The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Carolyn J Mattingly - One of the best experts on this subject based on the ideXlab platform.
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comparative Toxicogenomics database ctd update 2021
Nucleic Acids Research, 2021Co-Authors: Allan Peter Davis, Thomas C Wiegers, Cynthia J Grondin, Robin J Johnson, Daniela Sciaky, Jolene Wiegers, Carolyn J MattinglyAbstract: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.
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the comparative Toxicogenomics database update 2019
Nucleic Acids Research, 2019Co-Authors: Allan Peter Davis, Thomas C Wiegers, Cynthia J Grondin, Robin J Johnson, Daniela Sciaky, Roy Mcmorran, Jolene Wiegers, Carolyn J MattinglyAbstract: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.
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accessing an expanded exposure science module at the comparative Toxicogenomics database
Environmental Health Perspectives, 2018Co-Authors: Cynthia J Grondin, Allan Peter Davis, Thomas C Wiegers, Jolene Wiegers, Carolyn J MattinglyAbstract:Summary: The Comparative Toxicogenomics Database (CTD; http://ctdbase.org) is a free resource that provides manually curated information on chemical, gene, phenotype, and disease relationships to a...
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the comparative Toxicogenomics database update 2017
Nucleic Acids Research, 2017Co-Authors: Allan Peter Davis, Thomas C Wiegers, Cynthia J Grondin, Robin J Johnson, Daniela Sciaky, Benjamin L King, Roy Mcmorran, Jolene Wiegers, Carolyn J MattinglyAbstract: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.
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the comparative Toxicogenomics database s 10th year anniversary update 2015
Nucleic Acids Research, 2015Co-Authors: Allan Peter Davis, Thomas C Wiegers, Cynthia J Grondin, Daniela Sciaky, Benjamin L King, Kelley Lennonhopkins, Cynthia Saracenirichards, Carolyn J MattinglyAbstract: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. CTD's 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.
Allan Peter Davis - One of the best experts on this subject based on the ideXlab platform.
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comparative Toxicogenomics database ctd update 2021
Nucleic Acids Research, 2021Co-Authors: Allan Peter Davis, Thomas C Wiegers, Cynthia J Grondin, Robin J Johnson, Daniela Sciaky, Jolene Wiegers, Carolyn J MattinglyAbstract: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.
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the comparative Toxicogenomics database update 2019
Nucleic Acids Research, 2019Co-Authors: Allan Peter Davis, Thomas C Wiegers, Cynthia J Grondin, Robin J Johnson, Daniela Sciaky, Roy Mcmorran, Jolene Wiegers, Carolyn J MattinglyAbstract: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.
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accessing an expanded exposure science module at the comparative Toxicogenomics database
Environmental Health Perspectives, 2018Co-Authors: Cynthia J Grondin, Allan Peter Davis, Thomas C Wiegers, Jolene Wiegers, Carolyn J MattinglyAbstract:Summary: The Comparative Toxicogenomics Database (CTD; http://ctdbase.org) is a free resource that provides manually curated information on chemical, gene, phenotype, and disease relationships to a...
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the comparative Toxicogenomics database update 2017
Nucleic Acids Research, 2017Co-Authors: Allan Peter Davis, Thomas C Wiegers, Cynthia J Grondin, Robin J Johnson, Daniela Sciaky, Benjamin L King, Roy Mcmorran, Jolene Wiegers, Carolyn J MattinglyAbstract: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.
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the comparative Toxicogenomics database s 10th year anniversary update 2015
Nucleic Acids Research, 2015Co-Authors: Allan Peter Davis, Thomas C Wiegers, Cynthia J Grondin, Daniela Sciaky, Benjamin L King, Kelley Lennonhopkins, Cynthia Saracenirichards, Carolyn J MattinglyAbstract: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. CTD's 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.
Thomas C Wiegers - One of the best experts on this subject based on the ideXlab platform.
