CTD tetramers: a new online tool that computationally links curated chemicals, genes, phenotypes, and diseases to inform molecular mechanisms for environmental health.

The molecular mechanisms connecting environmental exposures to adverse endpoints are often unknown, reflecting knowledge gaps. At the Comparative Toxicogenomics Database (CTD), we developed a bioinformatics approach that integrates manually curated, literature-based interactions from CTD to generate a "CGPD-tetramer": a 4-unit block of information organized as a step-wise molecular mechanism linking an initiating Chemical, an interacting Gene, a Phenotype, and a Disease outcome. Here, we describe a novel, user-friendly tool called CTD Tetramers that generates these evidence-based CGPD-tetramers for any curated chemical, gene, phenotype, or disease of interest. Tetramers offer potential solutions for the unknown underlying mechanisms and intermediary phenotypes connecting a chemical exposure to a disease. Additionally, multiple tetramers can be assembled to construct detailed modes-of-action for chemical-induced disease pathways. As well, tetramers can help inform environmental influences on adverse outcome pathways (AOPs). We demonstrate the tool's utility with relevant use cases for a variety of environmental chemicals (eg, perfluoroalkyl substances, bisphenol A), phenotypes (eg, apoptosis, spermatogenesis, inflammatory response), and diseases (eg, asthma, obesity, male infertility). Finally, we map AOP adverse outcome terms to corresponding CTD terms, allowing users to query for tetramers that can help augment AOP pathways with additional stressors, genes, and phenotypes, as well as formulate potential AOP disease networks (eg, liver cirrhosis and prostate cancer). This novel tool, as part of the complete suite of tools offered at CTD, provides users with computational datasets and their supporting evidence to potentially fill exposure knowledge gaps and develop testable hypotheses about environmental health.

Comparative Toxicogenomics Database (CTD): update 2023.

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 diseases 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.

Predicting molecular mechanisms, pathways, and health outcomes induced by Juul e-cigarette aerosol chemicals using the Comparative Toxicogenomics Database.

There is a critical need to understand the health risks associated with vaping e-cigarettes, which has reached epidemic levels among teens. Juul is currently the most popular type of e-cigarette on the market. Using the Comparative Toxicogenomics Database (CTD; http://ctdbase.org), a public resource that integrates chemical, gene, phenotype and disease data, we aimed to analyze the potential molecular mechanisms of eight chemicals detected in the aerosols generated by heating Juul e-cigarette pods: nicotine, acetaldehyde, formaldehyde, free radicals, crotonaldehyde, acetone, pyruvaldehyde, and particulate matter. Curated content in CTD, including chemical-gene, chemical-phenotype, and chemical-disease interactions, as well as associated phenotypes and pathway enrichment, were analyzed to help identify potential molecular mechanisms and diseases associated with vaping. Nicotine shows the most direct disease associations of these chemicals, followed by particulate matter and formaldehyde. Together, these chemicals show a direct marker or mechanistic relationship with 400 unique diseases in CTD, particularly in the categories of cardiovascular diseases, nervous system diseases, respiratory tract diseases, cancers, and mental disorders. We chose three respiratory tract diseases to investigate further, and found that in addition to cellular processes of apoptosis and cell proliferation, prioritized phenotypes underlying Juul-associated respiratory tract disease outcomes include response to oxidative stress, inflammatory response, and several cell signaling pathways (p38MAPK, NIK/NFkappaB, calcium-mediated).

CTD Anatomy: analyzing chemical-induced phenotypes and exposures from an anatomical perspective, with implications for environmental health studies.

The Comparative Toxicogenomics Database (CTD) is a freely available public resource that curates and interrelates chemical, gene/protein, phenotype, disease, organism, and exposure data. CTD can be used to address toxicological mechanisms for environmental chemicals and facilitate the generation of testable hypotheses about how exposures affect human health. At CTD, manually curated interactions for chemical-induced phenotypes are enhanced with anatomy terms (tissues, fluids, and cell types) to describe the physiological system of the reported event. These same anatomy terms are used to annotate the human media (e.g., urine, hair, nail, blood, etc.) in which an environmental chemical was assayed for exposure. Currently, CTD uses more than 880 unique anatomy terms to contextualize over 255,000 chemical-phenotype interactions and 167,000 exposure statements. These annotations allow chemical-phenotype interactions and exposure data to be explored from a novel, anatomical perspective. Here, we describe CTD's anatomy curation process (including the construction of a controlled, interoperable vocabulary) and new anatomy webpages (that coalesce and organize the curated chemical-phenotype and exposure data sets). We also provide examples that demonstrate how this feature can be used to identify system- and cell-specific chemical-induced toxicities, help inform exposure data, prioritize phenotypes for environmental diseases, survey tissue and pregnancy exposomes, and facilitate data connections with external resources. Anatomy annotations advance understanding of environmental health by providing new ways to explore and survey chemical-induced events and exposure studies in the CTD framework.

