Toxicogenomics

Abstract: The availability of genome-scale DNA sequence information and reagents has radically altered life-science research. This revolution has led to the development of a new scientific subdiscipline derived from a combination of the fields of toxicology and genomics. This subdiscipline, termed toxicogenomics, is concerned with the identification of potential human and environmental toxicants, and their putative mechanisms of action, through the use of genomics resources. One such resource is DNA microarrays or “chips,” which allow the monitoring of the expression levels of thousands of genes simultaneously. Here we propose a general method by which gene expression, as measured by cDNA microarrays, can be used as a highly sensitive and informative marker for toxicity. Our purpose is to acquaint the reader with the development and current state of microarray technology and to present our view of the usefulness of microarrays to the field of toxicology. Mol. Carcinog. 24:153‐ 159, 1999. © 1999 Wiley-Liss, Inc.

Abstract: The use of fish embryos is not regulated by current legislations on animal welfare and is therefore considered as a refinement, if not replacement of animal experiments. Fish embryos represent an attractive model for environmental risk assessment of chemicals since they offer the possibility to perform small-scale, high-throughput analyses. Beyond their application for determining the acute toxicity, fish embryos are also excellent models for studies aimed at the understanding of toxic mechanisms and the indication of possible adverse and long-term effects. Therefore, we have reviewed the scientific literature in order to indicate alternative applications of the fish embryo model with focus on embryos of the zebrafish. The analysis of the mode of action is important for the risk assessment of environmental chemicals and can assist in indicating adverse and long-term effects. Toxicogenomics present a promising approach to unravel the potential mechanisms. Therefore, we present examples of the use of zebrafish embryos to study the effect of chemicals on gene and protein patterns, and the potential implications of differential expression for toxicity. The possible application of other methods, such as kinase arrays or metabolomic profiling, is also highlighted. Furthermore, we show examples of toxicokinetic studies (bioconcentration, ABC transporters) and discuss limitations that might be caused by the potential barrier function of the chorion. Finally, we demonstrate that biomarkers of endocrine disruption, immune modulation, genotoxicity or chronic toxicity could be used as indicators or predictors of sub-acute and long-term effects. The zebrafish embryo represents a model with an impressive range of possible applications in environmental sciences. Particularly, the adaptation of molecular, system-wide approaches from biomedical research is likely to extend its use in ecotoxicology. Challenges for future research are (1) the identification of further suitable molecular markers as indicators of the mode of action, (2) the establishment of strong links between (molecular) effects in short-term assays in embryos and long-term (toxic) effects on individuals, (3) the definition of limitations of the model and (4) the development of tests that can be used for regulatory purposes.

Abstract: Drug-induced hepatotoxicity is a frequent cause of liver injury. The predominant clinical presentation is acute hepatitis and/or cholestasis, although almost any clinical pathological pattern of acute or chronic liver disease can occur. The pathogenesis of drug-induced liver disease usually involves the participation of the parent drug or metabolites that either directly affect the cell biochemistry or elicit an immune response. Each hepatotoxin is associated with a characteristic signature regarding the pattern of injury and latency. However, some drugs may exhibit >1 signature. Susceptibility to drug-induced hepatotoxicity is also influenced by genetic and environmental risk factors. Unpredictable, low-frequency, idiosyncratic reactions often occur on a background of a higher rate of mild asymptomatic liver injury and, although difficult to predict, they may be detected by monitoring serum alanine aminotransferase levels. Recent and future advances in toxicogenomics and proteomics should improve the identification of risk factors and the understanding of idiosyncratic hepatotoxicity.

Abstract: Authors Richard P Horgan / Louise C Kenny Key content: • ‘Omic’ technologies are primarily aimed at the universal detection of genes (genomics), mRNA (transcriptomics), proteins (proteomics) and metabolites (metabolomics) in a specific biological sample. • Omic technologies have a broad range of applications. • Genomic and transcriptomic research has progressed due to advances in microarray technology. • Mass spectrometry is the most common method used for the detection of analytes in proteomic and metabolomic research. • Data analysis is complex as a huge amount of data is generated and statistician and bioinformatician involvement in the process is essential. • Much of the omic research in obstetrics and gynaecology has concentrated on using the technology to develop screening tests for gynaecological cancers and obstetric complications.