 20 min exposure to a sublethal concentration (1 mM) of peracetic acid. As a result, we identified that 570 out of a total of 5570 P. aeruginosa genes showed statistically significant transcript level changes. Our findings indicate that (i) many genes associated with cellular protective processes were induced, (ii) the transcription of genes involved in primary metabolic pathways was repressed, and (iii) the transcription of genes encoding membrane proteins and small molecule transporters was altered. We also observed that genes within operons were highly cotranscribed in this study. Finally, this global transcriptional profile can help identify signature genes that are also activated with other oxidative disinfectants, which may be used to design new more effective treatments or more efficaciously apply existing compounds.

Disinfectants↗
PubMed2005

Isolation of the retinoblastoma cDNA from the marine flatfish dab (Limanda limanda) and evidence of mutational alterations in liver tumors.

We have isolated a dab (Limanda limanda) homologue of the human retinoblastoma (Rb) tumor suppressor gene. The L. limanda partial Rb cDNA encodes a partial predicted protein of 753 amino acids. DNA sequence analysis with other vertebrate Rb sequences demonstrates that the L. limanda Rb cDNA is highly conserved in regions of functional importance. The sequence reported herein, combined with the high degree of conservation observed in critical domains, has also facilitated an investigation of the molecular etiology of environmentally induced liver tumor samples in a feral fish species. Mutational alterations were detected in liver adenoma samples, also in apparently "normal" regions of liver samples dissected from fish displaying adenoma, but not in normal liver samples from otherwise healthy feral fish. These results are the first reporting the appearance of Rb mutations in wild-caught fish and suggest that the molecular etiology of fish cancer appears to involve Rb-implicated tumorigenesis. The ecotoxicological relevance of the Rb mutations in feral fish liver tumors, in terms of future genome instability and possible development of a genotoxicity biomarker, is discussed.

Animals↗
PubMed2006

Toxicogenomic response of Staphylococcus aureus to peracetic acid.

Staphylococcus aureus is responsible for many incidents of hospital-acquired infection, which causes 90,000 deaths and dollars 4.5 billion loss a year in the United States. Despite a wide use of disinfectants such as peracetic acid in health care environments, we certainly need better understanding of the effects of antimicrobial application on target pathogens to avert infection outbreaks. Consequently, herein, we explored for the first time the toxicogenomic response of S. aureus to a sublethal concentration of peracetic acid (1 mM) by using microarray-based transcriptome analysis. In particular, we investigated the dynamics of global gene expression profiles during its cellular response, which involved initial growth inhibition (10 min) and subsequent partial recovery (20 min). Further, we compared transcriptome responses to peracetic acid between S. aureus and Pseudomonas aeruginosa. Our findings show that (i) the regulation of membrane transport genes was significantly altered, (ii) DNA repair and replication genes were selectively induced, and (iii) primary metabolism-related genes were differently repressed between the two growth states. Most intriguingly, we revealed that many virulence factor genes were induced upon the exposure, which proposes a possibilitythatthe pathogenesis of S. aureus may be stimulated in response to peracetic acid.

Anti-Infective Agents↗
PubMed2006

Identification of potential genomic biomarkers of hepatotoxicity caused by reactive metabolites of N-methylformamide: Application of stable isotope labeled compounds in toxicogenomic studies.