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comparative Toxicogenomics database ctd update 2021
Nucleic Acids Research, 2021Co-Authors: Allan Peter Davis, Thomas C Wiegers, Cynthia J Grondin, Robin J Johnson, Daniela Sciaky, Jolene Wiegers, Carolyn J MattinglyAbstract: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.
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the comparative Toxicogenomics database update 2019
Nucleic Acids Research, 2019Co-Authors: Allan Peter Davis, Thomas C Wiegers, Cynthia J Grondin, Robin J Johnson, Daniela Sciaky, Roy Mcmorran, Jolene Wiegers, Carolyn J MattinglyAbstract: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.
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accessing an expanded exposure science module at the comparative Toxicogenomics database
Environmental Health Perspectives, 2018Co-Authors: Cynthia J Grondin, Allan Peter Davis, Thomas C Wiegers, Jolene Wiegers, Carolyn J MattinglyAbstract:Summary: The Comparative Toxicogenomics Database (CTD; http://ctdbase.org) is a free resource that provides manually curated information on chemical, gene, phenotype, and disease relationships to a...
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the comparative Toxicogenomics database update 2017
Nucleic Acids Research, 2017Co-Authors: Allan Peter Davis, Thomas C Wiegers, Cynthia J Grondin, Robin J Johnson, Daniela Sciaky, Benjamin L King, Roy Mcmorran, Jolene Wiegers, Carolyn J MattinglyAbstract: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.
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the comparative Toxicogenomics database s 10th year anniversary update 2015
Nucleic Acids Research, 2015Co-Authors: Allan Peter Davis, Thomas C Wiegers, Cynthia J Grondin, Daniela Sciaky, Benjamin L King, Kelley Lennonhopkins, Cynthia Saracenirichards, Carolyn J MattinglyAbstract: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. CTD's 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.
Andrew Williams - One of the best experts on this subject based on the ideXlab platform.
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Transcriptional Profiling of Dibenzo[def,p]chrysene-induced Spleen Atrophy Provides Mechanistic Insights into its Immunotoxicity in MutaMouse.
Toxicological Sciences, 2015Co-Authors: Nikolai L. Chepelev, Byron Kuo, Andrew Williams, Volker M. Arlt, David H. Phillips, Paul D. White, Alexandra S. Long, Rémi Gagné, Dean A. Kennedy, Carole L YaukAbstract:Dibenzo[def,p]chrysene (DBC) is the most carcinogenic polycyclic aromatic hydrocarbon (PAH) examined to date. We investigated the immunotoxicity of DBC, manifested as spleen atrophy, following acute exposure of adult MutaMouse males by oral gavage. Mice were exposed to 0, 2.0, 6.2, or 20.0 mg DBC /kg-bw per day, for 3 days. Genotoxic endpoints (DBC-DNA adducts and lacZ mutant frequency in spleen and bone marrow, and red blood cell micronucleus frequency) and global gene expression changes were measured. All of the genotoxicity measures increased in a dose-dependent manner in spleen and bone marrow. Gene expression analysis showed that DBC activates p53 signaling pathways related to cellular growth and proliferation, which was evident even at the low dose. Strikingly, the expression profiles of DBC exposed mouse spleens were highly inversely correlated with the expression profiles of the only published Toxicogenomics dataset of enlarged mouse spleen. This analysis suggested a central role for Bnip3l, a pro-apoptotic protein involved in negative regulation of erythroid maturation. RT-PCR confirmed expression changes in several genes related to apoptosis, iron metabolism, and aryl hydrocarbon receptor signaling that are regulated in the opposite direction during spleen atrophy versus benzo[a]pyrene-mediated splenomegaly. In addition, benchmark dose modeling of Toxicogenomics data yielded toxicity estimates that are very close to traditional toxicity endpoints. This work illustrates the power of Toxicogenomics to reveal rich mechanistic information for immunotoxic compounds and its ability to provide information that is quantitatively similar to that derived from standard toxicity methods in health risk assessment.
