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Nucleic Acids Research Jan 2021The public Comparative Toxicogenomics Database (CTD; http://ctdbase.org/) is an innovative digital ecosystem that relates toxicological information for chemicals, genes,...
The public Comparative Toxicogenomics Database (CTD; http://ctdbase.org/) is an innovative digital ecosystem that relates toxicological information for chemicals, genes, phenotypes, diseases, and exposures to advance understanding about human health. Literature-based, manually curated interactions are integrated to create a knowledgebase that harmonizes cross-species heterogeneous data for chemical exposures and their biological repercussions. In this biennial update, we report a 20% increase in CTD curated content and now provide 45 million toxicogenomic relationships for over 16 300 chemicals, 51 300 genes, 5500 phenotypes, 7200 diseases and 163 000 exposure events, from 600 comparative species. Furthermore, we increase the functionality of chemical-phenotype content with new data-tabs on CTD Disease pages (to help fill in knowledge gaps for environmental health) and new phenotype search parameters (for Batch Query and Venn analysis tools). As well, we introduce new CTD Anatomy pages that allow users to uniquely explore and analyze chemical-phenotype interactions from an anatomical perspective. Finally, we have enhanced CTD Chemical pages with new literature-based chemical synonyms (to improve querying) and added 1600 amino acid-based compounds (to increase chemical landscape). Together, these updates continue to augment CTD as a powerful resource for generating testable hypotheses about the etiologies and molecular mechanisms underlying environmentally influenced diseases.
Topics: Databases, Chemical; Databases, Factual; Databases, Genetic; Gene-Environment Interaction; Genome, Human; Genomics; Genotype; Humans; Internet; Knowledge Bases; Organ Specificity; Phenotype; Prescription Drugs; Software; Toxicogenetics; Xenobiotics
PubMed: 33068428
DOI: 10.1093/nar/gkaa891 -
Frontiers in Genetics 2018Toxicogenomics is the study of the molecular effects of chemical, biological and physical agents in biological systems, with the aim of elucidating toxicological...
Toxicogenomics is the study of the molecular effects of chemical, biological and physical agents in biological systems, with the aim of elucidating toxicological mechanisms, building predictive models and improving diagnostics. The vast majority of toxicogenomics data has been generated at the transcriptome level, including RNA-seq and microarrays, and large quantities of drug-treatment data have been made publicly available through databases and repositories. Besides the identification of differentially expressed genes (DEGs) from case-control studies or drug treatment time series studies, bioinformatics methods have emerged that infer gene expression data at the molecular network and pathway level in order to reveal mechanistic information. In this work we describe different resources and tools that have been developed by us and others that relate gene expression measurements with known pathway information such as over-representation and gene set enrichment analyses. Furthermore, we highlight approaches that integrate gene expression data with molecular interaction networks in order to derive network modules related to drug toxicity. We describe the two main parts of the approach, i.e., the construction of a suitable molecular interaction network as well as the conduction of network propagation of the experimental data through the interaction network. In all cases we apply methods and tools to publicly available rat data on anthracyclines, an important class of anti-cancer drugs that are known to induce severe cardiotoxicity in patients. We report the results and functional implications achieved for four anthracyclines (doxorubicin, epirubicin, idarubicin, and daunorubicin) and compare the information content inherent in the different computational approaches.
PubMed: 30405693
DOI: 10.3389/fgene.2018.00484 -
Genes and Environment : the Official... Apr 2021Formaldehyde is a widely used but highly reactive and toxic chemical. The International Agency for Research on Cancer classifies formaldehyde as a Group 1 carcinogen,... (Review)
Review
Formaldehyde is a widely used but highly reactive and toxic chemical. The International Agency for Research on Cancer classifies formaldehyde as a Group 1 carcinogen, based on nasopharyngeal cancer and leukemia studies. However, the correlation between formaldehyde exposure and leukemia incidence is a controversial issue. To understand the association between formaldehyde exposure and leukemia, we explored biological networks based on formaldehyde-related genes retrieved from public and commercial databases. Through the literature-based network approach, we summarized qualitative associations between formaldehyde exposure and leukemia. Our results indicate that oxidative stress-mediated genetic changes induced by formaldehyde could disturb the hematopoietic system, possibly leading to leukemia. Furthermore, we suggested major genes that are thought to be affected by formaldehyde exposure and associated with leukemia development. Our suggestions can be used to complement experimental data for understanding and identifying the leukemogenic mechanism of formaldehyde.