The inability to predict if a metabolically bioactivated compound will cause toxicity in later stages of drug development or post-marketing is of serious concern. One approach for improving the predictive success of compound toxicity has been to compare the gene expression profile in preclinical models dosed with novel compounds to a gene expression database generated from compounds with known toxicity. While this guilt-by-association approach can be useful, it is often difficult to elucidate gene expression changes that may be related to the generation of reactive metabolites. In an effort to address this issue, we compared the gene expression profiles obtained from animals treated with a soft-electrophile-producing hepatotoxic compound against corresponding deuterium labeled analogues resistant to metabolic processing. Our aim was to identify a subset of potential biomarker genes for hepatotoxicity caused by soft-electrophile-producing compounds. The current study utilized a known hepatotoxic compound N-methylformamide (NMF) and its two analogues labeled with deuterium at different positions to block metabolic oxidation at the formyl (d(1)) and methyl (d(3)) moieties. Groups of mice were dosed with each compound, and their livers were harvested at different time intervals. RNA was prepared and analyzed on Affymetrix GeneChip arrays. RNA transcripts showing statistically significant changes were identified, and selected changes were confirmed using TaqMan RT-PCR. Serum clinical chemistry and histopathologic evaluations were performed on selected samples as well. The data set generated from the different groups of animals enabled us to determine which gene expression changes were attributed to the bioactivating pathway. We were able to selectively modulate the metabolism of NMF by labeling various positions of the molecule with a stable isotope, allowing us to monitor gene changes specifically due to a particular metabolic pathway. Two groups of genes were identified, which were associated with the metabolism of a certain part of the NMF molecule. The metabolic pathway leading to the production of reactive methyl isocyanate resulted in distinct expression patterns that correlated with histopathologic findings. There was a clear correlation between the expression of certain genes involved in the cell cycle/apoptosis and inflammatory pathways and the presence of reactive metabolite. These genes may serve as potential genomic biomarkers of hepatotoxicity induced by soft-electrophile-producing compounds. However, the robustness of these potential genomic biomarkers will need to be validated using other hepatotoxicants (both soft- and hard-electrophile-producing agents) and compounds known to cause idiosyncratic liver toxicity before being adopted into the drug discovery screening process.

Animals↗
PubMed2006

Computational prediction of the chromosome-damaging potential of chemicals.

We report on the generation of computer-based models for the prediction of the chromosome-damaging potential of chemicals as assessed in the in vitro chromosome aberration (CA) test. On the basis of publicly available CA-test results of more than 650 chemical substances, half of which are drug-like compounds, we generated two different computational models. The first model was realized using the (Q)SAR tool MCASE. Results obtained with this model indicate a limited performance (53%) for the assessment of a chromosome-damaging potential (sensitivity), whereas CA-test negative compounds were correctly predicted with a specificity of 75%. The low sensitivity of this model might be explained by the fact that the underlying 2D-structural descriptors only describe part of the molecular mechanism leading to the induction of chromosome aberrations, that is, direct drug-DNA interactions. The second model was constructed with a more sophisticated machine learning approach and generated a classification model based on 14 molecular descriptors, which were obtained after feature selection. The performance of this model was superior to the MCASE model, primarily because of an improved sensitivity, suggesting that the more complex molecular descriptors in combination with statistical learning approaches are better suited to model the complex nature of mechanisms leading to a positive effect in the CA-test. An analysis of misclassified pharmaceuticals by this model showed that a large part of the false-negative predicted compounds were uniquely positive in the CA-test but lacked a genotoxic potential in other mutagenicity tests of the regulatory testing battery, suggesting that biologically nonsignificant mechanisms could be responsible for the observed positive CA-test result. Since such mechanisms are not amenable to modeling approaches it is suggested that a positive prediction made by the model reflects a biologically significant genotoxic potential. An integration of the machine-learning model as a screening tool in early discovery phases of drug development is proposed.

Chromosomes↗
PubMed2006

Rat toxicogenomic study reveals analytical consistency across microarray platforms.

To validate and extend the findings of the MicroArray Quality Control (MAQC) project, a biologically relevant toxicogenomics data set was generated using 36 RNA samples from rats treated with three chemicals (aristolochic acid, riddelliine and comfrey) and each sample was hybridized to four microarray platforms. The MAQC project assessed concordance in intersite and cross-platform comparisons and the impact of gene selection methods on the reproducibility of profiling data in terms of differentially expressed genes using distinct reference RNA samples. The real-world toxicogenomic data set reported here showed high concordance in intersite and cross-platform comparisons. Further, gene lists generated by fold-change ranking were more reproducible than those obtained by t-test P value or Significance Analysis of Microarrays. Finally, gene lists generated by fold-change ranking with a nonstringent P-value cutoff showed increased consistency in Gene Ontology terms and pathways, and hence the biological impact of chemical exposure could be reliably deduced from all platforms analyzed.

