Carolyn J. Mattingly

The Comparative Toxicogenomics Database: update 2011

The Comparative Toxicogenomics Database (CTD) is a public resource that promotes understanding about the interaction of environmental chemicals with gene products, and their effects on human health. Biocurators at CTD manually curate a triad of chemical–gene, chemical–disease and gene–disease relationships from the literature. These core data are then integrated to construct chemical–gene–disease networks and to predict many novel relationships using different types of associated data. Since 2009, we dramatically increased the content of CTD to 1.4 million chemical–gene–disease data points and added many features, statistical analyses and analytical tools, including GeneComps and ChemComps (to find comparable genes and chemicals that share toxicogenomic profiles), enriched Gene Ontology terms associated with chemicals, statistically ranked chemical–disease inferences, Venn diagram tools to discover overlapping and unique attributes of any set of chemicals, genes or disease, and enhanced gene pathway data content, among other features. Together, this wealth of expanded chemical–gene–disease data continues to help users generate testable hypotheses about the molecular mechanisms of environmental diseases. CTD is freely available at http://ctd.mdibl.org.

The Comparative Toxicogenomics Database's 10th year anniversary: update 2015

Ten years ago, the Comparative Toxicogenomics Database (CTD; http://ctdbase.org/) was developed out of a need to formalize, harmonize and centralize the information on numerous genes and proteins responding to environmental toxic agents across diverse species. CTDs initial approach was to facilitate comparisons of nucleotide and protein sequences of toxicologically significant genes by curating these sequences and electronically annotating them with chemical terms from their associated references. Since then, however, CTD has vastly expanded its scope to robustly represent a triad of chemical–gene, chemical–disease and gene–disease interactions that are manually curated from the scientific literature by professional biocurators using controlled vocabularies, ontologies and structured notation. Today, CTD includes 24 million toxicogenomic connections relating chemicals/drugs, genes/proteins, diseases, taxa, phenotypes, Gene Ontology annotations, pathways and interaction modules. In this 10th year anniversary update, we outline the evolution of CTD, including our increased data content, new ‘Pathway View’ visualization tool, enhanced curation practices, pilot chemical–phenotype results and impending exposure data set. The prototype database originally described in our first report has transformed into a sophisticated resource used actively today to help scientists develop and test hypotheses about the etiologies of environmentally influenced diseases.

Comparative Toxicogenomics Database: a knowledgebase and discovery tool for chemical–gene–disease networks

The Comparative Toxicogenomics Database (CTD) is a curated database that promotes understanding about the effects of environmental chemicals on human health. Biocurators at CTD manually curate chemical–gene interactions, chemical–disease relationships and gene–disease relationships from the literature. This strategy allows data to be integrated to construct chemical–gene–disease networks. CTD is unique in numerous respects: curation focuses on environmental chemicals; interactions are manually curated; interactions are constructed using controlled vocabularies and hierarchies; additional gene attributes (such as Gene Ontology, taxonomy and KEGG pathways) are integrated; data can be viewed from the perspective of a chemical, gene or disease; results and batch queries can be downloaded and saved; and most importantly, CTD acts as both a knowledgebase (by reporting data) and a discovery tool (by generating novel inferences). Over 116 000 interactions between 3900 chemicals and 13 300 genes have been curated from 270 species, and 5900 gene–disease and 2500 chemical–disease direct relationships have been captured. By integrating these data, 350 000 gene–disease relationships and 77 000 chemical–disease relationships can be inferred. This wealth of chemical–gene–disease information yields testable hypotheses for understanding the effects of environmental chemicals on human health. CTD is freely available at http://ctd.mdibl.org.

Text mining and manual curation of chemical-gene-disease networks for the Comparative Toxicogenomics Database (CTD)

BackgroundThe Comparative Toxicogenomics Database (CTD) is a publicly available resource that promotes understanding about the etiology of environmental diseases. It provides manually curated chemical-gene/protein interactions and chemical- and gene-disease relationships from the peer-reviewed, published literature. The goals of the research reported here were to establish a baseline analysis of current CTD curation, develop a text-mining prototype from readily available open source components, and evaluate its potential value in augmenting curation efficiency and increasing data coverage.ResultsPrototype text-mining applications were developed and evaluated using a CTD data set consisting of manually curated molecular interactions and relationships from 1,600 documents. Preliminary results indicated that the prototype found 80% of the gene, chemical, and disease terms appearing in curated interactions. These terms were used to re-rank documents for curation, resulting in increases in mean average precision (63% for the baseline vs. 73% for a rule-based re-ranking), and in the correlation coefficient of rank vs. number of curatable interactions per document (baseline 0.14 vs. 0.38 for the rule-based re-ranking).ConclusionThis text-mining project is unique in its integration of existing tools into a single workflow with direct application to CTD. We performed a baseline assessment of the inter-curator consistency and coverage in CTD, which allowed us to measure the potential of these integrated tools to improve prioritization of journal articles for manual curation. Our study presents a feasible and cost-effective approach for developing a text mining solution to enhance manual curation throughput and efficiency.

