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Environmental Health Perspectives Mar 2004The marriage of toxicology and genomics has created not only opportunities but also novel informatics challenges. As with the larger field of gene expression analysis,... (Review)
Review
The marriage of toxicology and genomics has created not only opportunities but also novel informatics challenges. As with the larger field of gene expression analysis, toxicogenomics faces the problems of probe annotation and data comparison across different array platforms. Toxicogenomics studies are generally built on standard toxicology studies generating biological end point data, and as such, one goal of toxicogenomics is to detect relationships between changes in gene expression and in those biological parameters. These challenges are best addressed through data collection into a well-designed toxicogenomics database. A successful publicly accessible toxicogenomics database will serve as a repository for data sharing and as a resource for analysis, data mining, and discussion. It will offer a vehicle for harmonizing nomenclature and analytical approaches and serve as a reference for regulatory organizations to evaluate toxicogenomics data submitted as part of registrations. Such a database would capture the experimental context of in vivo studies with great fidelity such that the dynamics of the dose response could be probed statistically with confidence. This review presents the collaborative efforts between the European Molecular Biology Laboratory-European Bioinformatics Institute ArrayExpress, the International Life Sciences Institute Health and Environmental Science Institute, and the National Institute of Environmental Health Sciences National Center for Toxigenomics Chemical Effects in Biological Systems knowledge base. The goal of this collaboration is to establish public infrastructure on an international scale and examine other developments aimed at establishing toxicogenomics databases. In this review we discuss several issues common to such databases: the requirement for identifying minimal descriptors to represent the experiment, the demand for standardizing data storage and exchange formats, the challenge of creating standardized nomenclature and ontologies to describe biological data, the technical problems involved in data upload, the necessity of defining parameters that assess and record data quality, and the development of standardized analytical approaches.
Topics: Animals; Databases, Genetic; Humans; Information Storage and Retrieval; International Cooperation; Reference Values; Research Design; Terminology as Topic; Toxicogenetics
PubMed: 15033600
DOI: 10.1289/ehp.6697 -
Environmental Science & Technology Mar 2022Toxicogenomics and physiologically based pharmacokinetic (PBPK) models are useful approaches in chemical risk assessment, but the methodology to incorporate...
Toxicogenomics and physiologically based pharmacokinetic (PBPK) models are useful approaches in chemical risk assessment, but the methodology to incorporate toxicogenomic data into a PBPK model to inform risk assessment remains to be developed. This study aimed to develop a probabilistic human health risk assessment approach by integrating toxicogenomic dose-response data and PBPK modeling using perfluorooctane sulfonate (PFOS) as a case study. Based on the available human and mouse toxicogenomic data, we identified the differentially expressed genes (DEGs) at each exposure paradigm/duration. Kyoto Encyclopedia of Genes and Genomes and disease ontology enrichment analyses were conducted on the DEGs to identify significantly enriched pathways and diseases. The dose-response data of DEGs were analyzed using the Bayesian benchmark dose (BMD) method. Using a previously published PBPK model, the gene BMDs were converted to human equivalent doses (HEDs), which were summarized to pathway and disease HEDs and then extrapolated to reference doses (RfDs) by considering an uncertainty factor of 30 for mouse data and 10 for human data. The results suggested that the median RfDs at different exposure paradigms were similar to the 2016 U.S. Environmental Protection Agency's recommended RfD, while the RfDs for the most sensitive pathways and diseases were closer to the recent European Food Safety Authority's guidance values. In conclusion, genomic dose-response data and PBPK modeling can be integrated to become a useful alternative approach in risk assessment of environmental chemicals. This approach considers multiple endpoints, provides toxicity mechanistic insights, and does not rely on apical toxicity endpoints.
Topics: Alkanesulfonic Acids; Animals; Bayes Theorem; Fluorocarbons; Humans; Mice; Models, Biological; Risk Assessment; Toxicogenetics
PubMed: 35194992
DOI: 10.1021/acs.est.1c06479 -
Environmental Health Perspectives Dec 2005
Topics: Databases, Genetic; Gene Expression; Humans; Inflammation; Phenotype; Toxicogenetics
PubMed: 16330328
DOI: 10.1289/ehp.113-a794 -
Genomic Medicine Dec 2008
PubMed: 19466583
DOI: 10.1007/s11568-009-9126-1 -
Current Issues in Molecular Biology Apr 2002Toxicogenomics is a rapidly developing discipline that promises to aid scientists in understanding the molecular and cellular effects of chemicals in biological systems.... (Review)
Review
Toxicogenomics is a rapidly developing discipline that promises to aid scientists in understanding the molecular and cellular effects of chemicals in biological systems. This field encompasses global assessment of biological effects using technologies such as DNA microarrays or high throughput NMR and protein expression analysis. This review provides an overview of advancing multiple approaches (genomic, proteomic, metabonomic) that may extend our understanding of toxicology and highlights the importance of coupling such approaches with classical toxicity studies.