Comparative Toxicogenomics Database (CTD): update 2021.

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.

Leveraging the Comparative Toxicogenomics Database to Fill in Knowledge Gaps for Environmental Health: A Test Case for Air Pollution-induced Cardiovascular Disease.

Environmental health studies relate how exposures (eg, chemicals) affect human health and disease; however, in most cases, the molecular and biological mechanisms connecting an exposure with a disease remain unknown. To help fill in these knowledge gaps, we sought to leverage content from the public Comparative Toxicogenomics Database (CTD) to identify potential intermediary steps. In a proof-of-concept study, we systematically compute the genes, molecular mechanisms, and biological events for the environmental health association linking air pollution toxicants with 2 cardiovascular diseases (myocardial infarction and hypertension) as a test case. Our approach integrates 5 types of curated interactions in CTD to build sets of "CGPD-tetramers," computationally constructed information blocks relating a Chemical- Gene interaction with a Phenotype and Disease. This bioinformatics strategy generates 653 CGPD-tetramers for air pollution-associated myocardial infarction (involving 5 pollutants, 58 genes, and 117 phenotypes) and 701 CGPD-tetramers for air pollution-associated hypertension (involving 3 pollutants, 96 genes, and 142 phenotypes). Collectively, we identify 19 genes and 96 phenotypes shared between these 2 air pollutant-induced outcomes, and suggest important roles for oxidative stress, inflammation, immune responses, cell death, and circulatory system processes. Moreover, CGPD-tetramers can be assembled into extensive chemical-induced disease pathways involving multiple gene products and sequential biological events, and many of these computed intermediary steps are validated in the literature. Our method does not require a priori knowledge of the toxicant, interacting gene, or biological system, and can be used to analyze any environmental chemical-induced disease curated within the public CTD framework. This bioinformatics strategy links and interrelates chemicals, genes, phenotypes, and diseases to fill in knowledge gaps for environmental health studies, as demonstrated for air pollution-associated cardiovascular disease, but can be adapted by researchers for any environmentally influenced disease-of-interest.

The Comparative Toxicogenomics Database: update 2019.

The Comparative Toxicogenomics Database (CTD; http://ctdbase.org/) is a premier public resource for literature-based, manually curated associations between chemicals, gene products, phenotypes, diseases, and environmental exposures. In this biennial update, we present our new chemical-phenotype module that codes chemical-induced effects on phenotypes, curated using controlled vocabularies for chemicals, phenotypes, taxa, and anatomical descriptors; this module provides unique opportunities to explore cellular and system-level phenotypes of the pre-disease state and allows users to construct predictive adverse outcome pathways (linking chemical-gene molecular initiating events with phenotypic key events, diseases, and population-level health outcomes). We also report a 46% increase in CTD manually curated content, which when integrated with other datasets yields more than 38 million toxicogenomic relationships. We describe new querying and display features for our enhanced chemical-exposure science module, providing greater scope of content and utility. As well, we discuss an updated MEDIC disease vocabulary with over 1700 new terms and accession identifiers. To accommodate these increases in data content and functionality, CTD has upgraded its computational infrastructure. These updates continue to improve CTD and help inform new testable hypotheses about the etiology and mechanisms underlying environmentally influenced diseases.

Chemical-Induced Phenotypes at CTD Help Inform the Predisease State and Construct Adverse Outcome Pathways.

The Comparative Toxicogenomics Database (CTD; http://ctdbase.org) is a public resource that manually curates the scientific literature to provide content that illuminates the molecular mechanisms by which environmental exposures affect human health. We introduce our new chemical-phenotype module that describes how chemicals can affect molecular, cellular, and physiological phenotypes. At CTD, we operationally distinguish between phenotypes and diseases, wherein a phenotype refers to a nondisease biological event: eg, decreased cell cycle arrest (phenotype) versus liver cancer (disease), increased fat cell proliferation (phenotype) versus morbid obesity (disease), etc. Chemical-phenotype interactions are expressed in a formal structured notation using controlled terms for chemicals, phenotypes, taxon, and anatomical descriptors. Combining this information with CTD's chemical-disease module allows inferences to be made between phenotypes and diseases, yielding potential insight into the predisease state. Integration of all 4 CTD modules furnishes unique opportunities for toxicologists to generate computationally predictive adverse outcome pathways, linking chemical-gene molecular initiating events with phenotypic key events, adverse diseases, and population-level health outcomes. As examples, we present 3 diverse case studies discerning the effect of vehicle emissions on altered leukocyte migration, the role of cadmium in influencing phenotypes preceding Alzheimer disease, and the connection of arsenic-induced glucose metabolic phenotypes with diabetes. To date, CTD contains over 165 000 interactions that connect more than 6400 chemicals to 3900 phenotypes for 760 anatomical terms in 215 species, from over 19 000 scientific articles. To our knowledge, this is the first comprehensive set of manually curated, literature-based, contextualized, chemical-induced, nondisease phenotype data provided to the public.

