Toxicogenomics is the study of the influence of toxic or potentially toxic substances on gene expression in different tissues.
Understanding the gene regulation effect of a toxic substance contributes to the understanding of the toxicity mechanism of that substance.
Toxicogenomic research based on in vitro studies using human cell lines and in vivo studies using animal models (rats, dogs, mice, etc.) is an important step in the testing of new medicinal products.
Although classic toxicological tests are still useful, gene expression analysis (such as DNA microarray technology) is having an increasing impact on toxicology studies.
DNAVision provides GLP toxicogenomic studies using the latest genomic technologies.
In DNAVision in a high quality environment (ISO17025 and GLP) we use the Affymetrix technology and more specially the ToxFX™ Analysis Suite which provides a complete toxicogenomics solution—from protocols and microarrays for generating gene expression data to an automated analysis and a final toxicological report enabling rapid access to information capable of impacting the decision-making process—to help researchers better understand compound safety issues in early drug discovery and development. The Suite offers an easy-to-use and rapid assay that combines Affymetrix microarrays with an automated analysis developed by Iconix Biosciences.
Researchers can generate a compound safety profile within minutes of submitting gene expression data; the profile reports predicted safety issues for more than 50 toxicological outcomes, the genes that are likely to be most important in relation to those problems and the biological pathways that are most likely to play a role in any predicted toxicity. These results enable decision-making far sooner than the weeks or months necessary to produce a typical pathology report. The ToxFX analysis accomplishes this task by using several tools including Iconix' DrugMatrix reference database, Drug Signatures and Pathway Impact analysis.
A final comprehensive report detailing the study design and its findings is immediately ready to be shared with the project team to help:
We can use either the whole genome GeneChip Rat Genome 230 2.0 Array or the focused GeneChip Rat ToxFX 1.0 Array, representing a subset of genes carefully selected for use with the ToxFX Analysis Suite. Considerations for each array are:
Each report study is fully documented in a comprehensive and easy-to-read report. The Report is automatically generated as a PDF document and provides an in-depth summary of all aspects of the study and its results. Data are summarized in the report at a variety of levels allowing the user to first get an overall impression of the study outcome and then delve deeper into specific results of interest. Each Report is written using standard toxicology terminology and is designed to be standalone documentation of the study.
The different parts are:
ExecutiveSummary
The Executive summary is a single-page overview of the complete Report. It presents key signature, pathway responses and gene expression responses along with information on the experimental protocol and experiment quality. It provides a text level view of the report contents presented in a form that can be read in five to ten minutes.
QualityControl
The quality control module confirms the correlation among replicate animal treatments before data are submitted for analysis. It is intended to supplement the standard Affymetrix quality controls. Close correlation between replicate animals is a prerequisite for a successful analysis and lack of correlation flags potential errors in the sample labeling or submission.
Drug Signatures
Drug Signatures link patterns of gene expression to toxicological endpoints such as histopathology and clinical chemistry as well as to pharmacologic observations and drug structure classes. Drug Signatures translate highly complex gene expression data into language that is more familiar to the toxicologist. The results are easy to interpret, provide an early warning of potential toxicological effects and can be used to generate testable hypotheses and as an entry point for deeper analysis.
P450 Panel
The p450 panel is an expression-level screen of key cytochrome p450 genes. This allows early and sensitive screening for a total of 63 different p450 responses. The report provides the expression level response for each transcript as well as an overview of the response to drugs in different tissues across the DrugMatrix database. It is widely understood that the expression levels of many p450 genes are often non-specifically perturbed. Comparison to our reference data set ensures that accurate distinctions can be made between non-specific and relevant changes.
Pathways
The pathways provided in the report are functional gene groupings based on critical biological processes and key toxicological responses. Many gene products are involved in both biological processes and in adaptive, defensive or reparative responses to a xenobiotic insult. Most pathways in the literature are constructed based only on the biological function of the genes. In contrast, the pathways in the report focus on processes important to understanding toxicological responses in liver, kidney and heart. Pathway legends provide descriptions and curated background information for these functions. Pathways and annotations are based on extensive literature surveys and tailored to provide optimal information necessary to understand mechanism of action and mechanism of toxicity.
Gene-level information
The report contains expression information on genes that are most significantly perturbed in pathways or are the most consistently up and down regulated in the submitted set of experiments. These up and down regulated genes may act as indicators of responses outside the toxicological pathways represented in the report.
The report provides a comprehensive analysis of the Toxicogenomic properties of a specific drug. It is organized in a way that is easy to read and navigate, and it provides the most relevant interpretations that can be used by a drug safety team.