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impact of genomics platform and statistical filtering on transcriptional benchmark doses bmd and multiple approaches for selection of chemical point of departure pod
PLOS ONE, 2015Co-Authors: Nikolai L. Chepelev, Andrew Williams, Rémi Gagné, Leslie Recio, Francina A Webster, Carole L YaukAbstract:Many regulatory agencies are exploring ways to integrate toxicogenomic data into their chemical risk assessments. The major challenge lies in determining how to distill the complex data produced by high-content, multi-dose gene expression studies into quantitative information. It has been proposed that benchmark dose (BMD) values derived from Toxicogenomics data be used as point of departure (PoD) values in chemical risk assessments. However, there is limited information regarding which genomics platforms are most suitable and how to select appropriate PoD values. In this study, we compared BMD values modeled from RNA sequencing-, microarray-, and qPCR-derived gene expression data from a single study, and explored multiple approaches for selecting a single PoD from these data. The strategies evaluated include several that do not require prior mechanistic knowledge of the compound for selection of the PoD, thus providing approaches for assessing data-poor chemicals. We used RNA extracted from the livers of female mice exposed to non-carcinogenic (0, 2 mg/kg/day, mkd) and carcinogenic (4, 8 mkd) doses of furan for 21 days. We show that transcriptional BMD values were consistent across technologies and highly predictive of the two-year cancer bioassay-based PoD. We also demonstrate that filtering data based on statistically significant changes in gene expression prior to BMD modeling creates more conservative BMD values. Taken together, this case study on mice exposed to furan demonstrates that high-content Toxicogenomics studies produce robust data for BMD modelling that are minimally affected by inter-technology variability and highly predictive of cancer-based PoD doses.
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comparison of Toxicogenomics and traditional approaches to inform mode of action and points of departure in human health risk assessment of benzo a pyrene in drinking water
Critical Reviews in Toxicology, 2015Co-Authors: Ivy Moffat, Sarah Labib, Byron Kuo, Julie K. Buick, Amal I. Malik, Nikolai L. Chepelev, Andrew Williams, Sabina Halappanavar, Julie Bourdonlacombe, Mirjam LuijtenAbstract:Toxicogenomics is proposed to be a useful tool in human health risk assessment. However, a systematic comparison of traditional risk assessment approaches with those applying Toxicogenomics has never been done. We conducted a case study to evaluate the utility of Toxicogenomics in the risk assessment of benzo[a]pyrene (BaP), a well-studied carcinogen, for drinking water exposures. Our study was intended to compare methodologies, not to evaluate drinking water safety. We compared traditional (RA1), genomics-informed (RA2) and genomics-only (RA3) approaches. RA2 and RA3 applied Toxicogenomics data from human cell cultures and mice exposed to BaP to determine if these data could provide insight into BaP's mode of action (MOA) and derive tissue-specific points of departure (POD). Our global gene expression analysis supported that BaP is genotoxic in mice and allowed the development of a detailed MOA. Toxicogenomics analysis in human lymphoblastoid TK6 cells demonstrated a high degree of consistency in perturbed pathways with animal tissues. Quantitatively, the PODs for traditional and transcriptional approaches were similar (liver 1.2 vs. 1.0 mg/kg-bw/day; lungs 0.8 vs. 3.7 mg/kg-bw/day; forestomach 0.5 vs. 7.4 mg/kg-bw/day). RA3, which applied Toxicogenomics in the absence of apical toxicology data, demonstrates that this approach provides useful information in data-poor situations. Overall, our study supports the use of Toxicogenomics as a relatively fast and cost-effective tool for hazard identification, preliminary evaluation of potential carcinogens, and carcinogenic potency, in addition to identifying current limitations and practical questions for future work.