The Comparative Toxicogenomics Database: update 2017.

The Comparative Toxicogenomics Database (CTD; http://ctdbase.org/) provides information about interactions between chemicals and gene products, and their relationships to diseases. Core CTD content (chemical-gene, chemical-disease and gene-disease interactions manually curated from the literature) are integrated with each other as well as with select external datasets to generate expanded networks and predict novel associations. Today, core CTD includes more than 30.5 million toxicogenomic connections relating chemicals/drugs, genes/proteins, diseases, taxa, Gene Ontology (GO) annotations, pathways, and gene interaction modules. In this update, we report a 33% increase in our core data content since 2015, describe our new exposure module (that harmonizes exposure science information with core toxicogenomic data) and introduce a novel dataset of GO-disease inferences (that identify common molecular underpinnings for seemingly unrelated pathologies). These advancements centralize and contextualize real-world chemical exposures with molecular pathways to help scientists generate testable hypotheses in an effort to understand the etiology and mechanisms underlying environmentally influenced diseases.

BioCreative V CDR task corpus: a resource for chemical disease relation extraction.

Community-run, formal evaluations and manually annotated text corpora are critically important for advancing biomedical text-mining research. Recently in BioCreative V, a new challenge was organized for the tasks of disease named entity recognition (DNER) and chemical-induced disease (CID) relation extraction. Given the nature of both tasks, a test collection is required to contain both disease/chemical annotations and relation annotations in the same set of articles. Despite previous efforts in biomedical corpus construction, none was found to be sufficient for the task. Thus, we developed our own corpus called BC5CDR during the challenge by inviting a team of Medical Subject Headings (MeSH) indexers for disease/chemical entity annotation and Comparative Toxicogenomics Database (CTD) curators for CID relation annotation. To ensure high annotation quality and productivity, detailed annotation guidelines and automatic annotation tools were provided. The resulting BC5CDR corpus consists of 1500 PubMed articles with 4409 annotated chemicals, 5818 diseases and 3116 chemical-disease interactions. Each entity annotation includes both the mention text spans and normalized concept identifiers, using MeSH as the controlled vocabulary. To ensure accuracy, the entities were first captured independently by two annotators followed by a consensus annotation: The average inter-annotator agreement (IAA) scores were 87.49% and 96.05% for the disease and chemicals, respectively, in the test set according to the Jaccard similarity coefficient. Our corpus was successfully used for the BioCreative V challenge tasks and should serve as a valuable resource for the text-mining research community.Database URL: http://www.biocreative.org/tasks/biocreative-v/track-3-cdr/.

Generating Gene Ontology-Disease Inferences to Explore Mechanisms of Human Disease at the Comparative Toxicogenomics Database.

Strategies for discovering common molecular events among disparate diseases hold promise for improving understanding of disease etiology and expanding treatment options. One technique is to leverage curated datasets found in the public domain. The Comparative Toxicogenomics Database (CTD; http://ctdbase.org/) manually curates chemical-gene, chemical-disease, and gene-disease interactions from the scientific literature. The use of official gene symbols in CTD interactions enables this information to be combined with the Gene Ontology (GO) file from NCBI Gene. By integrating these GO-gene annotations with CTD's gene-disease dataset, we produce 753,000 inferences between 15,700 GO terms and 4,200 diseases, providing opportunities to explore presumptive molecular underpinnings of diseases and identify biological similarities. Through a variety of applications, we demonstrate the utility of this novel resource. As a proof-of-concept, we first analyze known repositioned drugs (e.g., raloxifene and sildenafil) and see that their target diseases have a greater degree of similarity when comparing GO terms vs. genes. Next, a computational analysis predicts seemingly non-intuitive diseases (e.g., stomach ulcers and atherosclerosis) as being similar to bipolar disorder, and these are validated in the literature as reported co-diseases. Additionally, we leverage other CTD content to develop testable hypotheses about thalidomide-gene networks to treat seemingly disparate diseases. Finally, we illustrate how CTD tools can rank a series of drugs as potential candidates for repositioning against B-cell chronic lymphocytic leukemia and predict cisplatin and the small molecule inhibitor JQ1 as lead compounds. The CTD dataset is freely available for users to navigate pathologies within the context of extensive biological processes, molecular functions, and cellular components conferred by GO. This inference set should aid researchers, bioinformaticists, and pharmaceutical drug makers in finding commonalities in disease mechanisms, which in turn could help identify new therapeutics, new indications for existing pharmaceuticals, potential disease comorbidities, and alerts for side effects.

