A Decade of Toxicogenomic Research and Its Contribution to Toxicological Science

Article (PDF Available)inToxicological Sciences 130(2) · July 2012with42 Reads
DOI: 10.1093/toxsci/kfs223 · Source: PubMed
Toxicogenomics enjoyed considerable attention as a ground-breaking addition to conventional toxicology assays at its inception. However, the pace at which toxicogenomics was expected to perform has been tempered in recent years. Next to cost, the lack of advanced knowledge discovery and data mining tools significantly hampered progress in this new field of toxicological sciences. Recently, two of the largest toxicogenomics databases were made freely available to the public. These comprehensive studies are expected to stimulate knowledge discovery and development of novel data mining tools, which are essential to advance this field. In this review, we provide a concise summary of each of these two databases with a brief discussion on the commonalities and differences between them. We place our emphasis on some key questions in toxicogenomics and how these questions can be appropriately addressed with the two databases. Finally, we provide a perspective on the future direction of toxicogenomics and how new technologies such as RNA-Seq may impact this field.
    • "Acute, sublethal effects were also investigated using genes involved in the cellular stress response and endocrine regulation as endpoints . Toxicogenomics is gaining momentum because information concerning genes respond to different chemical compounds is highly powerful for identifying molecular mechanisms and cellular pathways specific to the mode of action of a number of toxicants and drugs (Chen et al., 2012). "
    [Show abstract] [Hide abstract] ABSTRACT: Several organic UV filters have hormonal activity in vertebrates, as demonstrated in fishes, rodents and human cells. Despite the accumulation of filter contaminants in aquatic systems, research on their effects on the endocrine systems of freshwaters invertebrates is scarce. In this work, the effects of five frequently used UV filters were investigated in embryos and larvae of Chironomus riparius, which is a reference organism in ecotoxicology. LC50 values for larvae as well as the percentage of eclosion of eggs were determined following exposures to: octyl-p-methoxycinnamate (OMC) also known as 2-ethylhexyl-4-methoxycinnamate (EHMC); 4-methylbenzylidene camphor (4MBC); 4-hydroxybenzophenone (4HB); octocrylene (OC); and octyldimethyl-p-aminobenzoate (OD-PABA). To assess sublethal effects, expression levels of the genes coding for the ecdysone receptor (EcR) and heat shock protein HSP70 were investigated as biomarkers for endocrine and stress effects at the cellular level. Life-stage-dependent sensitivity was found. In embryos, all of the UV filters provoked a significant overexpression of EcR at 24h after exposure. OC, 4MBC and OD-PABA also triggered transcriptional activation of the hsp70 stress gene in embryos. In contrast, in larvae, only 4MBC and OMC/EHMC increased EcR and hsp70 mRNA levels and OD-PABA upregulated only the EcR gene. These results revealed that embryos are particularly sensitive to UV filters, which affect endocrine regulation during development. Most UV filters also triggered the cellular stress response, and thus exhibit proteotoxic effects. The differences observed between embryos and larvae and the higher sensitivity of embryos highlight the importance of considering different life stages when evaluating the environmental risks of pollutants, particularly when analyzing endocrine effects.
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    • "Representative toxic substances are listed. For reference see: [1][2][3][4][5][6]8,9,17,19,20,24,28,36,37,52,78,81,94,120, 123,168,196,198,199]. Substance "
    [Show abstract] [Hide abstract] ABSTRACT: The interest in food toxicology is evident by the dependency of humankind on nutrition by virtue of their heterotrophic metabolism. By means of modern biochemistry, molecular and cell biology, computer science, bioinformatics as well as high-throughput and high-content screening technologies it has been possible to identify adverse effects and characterize potential toxicants in food. The mechanisms of toxicant actions are multifactorial but many toxic effects converge on the generation of oxidative stress and chronic inflammation resulting in cell death, aging and degenerative diseases. Integration of food toxicology data obtained throughout biochemical and cell-based _in vitro_, animal _in vivo_ and human clinical settings has enabled the establishment of alternative, highly predictable _in silico_ models. These systems utilize a combination of complex _in vitro_ cell-based models with computer-based algorithms. A decrease of rodent animal testing with its limitations of high costs, low throughput readouts, inconsistent responses, ethical issues and concerns of extrapolability to humans have led to an increased use of these but also alternative lower hierarchy surrogate animal models (e.g. _D. melagonaster_; _C. elegans_ or _D. rerio_) and efforts to integrate organotypic systems and stem cell-based assays. Despite those achievements, there are numerous challenges in various disciplines of food toxicology.
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    • "This also requires a mechanistic understanding of the underlying cellular processes (Bissell et al. 2001; Schimmel et al. 2004; Holt and Ju 2006; Russmann et al. 2009). Current advances in systems toxicology provide novel insights into central mechanisms involved in drug-induced toxicity (Waters and Fostel 2004; Heijne et al. 2005; Chen et al. 2012 ). Changes at different biological levels can nowadays be measured by -omics technologies to describe cellular alterations in response to toxic drug concentrations. "
    [Show abstract] [Hide abstract] ABSTRACT: Understanding central mechanisms underlying drug-induced toxicity plays a crucial role in drug development and drug safety. However, a translation of cellular in vitro findings to an actual in vivo context remains challenging. Here, physiologically based pharmacokinetic (PBPK) modeling was used for in vivo contextualization of in vitro toxicity data (PICD) to quantitatively predict in vivo drug response over time by integrating multiple levels of biological organization. Explicitly, in vitro toxicity data at the cellular level were integrated into whole-body PBPK models at the organism level by coupling in vitro drug exposure with in vivo drug concentration-time profiles simulated in the extracellular environment within the organ. PICD was exemplarily applied on the hepatotoxicant azathioprine to quantitatively predict in vivo drug response of perturbed biological pathways and cellular processes in rats and humans. The predictive accuracy of PICD was assessed by comparing in vivo drug response predicted for rats with observed in vivo measurements. To demonstrate clinical applicability of PICD, in vivo drug responses of a critical toxicity-related pathway were predicted for eight patients following acute azathioprine overdoses. Moreover, acute liver failure after multiple dosing of azathioprine was investigated in a patient case study by use of own clinical data. Simulated pharmacokinetic profiles were therefore related to in vivo drug response predicted for genes associated with observed clinical symptoms and to clinical biomarkers measured in vivo. PICD provides a generic platform to investigate drug-induced toxicity at a patient level and thus may facilitate individualized risk assessment during drug development.
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