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comparison of Toxicogenomics and traditional approaches to inform mode of action and points of departure in human health risk assessment of benzo a pyrene in drinking water
Critical Reviews in Toxicology, 2015Co-Authors: Ivy Moffat, Sarah Labib, Byron Kuo, Julie K. Buick, Amal I. Malik, Nikolai L. Chepelev, Andrew Williams, Sabina Halappanavar, Julie Bourdonlacombe, Mirjam LuijtenAbstract:AbstractToxicogenomics is proposed to be a useful tool in human health risk assessment. However, a systematic comparison of traditional risk assessment approaches with those applying Toxicogenomics has never been done. We conducted a case study to evaluate the utility of Toxicogenomics in the risk assessment of benzo[a]pyrene (BaP), a well-studied carcinogen, for drinking water exposures. Our study was intended to compare methodologies, not to evaluate drinking water safety. We compared traditional (RA1), genomics-informed (RA2) and genomics-only (RA3) approaches. RA2 and RA3 applied Toxicogenomics data from human cell cultures and mice exposed to BaP to determine if these data could provide insight into BaP's mode of action (MOA) and derive tissue-specific points of departure (POD). Our global gene expression analysis supported that BaP is genotoxic in mice and allowed the development of a detailed MOA. Toxicogenomics analysis in human lymphoblastoid TK6 cells demonstrated a high degree of consistency in...
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Integrating Toxicogenomics into human health risk assessment: Lessons learned from the benzo[a]pyrene case study
Critical Reviews in Toxicology, 2015Co-Authors: Nikolai L. Chepelev, Ivy D. Moffat, Sarah Labib, Julie Bourdon-lacombe, Byron Kuo, Julie K. Buick, Amal I. Malik, F. Lemieux, Sabina Halappanavar, Andrew WilliamsAbstract:The use of short-term toxicogenomic tests to predict cancer (or other health effects) offers considerable advantages relative to traditional toxicity testing methods. The advantages include increased throughput, increased mechanistic data, and significantly reduced costs. However, precisely how Toxicogenomics data can be used to support human health risk assessment (RA) is unclear. In a companion paper (Moffat et al. 2014), we present a case study evaluating the utility of Toxicogenomics in the RA of benzo[ a ]pyrene (BaP), a known human carcinogen. The case study is meant as a proof-of-principle exercise using a well- established mode of action (MOA) that impacts multiple tissues, which should provide a best case example. We found that Toxicogenomics provided rich mechanistic data applicable to hazard identification, dose – response analysis, and quantitative RA of BaP. Based on this work, here we share some useful lessons for both research and RA, and outline our perspective on how Toxicogenomics can benefit RA in the short- and long-term. Specifically, we focus on (1) obtaining biologically relevant data that are readily suitable for establishing an MOA for toxicants, (2) examining the human relevance of an MOA from animal testing, and (3) proposing appropriate quantitative values for RA. We describe our envisioned strategy on how Toxicogenomics can become a tool in RA, especially when anchored to other short-term toxicity tests (apical endpoints) to increase confidence in the proposed MOA, and emphasize the need for additional studies on other MOAs to define the best practices in the application of Toxicogenomics in RA.
Baohong Zhang - One of the best experts on this subject based on the ideXlab platform.