Animals↗
PubMed2004

Toxicogenomics and systems toxicology: aims and prospects.

Toxicogenomics combines transcript, protein and metabolite profiling with conventional toxicology to investigate the interaction between genes and environmental stress in disease causation. The patterns of altered molecular expression that are caused by specific exposures or disease outcomes have revealed how several toxicants act and cause disease. Despite these success stories, the field faces noteworthy challenges in discriminating the molecular basis of toxicity. We argue that toxicology is gradually evolving into a systems toxicology that will eventually allow us to describe all the toxicological interactions that occur within a living system under stress and use our knowledge of toxicogenomic responses in one species to predict the modes-of-action of similar agents in other species.

Animals↗
PubMed2003

Environmental health moves into the 21st century.

Over the past half century, environmental health research has branched from a descriptive, observational process into one of hypothesis driven and mechanistically based science. Nevertheless, the meaning of observed effects of exposures in experimental systems to human public health remains elusive. Recent advances in genetics and "omics" hold great promise to further our abilities to assess potential human health effects and to manage exposures properly. But the comfort of 100% certainty will not be available in the foreseeable future, leaving us with the challenge of designing relevant experiments and test systems upon which to base "logical" policy in risk management.

Animals↗
PubMed2003

Toxicity characterization of environmental chemicals by the US National Toxicology Program: an overview.

The US National Toxicology Program (NTP) is an interagency program whose mission is to evaluate agents of public health concern by developing and applying the tools of modern toxicology and molecular biology. Chemicals substances or physical agents selected for toxicology and carcinogenesis evaluations by the NTP are usually studied in a series of subacute (14-day exposure), subchronic (90-day exposure) and chronic (2-year exposure) studies in rodents. The NTP has published more than 500 reports of the findings and conclusions from its toxicology and carcinogenesis studies. In more specialized studies, the NTP also evaluates adverse effects on the structure and function of the immune, reproductive, nervous, and respiratory systems. The program attempts to evaluate and appropriately incorporate new technologies to improve the way we study the toxicity of chemicals. For example, the program has extensively evaluated several transgenic mouse models for their potential use as short-term cancer screens and has been a full participant in an international effort to examine their usefulness in pharmaceutical registration. Toxicogenomics, an emerging scientific field that examines the expression of thousands of genes simultaneously in response to chemical exposure, holds promise for future application to better understand the underlying mechanisms of chemical toxicity. A number of public health issues being addressed by the NTP are not only of national importance but also have global impact, such as the potential for endocrine disruptors to influence development and carcinogenesis and the safety of herbal medicines and dietary supplements. The program participates in the preparation of national and international toxicity testing guidelines and the findings from NTP studies are widely used for risk assessments by international organizations and federal agencies. The NTP maintains databases that contain toxicity, and health and safety information on a large number of chemicals. These databases are available from the NTP web site (http://ntp-server.niehs.nih.gov) and are accessed over 100000 times a month from around the world.

Animals↗
PubMedDate not supplied

Predictive models of hepatotoxicity using gene expression data from primary rat hepatocytes.

With the aim of evaluating the usefulness of an in vitro system for assessing the potential hepatotoxicity of compounds, the paper describes several methods of obtaining mathematical models for the prediction of compound-induced toxicity in vivo. These models are based on data derived from treating rat primary hepatocytes with various compounds, and thereafter using microarrays to obtain gene expression 'profiles' for each compound. Predictive models were constructed so as to reduce the number of 'probesets' (genes) required, and subjected to rigorous cross-validation. Since there are a number of possible approaches to derive predictive models, several distinct modelling strategies were applied to the same data set, and the outcomes were compared and contrasted. While all the strategies tested showed significant predictive capability, it was interesting to note that the different approaches generated models based on widely disparate probesets. This implies that while these models may be useful in ascribing relative potential toxicity to compounds, they are unlikely to provide significant information on underlying toxicity mechanisms. Improved predictivity will be obtained through the generation of more comprehensive gene expression databases, covering more 'toxicity space', and by the development of models that maximize the observation, and combination, of individual differences between compounds.

Animals↗