PubMed: 33845901
DOI: 10.1186/s41021-021-00183-5 -
Nucleic Acids Research Jan 2023The Comparative Toxicogenomics Database (CTD; http://ctdbase.org/) harmonizes cross-species heterogeneous data for chemical exposures and their biological repercussions...
The Comparative Toxicogenomics Database (CTD; http://ctdbase.org/) harmonizes cross-species heterogeneous data for chemical exposures and their biological repercussions by manually curating and interrelating chemical, gene, phenotype, anatomy, disease, taxa, and exposure content from the published literature. This curated information is integrated to generate inferences, providing potential molecular mediators to develop testable hypotheses and fill in knowledge gaps for environmental health. This dual nature, acting as both a knowledgebase and a discoverybase, makes CTD a unique resource for the scientific community. Here, we report a 20% increase in overall CTD content for 17 100 chemicals, 54 300 genes, 6100 phenotypes, 7270 diseasesĀ and 202 000 exposure statements. We also present CTD Tetramers, a novel tool that computationally generates four-unit information blocks connecting a chemical, gene, phenotype, and disease to construct potential molecular mechanistic pathways. Finally, we integrate terms for human biological media used in the CTD Exposure module to corresponding CTD Anatomy pages, allowing users to survey the chemical profiles for any tissue-of-interest and see how these environmental biomarkers are related to phenotypes for any anatomical site. These, and other webpage visual enhancements, continue to promote CTD as a practical, user-friendly, and innovative resource for finding information and generating testable hypotheses about environmental health.
Topics: Humans; Toxicogenetics; Databases, Factual; Phenotype
PubMed: 36169237
DOI: 10.1093/nar/gkac833 -
Environmental Health Perspectives Oct 2020Some 20 y ago, scientific and regulatory communities identified the potential of omics sciences (genomics, transcriptomics, proteomics, metabolomics) to improve chemical...
BACKGROUND
Some 20 y ago, scientific and regulatory communities identified the potential of omics sciences (genomics, transcriptomics, proteomics, metabolomics) to improve chemical risk assessment through development of toxicogenomics. Recognizing that regulators adopt new scientific methods cautiously given accountability to diverse stakeholders, the scope and pace of adoption of toxicogenomics tools and data have nonetheless not met the ambitious, early expectations of omics proponents.
OBJECTIVE
Our objective was, therefore, to inventory, investigate, and derive insights into drivers of and obstacles to adoption of toxicogenomics in chemical risk assessment. By invoking established social science frameworks conceptualizing innovation adoption, we also aimed to develop recommendations for proponents of toxicogenomics and other new approach methodologies (NAMs).
METHODS
We report findings from an analysis of 56 scientific and regulatory publications from 1998 through 2017 that address the adoption of toxicogenomics for chemical risk assessment. From this purposeful sample of toxicogenomics discourse, we identified major categories of drivers of and obstacles to adoption of toxicogenomics tools and data sets. We then mapped these categories onto social science frameworks for conceptualizing innovation adoption to generate actionable insights for proponents of toxicogenomics.
DISCUSSION
We identify the most salient drivers and obstacles. From 1998 through 2017, adoption of toxicogenomics was understood to be helped by drivers such as those we labeled , , and but hindered by obstacles such as those we labeled , , and . Leveraging social science frameworks, we find that arguments for adoption that draw on the most salient drivers, which emphasize superior and novel functionality of omics as rationales, overlook potential adopters' key concerns: simplicity of use and compatibility with existing practices. We also identify two perspectives-innovation-centric and adopter-centric-on omics adoption and explain how overreliance on the former may be undermining efforts to promote toxicogenomics. https://doi.org/10.1289/EHP6500.