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evaluation and identification of reliable reference genes for pharmacogenomics Toxicogenomics and small rna expression analysis
Journal of Cellular Physiology, 2011Co-Authors: Dongliang Chen, Peng Xiao, Mary A Farwell, Baohong ZhangAbstract:Pharmacogenomics, Toxicogenomics, and small RNA expression analysis are three of the most active research topics in the biological, biomedical, pharmaceutical, and toxicological fields. All of these studies are based on gene expression analysis, which requires reference genes to reduce the variations derived from different amounts of starting materials and different efficiencies of RNA extraction and cDNA synthesis. Thus, accurate normalization to one or several constitutively expressed reference genes is a prerequisite to valid gene expression studies. Although selection of reliable reference genes has been conducted in previous studies in several animals and plants, no research has been focused on pharmacological targets, and very few studies have had a toxicological context. More interestingly, no studies have been performed to identify reference genes for small RNA analysis although small RNA, particularly microRNA (miRNA)-related research is currently one of the fastest-moving topics. In this study, using MCF-7 breast cancer cells as a model, we employed quantitative real-time PCR (qRT-PCR), one of the most reliable methods for gene expression analysis in many research fields, to evaluate and to determine the most reliable reference genes for pharmacogenomics and Toxicogenomics studies as well as for small RNA expression analysis. We tested the transcriptional expression of five protein-coding genes as well as five non-coding genes in MCF-7 cells treated with five different pharmaceuticals or toxicants [paclitaxel (PTX), gossypol (GOS), methyl jasmonate (JAS), L-nicotine (NIC), and melamine (mela)] and analyzed the stability of the selected reference genes by four different methods: geNorm, NormFinder, BestKeeper, and the comparative ΔCt method. According to our analysis, a protein-coding gene, hTBCA and four non-coding genes, hRNU44, hRNU48, hU6, and hRNU47, appear to be the most reliable reference genes for the five chemical treatments. Similar results were also obtained in dose-response and time-course assays with gossypol (GOS) treatment. Our results demonstrated that traditionally used reference genes, such as 18s RNA, β-actin, and GAPDH, are not reliable reference genes for pharmacogenomics and Toxicogenomics studies. In contrast, hTBCA and small RNAs are more stable during drug treatment, and they are better reference genes for pharmacogenomics and Toxicogenomics studies. To widely use these genes as reference genes, these results should be corroborated by studies with other human cell lines and additional drugs classes and hormonal treatments. J. Cell. Physiol. 226: 2469–2477, 2011. © 2011 Wiley-Liss, Inc.
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evaluation and identification of reliable reference genes for pharmacogenomics Toxicogenomics and small rna expression analysis
Journal of Cellular Physiology, 2011Co-Authors: Dongliang Chen, Peng Xiao, Mary A Farwell, Xiaoping Pan, Baohong ZhangAbstract:Pharmacogenomics, Toxicogenomics, and small RNA expression analysis are three of the most active research topics in the biological, biomedical, pharmaceutical, and toxicological fields. All of these studies are based on gene expression analysis, which requires reference genes to reduce the variations derived from different amounts of starting materials and different efficiencies of RNA extraction and cDNA synthesis. Thus, accurate normalization to one or several constitutively expressed reference genes is a prerequisite to valid gene expression studies. Although selection of reliable reference genes has been conducted in previous studies in several animals and plants, no research has been focused on pharmacological targets, and very few studies have had a toxicological context. More interestingly, no studies have been performed to identify reference genes for small RNA analysis although small RNA, particularly microRNA (miRNA)-related research is currently one of the fastest-moving topics. In this study, using MCF-7 breast cancer cells as a model, we employed quantitative real-time PCR (qRT-PCR), one of the most reliable methods for gene expression analysis in many research fields, to evaluate and to determine the most reliable reference genes for pharmacogenomics and Toxicogenomics studies as well as for small RNA expression analysis. We tested the transcriptional expression of five protein-coding genes as well as five non-coding genes in MCF-7 cells treated with five different pharmaceuticals or toxicants [paclitaxel (PTX), gossypol (GOS), methyl jasmonate (JAS), L-nicotine (NIC), and melamine (mela)] and analyzed the stability of the selected reference genes by four different methods: geNorm, NormFinder, BestKeeper, and the comparative ΔCt method. According to our analysis, a protein-coding gene, hTBCA and four non-coding genes, hRNU44, hRNU48, hU6, and hRNU47, appear to be the most reliable reference genes for the five chemical treatments. Similar results were also obtained in dose-response and time-course assays with gossypol (GOS) treatment. Our results demonstrated that traditionally used reference genes, such as 18s RNA, β-actin, and GAPDH, are not reliable reference genes for pharmacogenomics and Toxicogenomics studies. In contrast, hTBCA and small RNAs are more stable during drug treatment, and they are better reference genes for pharmacogenomics and Toxicogenomics studies. To widely use these genes as reference genes, these results should be corroborated by studies with other human cell lines and additional drugs classes and hormonal treatments.