Estrogen Receptor Reduces CYP1A1 Induction in Cultured Human Endometrial Cells

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) exerts its toxic action via the aryl hydrocarbon (Ah) receptor, which induces a battery of xenobiotic-metabolizing enzymes, including the cytochrome P450 isozyme, CYP1A1. TCDD-induced 7-ethoxycoumarin-O-deethylase activity was reduced 75% in cultured human endometrial ECC-1 cells exposed to various concentrations of 17β-estradiol for up to 72 h, with a half-maximal effective concentration (EC50) of 0.9 nm. Reduced enzyme activity was correlated with decreased CYP1A1 mRNA levels, and transcription. Exposure to TCDD plus 17β-estradiol also reduced CYP1A1 activity in MCF-7 breast cancer cells but not in Hep-3B human liver cells or HuE primary human keratinocytes, suggesting that the effect was specific to estrogen-regulated cells. Estrogen receptor antagonists 4-hydroxytamoxifen and 7α-[9-(4,4,5,5,5-pentafluoro-pentylsulfinyl)nonyl]estra-1,3,5(10)-triene3, 17β-diol restored TCDD-induced CYP1A1 transcription, steady-state mRNA levels, and enzymatic activity in ECC-1 cells. Gel mobility shift assay showed that 17β-estradiol had little effect on Ah receptor binding to its DNA-responsive element. 17β-Estradiol did not alter the induction of another Ah receptor-regulated gene,CYP1B1, suggesting that altered Ah receptor binding to DNA does not mediate reduced CYP1A1 transcription. Transfecting ECC-1 cells with a general transcription factor involved in CYP1A1 induction, nuclear factor-1, reversed 17β-estradiol antagonism of dioxin induced-CYP1A1. The data suggest that 17β-estradiol reduced CYP1A1 expression at the transcriptional level by squelching available nuclear factor-1, a transcription factor that interacts with both Ah and estrogen receptors.

MEDIC: a practical disease vocabulary used 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 manually curate a triad of chemical–gene, chemical–disease and gene–disease relationships from the scientific literature. The CTD curation paradigm uses controlled vocabularies for chemicals, genes and diseases. To curate disease information, CTD first had to identify a source of controlled terms. Two resources seemed to be good candidates: the Online Mendelian Inheritance in Man (OMIM) and the ‘Diseases’ branch of the National Library of Medicines Medical Subject Headers (MeSH). To maximize the advantages of both, CTD biocurators undertook a novel initiative to map the flat list of OMIM disease terms into the hierarchical nature of the MeSH vocabulary. The result is CTD’s ‘merged disease vocabulary’ (MEDIC), a unique resource that integrates OMIM terms, synonyms and identifiers with MeSH terms, synonyms, definitions, identifiers and hierarchical relationships. MEDIC is both a deep and broad vocabulary, composed of 9700 unique diseases described by more than 67 000 terms (including synonyms). It is freely available to download in various formats from CTD. While neither a true ontology nor a perfect solution, this vocabulary has nonetheless proved to be extremely successful and practical for our biocurators in generating over 2.5 million disease-associated toxicogenomic relationships in CTD. Other external databases have also begun to adopt MEDIC for their disease vocabulary. Here, we describe the construction, implementation, maintenance and use of MEDIC to raise awareness of this resource and to offer it as a putative scaffold in the formal construction of an official disease ontology. Database URL: http://ctd.mdibl.org/voc.go?type=disease

Genetic and environmental pathways to complex diseases

BackgroundPathogenesis of complex diseases involves the integration of genetic and environmental factors over time, making it particularly difficult to tease apart relationships between phenotype, genotype, and environmental factors using traditional experimental approaches.ResultsUsing gene-centered databases, we have developed a network of complex diseases and environmental factors through the identification of key molecular pathways associated with both genetic and environmental contributions. Comparison with known chemical disease relationships and analysis of transcriptional regulation from gene expression datasets for several environmental factors and phenotypes clustered in a metabolic syndrome and neuropsychiatric subnetwork supports our network hypotheses. This analysis identifies natural and synthetic retinoids, antipsychotic medications, Omega 3 fatty acids, and pyrethroid pesticides as potential environmental modulators of metabolic syndrome phenotypes through PPAR and adipocytokine signaling and organophosphate pesticides as potential environmental modulators of neuropsychiatric phenotypes.ConclusionIdentification of key regulatory pathways that integrate genetic and environmental modulators define disease associated targets that will allow for efficient screening of large numbers of environmental factors, screening that could set priorities for further research and guide public health decisions.