Topics: Computational Biology; Environmental Policy; Genomics; Humans; Metabolomics; Risk Assessment; Social Sciences; Toxicogenetics
PubMed: 33112659
DOI: 10.1289/EHP6500 -
The American Journal of Medicine Dec 2021Each of us reflects a unique convergence of DNA and the environment. Over the past 2 decades, huge biobanks linked to electronic medical records have positioned the... (Review)
Review
Each of us reflects a unique convergence of DNA and the environment. Over the past 2 decades, huge biobanks linked to electronic medical records have positioned the clinical and scientific communities to understand the complex genetic architecture underlying many common diseases. Although these efforts are producing increasingly accurate gene-based risk prediction algorithms for use in routine clinical care, the algorithms often fail to include environmental factors. This review explores the concept of heritability (genetic vs nongenetic determinants of disease), with emphasis on the role of environmental factors as risk determinants for common complex diseases influenced by air and water quality. Efforts to define patient exposure to specific toxicants in practice-based data sets will deepen our understanding of diseases with low heritability, and improved land management practices will reduce the burden of disease.
Topics: Air Pollution; Environmental Exposure; Gene-Environment Interaction; Humans; Pulmonary Disease, Chronic Obstructive; Renal Insufficiency, Chronic; Toxicogenetics; Water Quality
PubMed: 34343516
DOI: 10.1016/j.amjmed.2021.07.006 -
International Journal of Environmental... Nov 2019The last decade witnessed extraordinary advances in "omics" methods, particularly transcriptomics, proteomics and metabolomics, enabling toxicologists to integrate... (Review)
Review
The last decade witnessed extraordinary advances in "omics" methods, particularly transcriptomics, proteomics and metabolomics, enabling toxicologists to integrate toxicokinetics and toxicodynamics with mechanistic insights on the mode-of-action of noxious chemicals, single or combined. The toxicology of mixtures is, nonetheless, a most challenging enterprise, especially for environmental toxicologists and ecotoxicologists, who invariably deal with chemical mixtures, many of which contain unknowns. Despite costs and demanding computations, the systems toxicology framework, of which "omics" is a major component, endeavors extracting adverse outcome pathways for complex mixtures. Still, the interplay between the multiple components of gene expression and cell metabolism tends to be overlooked. As an example, the proteome allocates DNA methyltransferases whose altered transcription or loss of function by action of chemicals can have a global impact on gene expression in the cell. On the other hand, chemical insult can produce reactive metabolites and radicals that can intercalate or bind to DNA as well as to enzymes and structural proteins, compromising their activity. These examples illustrate the importance of exploring multiple "omes" and the purpose of "omics" and multi-"omics" for building truly predictive models of hazard and risk. Here we will review the state-of-the-art of toxicogenomics highlighting successes, shortcomings and perspectives for next-generation environmental toxicologists.
Topics: Ecotoxicology; Gene Expression; Hazardous Substances; Humans; Methyltransferases; Toxicogenetics
PubMed: 31779274
DOI: 10.3390/ijerph16234718 -
Toxicological Sciences : An Official... Dec 2011Pentamethyl-6-chromanol (PMCol), a chromanol-type compound related to vitamin E, was proposed as an anticancer agent with activity against androgen-dependent cancers. In...
Pentamethyl-6-chromanol (PMCol), a chromanol-type compound related to vitamin E, was proposed as an anticancer agent with activity against androgen-dependent cancers. In repeat dose-toxicity studies in rats and dogs, PMCol caused hepatotoxicity, nephrotoxicity, and hematological effects. The objectives of this study were to determine the mechanisms of the observed toxicity and identify sensitive early markers of target organ injury by integrating classical toxicology, toxicogenomics, and metabolomic approaches. PMCol was administered orally to male Sprague-Dawley rats at 200 and 2000 mg/kg daily for 7 or 28 days. Changes in clinical chemistry included elevated alanine aminotransferase, total bilirubin, cholesterol and triglycerides-indicative of liver toxicity that was confirmed by microscopic findings (periportal hepatocellular hydropic degeneration and cytomegaly) in treated rats. Metabolomic evaluations of liver revealed time- and dose-dependent changes, including depletion of total glutathione and glutathione conjugates, decreased methionine, and increased S-adenosylhomocysteine, cysteine, and cystine. PMCol treatment also decreased cofactor levels, namely, FAD and increased NAD(P)+. Microarray analysis of liver found that differentially expressed genes were enriched in the glutathione and cytochrome P450 pathways by PMCol treatment. Reverse transcription-polymerase chain reaction of six upregulated genes and one downregulated gene confirmed the microarray results. In conclusion, the use of metabolomics and toxicogenomics demonstrates that chronic exposure to high doses of PMCol induces liver damage and dysfunction, probably due to both direct inhibition of glutathione synthesis and modification of drug metabolism pathways. Depletion of glutathione due to PMCol exposure ultimately results in a maladaptive response, increasing the consumption of hepatic dietary antioxidants and resulting in elevated reactive oxygen species levels associated with hepatocellular damage and deficits in liver function.
Topics: Animals; Biomarkers; Chemical and Drug Induced Liver Injury; Chromans; Gene Expression; Gene Expression Profiling; Kidney; Liver; Male; Metabolomics; Molecular Structure; Oligonucleotide Array Sequence Analysis; Organ Size; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Toxicogenetics
PubMed: 21920950
DOI: 10.1093/toxsci/kfr238 -
The Journal of Nutrition Mar 2011Minerals are essential and toxic elements that have an impact on human health. Although we have learned a tremendous amount about the metabolism, biological roles, and... (Review)
Review
Minerals are essential and toxic elements that have an impact on human health. Although we have learned a tremendous amount about the metabolism, biological roles, and health effects of minerals with the tools of biochemistry, cell biology, and molecular genetics, there are gaps in our knowledge of mineral biology that will benefit from new approaches. Forward genetics, whereby variations in phenotypes are mapped to natural genetic variation in the genome, has been successfully used to increase our understanding of many biologically important traits but has not yet been used extensively for mineral metabolism. In addition, the well-appreciated existence of interactions between minerals justifies a broader, systems approach to the study of mineral metabolism, i.e., ionomics. This short review will explain the value of forward genetics and ionomics as tools for exploring mammalian mineral metabolism.
Topics: Animals; Diet; Genetic Phenomena; Genetic Variation; Humans; Minerals; Nutrigenomics; Plants; Research Design; Systems Biology; Toxicogenetics
PubMed: 21270371
DOI: 10.3945/jn.110.128736 -
Toxicological Sciences : An Official... Mar 2011As one reflects back through the past 50 years of scientific research, a significant accomplishment was the advance into the genomic era. Basic research scientists have... (Review)
Review
As one reflects back through the past 50 years of scientific research, a significant accomplishment was the advance into the genomic era. Basic research scientists have uncovered the genetic code and the foundation of the most fundamental building blocks for the molecular activity that supports biological structure and function. Accompanying these structural and functional discoveries is the advance of techniques and technologies to probe molecular events, in time, across environmental and chemical exposures, within individuals, and across species. The field of toxicology has kept pace with advances in molecular study, and the past 50 years recognizes significant growth and explosive understanding of the impact of the compounds and environment to basic cellular and molecular machinery. The advancement of molecular techniques applied in a whole-genomic capacity to the study of toxicant effects, toxicogenomics, is no doubt a significant milestone for toxicological research. Toxicogenomics has also provided an avenue for advancing a joining of multidisciplinary sciences including engineering and informatics in traditional toxicological research. This review will cover the evolution of the field of toxicogenomics in the context of informatics integration its current promise, and limitations.
Topics: Animals; Biomarkers; Computational Biology; DNA; Gene Expression; Genome; Humans; Microarray Analysis; Toxicogenetics; Toxicology; Xenobiotics
PubMed: 21177775
DOI: 10.1093/toxsci/kfq373