Text mining effectively scores and ranks the literature for improving chemical-gene-disease curation at the comparative toxicogenomics database.

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.

Targeted journal curation as a method to improve data currency at the Comparative Toxicogenomics Database.

The Comparative Toxicogenomics Database (CTD) is a public resource that promotes understanding about the effects of environmental chemicals on human health. CTD biocurators read the scientific literature and manually curate a triad of chemical-gene, chemical-disease and gene-disease interactions. Typically, articles for CTD are selected using a chemical-centric approach by querying PubMed to retrieve a corpus containing the chemical of interest. Although this technique ensures adequate coverage of knowledge about the chemical (i.e. data completeness), it does not necessarily reflect the most current state of all toxicological research in the community at large (i.e. data currency). Keeping databases current with the most recent scientific results, as well as providing a rich historical background from legacy articles, is a challenging process. To address this issue of data currency, CTD designed and tested a journal-centric approach of curation to complement our chemical-centric method. We first identified priority journals based on defined criteria. Next, over 7 weeks, three biocurators reviewed 2425 articles from three consecutive years (2009-2011) of three targeted journals. From this corpus, 1252 articles contained relevant data for CTD and 52 752 interactions were manually curated. Here, we describe our journal selection process, two methods of document delivery for the biocurators and the analysis of the resulting curation metrics, including data currency, and both intra-journal and inter-journal comparisons of research topics. Based on our results, we expect that curation by select journals can (i) be easily incorporated into the curation pipeline to complement our chemical-centric approach; (ii) build content more evenly for chemicals, genes and diseases in CTD (rather than biasing data by chemicals-of-interest); (iii) reflect developing areas in environmental health and (iv) improve overall data currency for chemicals, genes and diseases. Database URL: http://ctdbase.org/

Small molecule activators of SIRT1 replicate signaling pathways triggered by calorie restriction in vivo.

BACKGROUND: Calorie restriction (CR) produces a number of health benefits and ameliorates diseases of aging such as type 2 diabetes. The components of the pathways downstream of CR may provide intervention points for developing therapeutics for treating diseases of aging. The NAD+-dependent protein deacetylase SIRT1 has been implicated as one of the key downstream regulators of CR in yeast, rodents, and humans. Small molecule activators of SIRT1 have been identified that exhibit efficacy in animal models of diseases typically associated with aging including type 2 diabetes. To identify molecular processes induced in the liver of mice treated with two structurally distinct SIRT1 activators, SIRT501 (formulated resveratrol) and SRT1720, for three days, we utilized a systems biology approach and applied Causal Network Modeling (CNM) on gene expression data to elucidate downstream effects of SIRT1 activation. RESULTS: Here we demonstrate that SIRT1 activators recapitulate many of the molecular events downstream of CR in vivo, such as enhancing mitochondrial biogenesis, improving metabolic signaling pathways, and blunting pro-inflammatory pathways in mice fed a high fat, high calorie diet. CONCLUSION: CNM of gene expression data from mice treated with SRT501 or SRT1720 in combination with supporting in vitro and in vivo data demonstrates that SRT501 and SRT1720 produce a signaling profile that mirrors CR, improves glucose and insulin homeostasis, and acts via SIRT1 activation in vivo. Taken together these results are encouraging regarding the use of small molecule activators of SIRT1 for therapeutic intervention into type 2 diabetes, a strategy which is currently being investigated in multiple clinical trials.

Analysis of gene ontology features in microarray data using the Proteome BioKnowledge Library.

Microarray technology has resulted in an explosion of complex, valuable data. Integrating data analysis tools with a comprehensive underlying database would allow efficient identification of common properties among differentially regulated genes. In this study we sought to compare the utility of various databases in microarray analysis. The Proteome BioKnowledge Library (BKL), a manually curated, proteome-wide compilation of the scientific literature, was used to generate a list of Gene Ontology (GO) Biological Process (BP) terms enriched among proteins involved in cardiovascular disease. Analysis of DNA microarray data generated in a study of rat vascular smooth muscle cell responses revealed significant enrichment in a number of GO BPs that were also enriched among cardiovascular disease-related proteins. Using annotation from LocusLink and chip annotation from the Gene Expression Omnibus yielded fewer enriched cardiovascular disease-associated GO BP terms. Data sets of orthologous genes from mouse and human were generated using the BKL Retriever. Analysis of these sets focusing on BKL Disease annotation, revealed a significant association of these genes with cardiovascular disease. These results and the extensive presence of experimental evidence for BKL GO and Disease features, underscore the benefits of using this database for microarray analysis.