Topics: Animals; Chemistry, Pharmaceutical; DNA, Complementary; Databases as Topic; Drug Design; Drug Industry; Gene Expression; Genomics; Humans; Ligands; Magnetic Resonance Spectroscopy; Models, Biological; Oligonucleotide Array Sequence Analysis; Pharmacogenetics; Phenotype; RNA, Messenger; Rats; Toxicology
PubMed: 11931569
DOI: No ID Found -
Reproductive Toxicology (Elmsford, N.Y.) Sep 2020The use of genomic approaches in toxicological studies has greatly increased our ability to define the molecular profiles of environmental chemicals associated with... (Review)
Review
The use of genomic approaches in toxicological studies has greatly increased our ability to define the molecular profiles of environmental chemicals associated with developmental neurotoxicity (DNT). Integration of these approaches with adverse outcome pathways (AOPs), a framework that translates environmental exposures to adverse developmental phenotypes, can potentially inform DNT testing strategies. Here, using retinoic acid (RA) as a case example, we demonstrate that the integration of toxicogenomic profiles into the AOP framework can be used to establish a paradigm for chemical testing. RA is a critical regulatory signaling molecule involved in multiple aspects of mammalian central nervous system (CNS) development, including hindbrain formation/patterning and neuronal differentiation, and imbalances in RA signaling pathways are linked with DNT. While the mechanisms remain unresolved, environmental chemicals can cause DNT by disrupting the RA signaling pathway. First, we reviewed literature evidence of RA and other retinoid exposures and DNT to define a provisional AOP related to imbalances in RA embryonic bioavailability and hindbrain development. Next, by integrating toxicogenomic datasets, we defined a relevant transcriptomic signature associated with RA-induced developmental neurotoxicity (RA-DNT) in human and rodent models that was tested against zebrafish model data, demonstrating potential for integration into an AOP framework. Finally, we demonstrated how these approaches may be systematically utilized to identify chemical hazards by testing the RA-DNT signature against azoles, a proposed class of compounds that alters RA-signaling. The provisional AOP from this study can be expanded in the future to better define DNT biomarkers relevant to RA signaling and toxicity.
Topics: Adverse Outcome Pathways; Animals; Embryonic Development; Humans; Neurotoxicity Syndromes; Retinoids; Toxicity Tests; Toxicogenetics
PubMed: 32544423
DOI: 10.1016/j.reprotox.2020.06.007 -
Advanced Science (Weinheim,... Jan 2023Mechanistic toxicology provides a powerful approach to inform on the safety of chemicals and the development of safe-by-design compounds. Although toxicogenomics...
Mechanistic toxicology provides a powerful approach to inform on the safety of chemicals and the development of safe-by-design compounds. Although toxicogenomics supports mechanistic evaluation of chemical exposures, its implementation into the regulatory framework is hindered by uncertainties in the analysis and interpretation of such data. The use of mechanistic evidence through the adverse outcome pathway (AOP) concept is promoted for the development of new approach methodologies (NAMs) that can reduce animal experimentation. However, to unleash the full potential of AOPs and build confidence into toxicogenomics, robust associations between AOPs and patterns of molecular alteration need to be established. Systematic curation of molecular events to AOPs will create the much-needed link between toxicogenomics and systemic mechanisms depicted by the AOPs. This, in turn, will introduce novel ways of benefitting from the AOPs, including predictive models and targeted assays, while also reducing the need for multiple testing strategies. Hence, a multi-step strategy to annotate AOPs is developed, and the resulting associations are applied to successfully highlight relevant adverse outcomes for chemical exposures with strong in vitro and in vivo convergence, supporting chemical grouping and other data-driven approaches. Finally, a panel of AOP-derived in vitro biomarkers for pulmonary fibrosis (PF) is identified and experimentally validated.
Topics: Animals; Adverse Outcome Pathways; Risk Assessment; Toxicogenetics; Chemical Safety
PubMed: 36479815
DOI: 10.1002/advs.202203984 -
Nature Communications Feb 2017The laboratory rat has been used as a surrogate to study human biology for more than a century. Here we present the first genome-scale network reconstruction of Rattus...
The laboratory rat has been used as a surrogate to study human biology for more than a century. Here we present the first genome-scale network reconstruction of Rattus norvegicus metabolism, iRno, and a significantly improved reconstruction of human metabolism, iHsa. These curated models comprehensively capture metabolic features known to distinguish rats from humans including vitamin C and bile acid synthesis pathways. After reconciling network differences between iRno and iHsa, we integrate toxicogenomics data from rat and human hepatocytes, to generate biomarker predictions in response to 76 drugs. We validate comparative predictions for xanthine derivatives with new experimental data and literature-based evidence delineating metabolite biomarkers unique to humans. Our results provide mechanistic insights into species-specific metabolism and facilitate the selection of biomarkers consistent with rat and human biology. These models can serve as powerful computational platforms for contextualizing experimental data and making functional predictions for clinical and basic science applications.
Topics: Animals; Biomarkers; Computational Biology; Datasets as Topic; Gene Expression Profiling; Hepatocytes; Humans; Metabolic Networks and Pathways; Metabolomics; Models, Biological; Rats; Species Specificity; Toxicogenetics
PubMed: 28176778
DOI: 10.1038/ncomms14250 -
PloS One 2013The Comparative Toxicogenomics Database (CTD; http://ctdbase.org/) is a public resource that curates interactions between environmental chemicals and gene products, and... (Comparative Study)
Comparative Study
The Comparative Toxicogenomics Database (CTD; http://ctdbase.org/) is a public resource that curates interactions between environmental chemicals and gene products, and their relationships to diseases, as a means of understanding the effects of environmental chemicals on human health. CTD provides a triad of core information in the form of chemical-gene, chemical-disease, and gene-disease interactions that are manually curated from scientific articles. To increase the efficiency, productivity, and data coverage of manual curation, we have leveraged text mining to help rank and prioritize the triaged literature. Here, we describe our text-mining process that computes and assigns each article a document relevancy score (DRS), wherein a high DRS suggests that an article is more likely to be relevant for curation at CTD. We evaluated our process by first text mining a corpus of 14,904 articles triaged for seven heavy metals (cadmium, cobalt, copper, lead, manganese, mercury, and nickel). Based upon initial analysis, a representative subset corpus of 3,583 articles was then selected from the 14,094 articles and sent to five CTD biocurators for review. The resulting curation of these 3,583 articles was analyzed for a variety of parameters, including article relevancy, novel data content, interaction yield rate, mean average precision, and biological and toxicological interpretability. We show that for all measured parameters, the DRS is an effective indicator for scoring and improving the ranking of literature for the curation of chemical-gene-disease information at CTD. Here, we demonstrate how fully incorporating text mining-based DRS scoring into our curation pipeline enhances manual curation by prioritizing more relevant articles, thereby increasing data content, productivity, and efficiency.
Topics: Algorithms; Data Mining; Databases, Factual; Disease; Documentation; Humans; Metals, Heavy; Molecular Sequence Annotation; Publications; Reproducibility of Results; Toxicogenetics
PubMed: 23613709
DOI: 10.1371/journal.pone.0058201 -
Toxicological Sciences : An Official... Feb 2022Whether glyphosate-based herbicides (GBHs) are more potent than glyphosate alone at activating cellular mechanisms, which drive carcinogenesis remain controversial. As...
Whether glyphosate-based herbicides (GBHs) are more potent than glyphosate alone at activating cellular mechanisms, which drive carcinogenesis remain controversial. As GBHs are more cytotoxic than glyphosate, we reasoned they may also be more capable of activating carcinogenic pathways. We tested this hypothesis by comparing the effects of glyphosate with Roundup GBHs both in vitro and in vivo. First, glyphosate was compared with representative GBHs, namely MON 52276 (European Union), MON 76473 (United Kingdom), and MON 76207 (United States) using the mammalian stem cell-based ToxTracker system. Here, MON 52276 and MON 76473, but not glyphosate and MON 76207, activated oxidative stress and unfolded protein responses. Second, molecular profiling of liver was performed in female Sprague-Dawley rats exposed to glyphosate or MON 52276 (at 0.5, 50, and 175 mg/kg bw/day glyphosate) for 90 days. MON 52276 but not glyphosate increased hepatic steatosis and necrosis. MON 52276 and glyphosate altered the expression of genes in liver reflecting TP53 activation by DNA damage and circadian rhythm regulation. Genes most affected in liver were similarly altered in kidneys. Small RNA profiling in liver showed decreased amounts of miR-22 and miR-17 from MON 52276 ingestion. Glyphosate decreased miR-30, whereas miR-10 levels were increased. DNA methylation profiling of liver revealed 5727 and 4496 differentially methylated CpG sites between the control and glyphosate and MON 52276 exposed animals, respectively. Apurinic/apyrimidinic DNA damage formation in liver was increased with glyphosate exposure. Altogether, our results show that Roundup formulations cause more biological changes linked with carcinogenesis than glyphosate.
Topics: Animals; DNA Damage; Female; Glycine; Herbicides; Mammals; MicroRNAs; Rats; Rats, Sprague-Dawley; Stem Cells; Toxicogenetics; Glyphosate
PubMed: 34850229
DOI: 10.1093/toxsci/kfab143