Dataset Information

Integration of curated and high-throughput screening data to elucidate environmental influences on disease pathways.

ABSTRACT: Addressing the complex relationship between public health and environmental exposure requires multiple types and sources of data. An important source of chemical data derives from high-throughput screening (HTS) efforts, such as the Tox21/ToxCast program, which aim to identify chemical hazard using primarily in vitro assays to probe toxicity. While most of these assays target specific genes, assessing the disease-relevance of these assays remains challenging. Integration with additional data sets may help to resolve these questions by providing broader context for individual assay results. The Comparative Toxicogenomics Database (CTD), a publicly available database that builds networks of chemical, gene, and disease information from manually curated literature sources, offers a promising solution for contextual integration with HTS data. Here, we tested the value of integrating data across Tox21/ToxCast and CTD by linking elements common to both databases (i.e., assays, genes, and chemicals). Using polymarcine and Parkinson's disease as a case study, we found that their union significantly increased chemical-gene associations and disease-pathway coverage. Integration also enabled new disease associations to be made with HTS assays, expanding coverage of chemical-gene data associated with diseases. We demonstrate how integration enables development of predictive adverse outcome pathways using 4-nonylphenol, branched as an example. Thus, we demonstrate enhancements to each data source through database integration, including scenarios where HTS data can efficiently probe chemical space that may be understudied in the literature, as well as how CTD can add biological context to those results.

SUBMITTER: Kosnik MB

PROVIDER: S-EPMC6709694 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:BackgroundUnderstanding health risks to embryonic development from exposure to environmental chemicals is a significant challenge given the diverse chemical landscape and paucity of data for most of these compounds. High-throughput screening (HTS) in the U.S. Environmental Protection Agency (EPA) ToxCast™ project provides vast data on an expanding chemical library currently consisting of > 1,000 unique compounds across > 500 in vitro assays in phase I (complete) and Phase II (under way). This public data set can be used to evaluate concentration-dependent effects on many diverse biological targets and build predictive models of prototypical toxicity pathways that can aid decision making for assessments of human developmental health and disease.ObjectiveWe mined the ToxCast phase I data set to identify signatures for potential chemical disruption of blood vessel formation and remodeling.MethodsToxCast phase I screened 309 chemicals using 467 HTS assays across nine assay technology platforms. The assays measured direct interactions between chemicals and molecular targets (receptors, enzymes), as well as downstream effects on reporter gene activity or cellular consequences. We ranked the chemicals according to individual vascular bioactivity score and visualized the ranking using ToxPi (Toxicological Priority Index) profiles.ResultsTargets in inflammatory chemokine signaling, the vascular endothelial growth factor pathway, and the plasminogen-activating system were strongly perturbed by some chemicals, and we found positive correlations with developmental effects from the U.S. EPA ToxRefDB (Toxicological Reference Database) in vivo database containing prenatal rat and rabbit guideline studies. We observed distinctly different correlative patterns for chemicals with effects in rabbits versus rats, despite derivation of in vitro signatures based on human cells and cell-free biochemical targets, implying conservation but potentially differential contributions of developmental pathways among species. Follow-up analysis with antiangiogenic thalidomide analogs and additional in vitro vascular targets showed in vitro activity consistent with the most active environmental chemicals tested here.ConclusionsWe predicted that blood vessel development is a target for environmental chemicals acting as putative vascular disruptor compounds (pVDCs) and identified potential species differences in sensitive vascular developmental pathways.

Project description:BackgroundAdverse outcome pathways (AOPs) link adverse effects in individuals or populations to a molecular initiating event (MIE) that can be quantified using in vitro methods. Practical application of AOPs in chemical-specific risk assessment requires incorporation of knowledge on exposure, along with absorption, distribution, metabolism, and excretion (ADME) properties of chemicals.ObjectivesWe developed a conceptual workflow to examine exposure and ADME properties in relation to an MIE. The utility of this workflow was evaluated using a previously established AOP, acetylcholinesterase (AChE) inhibition.MethodsThirty chemicals found to inhibit human AChE in the ToxCast™ assay were examined with respect to their exposure, absorption potential, and ability to cross the blood-brain barrier (BBB). Structures of active chemicals were compared against structures of 1,029 inactive chemicals to detect possible parent compounds that might have active metabolites.ResultsApplication of the workflow screened 10 "low-priority" chemicals of 30 active chemicals. Fifty-two of the 1,029 inactive chemicals exhibited a similarity threshold of ≥ 75% with their nearest active neighbors. Of these 52 compounds, 30 were excluded due to poor absorption or distribution. The remaining 22 compounds may inhibit AChE in vivo either directly or as a result of metabolic activation.ConclusionsThe incorporation of exposure and ADME properties into the conceptual workflow eliminated 10 "low-priority" chemicals that may otherwise have undergone additional, resource-consuming analyses. Our workflow also increased confidence in interpretation of in vitro results by identifying possible "false negatives."CitationPhillips MB, Leonard JA, Grulke CM, Chang DT, Edwards SW, Brooks R, Goldsmith MR, El-Masri H, Tan YM. 2016. A workflow to investigate exposure and pharmacokinetic influences on high-throughput in vitro chemical screening based on adverse outcome pathways. Environ Health Perspect 124:53-60; http://dx.doi.org/10.1289/ehp.1409450.

Project description:BackgroundDiabetes and obesity are major threats to public health in the United States and abroad. Understanding the role that chemicals in our environment play in the development of these conditions is an emerging issue in environmental health, although identifying and prioritizing chemicals for testing beyond those already implicated in the literature is challenging. This review is intended to help researchers generate hypotheses about chemicals that may contribute to diabetes and to obesity-related health outcomes by summarizing relevant findings from the U.S. Environmental Protection Agency (EPA) ToxCast™ high-throughput screening (HTS) program.ObjectivesOur aim was to develop new hypotheses around environmental chemicals of potential interest for diabetes- or obesity-related outcomes using high-throughput screening data.MethodsWe identified ToxCast™ assay targets relevant to several biological processes related to diabetes and obesity (insulin sensitivity in peripheral tissue, pancreatic islet and β cell function, adipocyte differentiation, and feeding behavior) and presented chemical screening data against those assay targets to identify chemicals of potential interest.DiscussionThe results of this screening-level analysis suggest that the spectrum of environmental chemicals to consider in research related to diabetes and obesity is much broader than indicated by research papers and reviews published in the peer-reviewed literature. Testing hypotheses based on ToxCast™ data will also help assess the predictive utility of this HTS platform.ConclusionsMore research is required to put these screening-level analyses into context, but the information presented in this review should facilitate the development of new hypotheses.CitationAuerbach S, Filer D, Reif D, Walker V, Holloway AC, Schlezinger J, Srinivasan S, Svoboda D, Judson R, Bucher JR, Thayer KA. 2016. Prioritizing environmental chemicals for obesity and diabetes outcomes research: a screening approach using ToxCast™ high-throughput data. Environ Health Perspect 124:1141-1154; http://dx.doi.org/10.1289/ehp.1510456.

Dataset Information

Integration of curated and high-throughput screening data to elucidate environmental influences on disease pathways.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets