Toxicogenomics Evolution Of The Field

Toxicogenomics evolved from early gene expression studies on the response of a biological system to a particular toxicant or panel of reference agents, toward more mature investigations that integrate several -omics domains with toxicology and pathology data (see Table 5.1). Exposure-specific and outcome-specific patterns of gene, protein, and metabolite profiles have been used to identify molecular changes that serve as biomarkers of toxicity [23,38-44] and provide insights into mechanisms of toxicity [45-55] and disease causation [56-60]. Critical to this evolution were extensive and ongoing genome sequencing and annotation efforts [61,62] and the ability to describe response profiles

TABLE 5.1 Scope and Evolution of Toxicogenomics

Study Aim

Key References

Toxicogenomics tools and model systems

Tissues used in toxicogenomics studies

Phenotypic anchoring

Classes of toxicants characterized

Toxicogenomics began with "toxicology-specific" cDNA microarrays designed to measure the levels of acute phase and xenobiotic-metabolizing enzymes such as cytochrome P450s [4,199]. These were superseded as commercial platforms were developed for toxicologically important species such as rat. The armamentarium of pre-clinical gene expression platforms was completed with the canine microarray [62]. It is now possible to use commercial oligonucleotide microarrays (see Table 5.3) to measure expression responses in species ranging from nematode (Caenorhabditis elegans), to frog (Xenopus laevis) and zebrafish (Danio rerio) to rodents (rat and mouse), to nonhuman primates and humans. Toxicogenomics tools for sentinel aquatic species have been developed as well [97]. Later experiments began to focus on more challenging subjects such as subcellular organelles [200], nonstandard tissue such as saliva [118], less well characterized species [201], genetic models of diseases [202], and integration of data from different-omics disciplines [46,54,59,97,105,138]. Additionally comprehensive studies of yeast have become increasingly important [170,171,203].

Most toxicogenomics studies to date have involved hepatotoxicants [23,36, 38-44,47,49,50,52-55,57,59,60,204], as the liver is the primary source of xenobiotic metabolism and detoxification and because liver injury is the principal reason for withdrawal of new drugs from the market [205]. Toxicogenomics studies have also addressed nephrotoxicity [44,45,51], neurotoxicity [206,207], reproductive toxicity [48], as well as lung toxicity [39,56], skin toxicity [208], and cardio toxicity [209].

Phenotypic anchoring relates expression profiles to specific adverse effects defined by conventional measures of toxicity such as histopathology or clinical chemistry [22,26,70].

Experiments have been designed to correlate expression patterns with disease pathologies such as necrosis, apoptosis, fibrosis, and inflammation [36,38,56,62,210], Additionally phenotypic anchoring can be used to provide biological context for toxicogenomics observations made at subtoxic doses [41,53].

Studies have examined responses to toxicants with established mechanisms of toxicity [38,43,44,49,50,52,60,211], environmental toxicants [57,97,208,212], and exposures to suprapharmacological levels of drugs [39,41,46,47,53,54,59,204,209].

TABLE 5.1 (Continued)

Study Aim

Key References

Examples of toxicant or stressor mechanisms Importance of reporting husbandry and other technical details

Commercial database resources for toxicogenomics profiles

Integration of toxicogenomics efforts

Integration of data domains

Adverse effects of acetaminophen [41,46,54,204,213], estrogenic agents [48,214], oxidant stress [203,215], and peroxisome proliferators [23,42,44,50,52] are among the main toxicants being studied.

Expression profiles are altered by experimental conditions, including the harvest method, the in vitro culture method, and the vehicle used to deliver an agent, time of day of sacrifice, and diet. Up to 9% of the transcripts in mouse liver fluctuated with circadian cycling [216]. These included genes controlling glucose metabolism and vesicle trafficking or cytoskeleton, as might be anticipated from changes in the diet of animals during the day and night. In addition transcript levels of Cyp17 and Cyp2a4, which are important for steroid synthesis, and Cyp2e1, which is important for detoxification of xenobiotics, fluctuated. These changes might be expected to impact the response to test agents and reflect a requirement to report the time of day of dosing and sacrifice, along with the diet, vehicle and harvest and culture methods, when summarizing or publishing results of toxicogenomics studies.

Toxicogenomics studies for the purpose of developing commercial databases have been performed by both GeneLogic and Iconix, <http://www.genelogic.com> and <http://www.iconixpharm.com/>. These companies have each gathered data from several hundreds of samples produced from short-term exposures of agents at pharmacological and toxicological dose levels. Customers of either company can access the respective databases to classify the mode-of-action of novel agents of interest.

Through such consortia as the ILSI Committee on the

Application of Toxicogenomics to Risk Assessment [63,64], the Toxicogenomics Research Consortium (TRC), and the Consortium on Metabonomics and Toxicology (COMET) [65], the technical factors affecting data can be identified and overcome, approaches to data analysis and interpretation can be agreed upon, and high-quality public datasets prepared. The field of toxicoproteomics is currently not represented by a consortium (see Human Proteome Organization HUPO in Table 5.3), while the ILSI Genomics Committee and the TRC are working toxicogenomics consortia in transcriptomics, and COMET is a working toxicogenomics consortium in metabonomics.

By integration of data a more complete picture of the expression profiles associated with a particular treatment can be obtained, not only of what the cell is planning (transcriptomics) but what occurred in the proteome and metabonome [46,54,97,138,217].

Note: Peroxisome proliferators are compounds that induce increased numbers of peroxisomes— single-membrane cytoplasmic organelles that metabolize long-chain fatty acids.

in genetically and toxicologically important species such as mouse, rat, dog, and human. Another important contribution to toxicogenomics has been the formation of collaborative research consortia [63-65] that bring together scientists from regulatory agencies, industrial laboratories, and academic and governmental institutions to identify and address important issues for the field.

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