A CTD–Pfizer collaboration: manual curation of 88 000 scientific articles text mined for drug–disease and drug–phenotype interactions

Improving the prediction of chemical toxicity is a goal common to both environmental health research and pharmaceutical drug development. To improve safety detection assays, it is critical to have a reference set of molecules with well-defined toxicity annotations for training and validation purposes. Here, we describe a collaboration between safety researchers at Pfizer and the research team at the Comparative Toxicogenomics Database (CTD) to text mine and manually review a collection of 88 629 articles relating over 1 200 pharmaceutical drugs to their potential involvement in cardiovascular, neurological, renal and hepatic toxicity. In 1 year, CTD biocurators curated 2 54 173 toxicogenomic interactions (1 52 173 chemical–disease, 58 572 chemical–gene, 5 345 gene–disease and 38 083 phenotype interactions). All chemical–gene–disease interactions are fully integrated with public CTD, and phenotype interactions can be downloaded. We describe Pfizer’s text-mining process to collate the articles, and CTD’s curation strategy, performance metrics, enhanced data content and new module to curate phenotype information. As well, we show how data integration can connect phenotypes to diseases. This curation can be leveraged for information about toxic endpoints important to drug safety and help develop testable hypotheses for drug–disease events. The availability of these detailed, contextualized, high-quality annotations curated from seven decades’ worth of the scientific literature should help facilitate new mechanistic screening assays for pharmaceutical compound survival. This unique partnership demonstrates the importance of resource sharing and collaboration between public and private entities and underscores the complementary needs of the environmental health science and pharmaceutical communities. Database URL: http://ctdbase.org/

Posttranscriptional silencing of cytochrome P4501A1 (CYP1A1) during zebrafish (Danio rerio) development

Induction patterns of cytochrome P4501A1 (CYP1A1), an early biochemical marker of exposure to the environmental toxicant 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD, or dioxin) were investigated during zebrafish (Danio rerio) development. A zebrafish CYP1A1 cDNA fragment was cloned and used to detect CYP1A1 mRNA in embryos exposed to TCDD (1 or 10 nM). Induction of CYP1A1 activity was dependent on age and state of hatch. CYP1A1 mRNA was observed by 15 hr postfertilization. CYP1A1 protein and monooxygenase activity were not detected until 3 days postfertilization and after hatch, as determined by Western immunoblot analysis and ethoxyresorufin O‐deethylase (EROD) activity, respectively. In contrast to embryos, concomitant induction of mRNA and activity was detected in juvenile zebrafish (3 days posthatch) after 6 hr of TCDD exposure. Asynchronous induction of CYP1A1 mRNA and activity during development may be a general regulatory mechanism, as similar ontogenetic expression of this gene was demonstrated in mouse embryos. To our knowledge, this is the first report of CYP1A1 posttranscriptional silencing during embryogenesis. Our data suggest that TCDD‐mediated induction of CYP1A1 activity is regulated differentially in developing and mature systems.

Perturbation of Defense Pathways by Low-Dose Arsenic Exposure in Zebrafish Embryos

Background Exposure to arsenic is a critical risk factor in the complex interplay among genetics, the environment, and human disease. Despite the potential for in utero exposure, the mechanism of arsenic action on vertebrate development and disease is unknown. Objectives The objective of this study was to identify genes and gene networks perturbed by arsenic during development in order to enhance understanding of the molecular mechanisms of arsenic action. Methods We exposed zebrafish embryos at 0.25–1.25 hr postfertilization to 10 or 100 ppb arsenic for 24 or 48 hr. We then used total RNA to interrogate genome microarrays and to test levels of gene expression changes by quantitative real-time polymerase chain reaction (QPCR). Computational analysis was used to identify gene expression networks perturbed by arsenic during vertebrate development. Results We identified a set of 99 genes that responded to low levels of arsenic. Nineteen of these genes were predicted to function in a common regulatory network that was significantly associated with immune response and cancer (p < 10−41). Arsenic-mediated expression changes were validated by QPCR. Conclusions In this study we demonstrated that arsenic significantly down-regulates expression levels of multiple genes potentially critical for regulating the establishment of an immune response. The data also provide molecular evidence consistent with phenotypic observations reported in other model systems. Additional mechanistic studies will help explain molecular events regulating early stages of the immune system and long-term consequences of arsenic-mediated perturbation of this system during development.