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Hazard Assessment of High-Nitrogen Compounds: Coupling Transcriptomics with Multi-Cellular Co-Culture Assays Provides Accurate Systemic Toxicity Screening

ABSTRACT: Hazard Assessment of High-Nitrogen Compounds: Coupling Transcriptomics with Multi-Cellular Co-Culture Assays Provides Accurate Systemic Toxicity Screening

PROVIDER: PRJNA355187 | ENA |

REPOSITORIES: ENA

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Hazard Assessment of High-Nitrogen Compounds: Coupling Transcriptomics with Multi-Cellular Co-Culture Assays Provides Accurate Systemic Toxicity Screening [TNT]

Project description:Abstract - Current in vitro hazard assessment techniques lack the systems context necessary to holistically describe in vivo toxicity. To remedy this shortcoming, we have employed the Integrated discrete Multiple Organ Co-Culture (IdMOC) system in conjunction with global-transcriptomic expression assessment to provide a systems context of interactive organ and toxicity pathway responses. Specifically, IdMOC exposures containing hµMan cells representative of five organ types (kidney, liver, lung, vascular endotheliµM and heart muscle) were compared to mono-culture exposures, to evaluate toxic effects in a well-studied legacy munition, 2,4,6-trinitrotoluene (TNT) compared to a structurally similar insensitive munition, 2,4-dinitroanisole (DNAN) having sparsely described toxicity. DNAN toxicity, based on cell viability, was significantly lower than TNT for three cell lines: liver, vascular endotheliµM, and heart. Toxicity pathways enriched in transcriptional analysis of kidney cells exposed to TNT and DNAN through the IdMOC system reflected the literature-based in vivo mammalian toxicity of parent compounds and metabolites where multiple screening values matched chronic dosing levels within 1 order of magnitude. Enriched pathways were primarily unique to each chemical where TNT exposures affected xenobiotic metabolism, oxidative stress, and cell cycle pathways in addition to pathways providing potential screening for hematotoxicity, renal toxicity and urinary cancer. Ten pathway-level responses from IdMOC suggested that DNAN elicited toxicity representative of the primary metabolite, 2,4-dinitrophenol (2,4-DNP). Relative to monoculture, IdMOC results provided a higher nµMber and more robust enrichment of pathways involved in known in vivo toxicity mechanisms for TNT and a profile indicative of in vivo systemic toxicity of DNAN and metabolite 2,4-DNP.

2018-12-01 | GSE90618 | GEO

Hazard Assessment of High-Nitrogen Compounds: Coupling Transcriptomics with Multi-Cellular Co-Culture Assays Provides Accurate Systemic Toxicity Screening [DNAN]

Project description:Abstract - Current in vitro hazard assessment techniques lack the systems context necessary to holistically describe in vivo toxicity. To remedy this shortcoming, we have employed the Integrated discrete Multiple Organ Co-Culture (IdMOC) system in conjunction with global-transcriptomic expression assessment to provide a systems context of interactive organ and toxicity pathway responses. Specifically, IdMOC exposures containing human cells representative of five organ types (kidney, liver, lung, vascular endothelium and heart muscle) were compared to mono-culture exposures, to evaluate toxic effects in a well-studied legacy munition, 2,4,6-trinitrotoluene (TNT) compared to a structurally similar insensitive munition, 2,4-dinitroanisole (DNAN) having sparsely described toxicity. DNAN toxicity, based on cell viability, was significantly lower than TNT for three cell lines: liver, vascular endothelium, and heart. Toxicity pathways enriched in transcriptional analysis of kidney cells exposed to TNT and DNAN through the IdMOC system reflected the literature-based in vivo mammalian toxicity of parent compounds and metabolites where multiple screening values matched chronic dosing levels within 1 order of magnitude. Enriched pathways were primarily unique to each chemical where TNT exposures affected xenobiotic metabolism, oxidative stress, and cell cycle pathways in addition to pathways providing potential screening for hematotoxicity, renal toxicity and urinary cancer. Ten pathway-level responses from IdMOC suggested that DNAN elicited toxicity representative of the primary metabolite, 2,4-dinitrophenol (2,4-DNP). Relative to monoculture, IdMOC results provided a higher number and more robust enrichment of pathways involved in known in vivo toxicity mechanisms for TNT and a profile indicative of in vivo systemic toxicity of DNAN and metabolite 2,4-DNP.

2018-12-01 | GSE90617 | GEO

Hazard Assessment of High-Nitrogen Compounds: Coupling Transcriptomics with Multi-Cellular Co-Culture Assays Provides Accurate Systemic Toxicity Screening

Project description:This SuperSeries is composed of the SubSeries listed below.

2018-12-01 | GSE90619 | GEO

Homo sapiens

Project description:Hazard Assessment of High-Nitrogen Compounds: Coupling Transcriptomics with Multi-Cellular Co-Culture Assays Provides Accurate Systemic Toxicity Screening [TNT]

| PRJNA355198 | ENA

Homo sapiens

Project description:Hazard Assessment of High-Nitrogen Compounds: Coupling Transcriptomics with Multi-Cellular Co-Culture Assays Provides Accurate Systemic Toxicity Screening [DNAN]

| PRJNA355199 | ENA

Coupling genome-wide transcriptomics and developmental toxicity profiles in zebrafish to characterize polycyclic aromatic hydrocarbon (PAH) hazard

Project description:Coupling genome-wide transcriptomics and developmental toxicity profiles in zebrafish to characterize polycyclic aromatic hydrocarbon (PAH) hazard

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Simplified ChIP-exo assays

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Neuron-astrocyte metabolic coupling protects against activity-induced fatty acid toxicity

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Systems modeling of developmental vascular toxicity

Project description:More than 80,000 chemicals in commerce present a challenge for hazard assessments that toxicity testing in the 21st century strives to address through high-throughput screening (HTS) assays. Assessing chemical effects on human development adds an additional layer of complexity to the screening, with a need to capture complex and dynamic events essential for proper embryo-fetal development. HTS data from ToxCast/Tox21 informs systems toxicology models, which incorporate molecular targets and biological pathways into mechanistic models describing the effects of chemicals on human cells, 3D organotypic culture models, and small model organisms. Adverse Outcome Pathways (AOPs) provide a useful framework for integrating the evidence derived from these in silico and in vitro systems to inform chemical hazard characterization. To illustrate this formulation, we have built an AOP for developmental toxicity through a mode of action linked to embryonic vascular disruption (Aop43). Here, we review the model for quantitative prediction of developmental vascular toxicity from ToxCast HTS data and compare the HTS results to functional vascular development assays in complex cell systems, virtual tissues, and small model organisms. ToxCast HTS predictions from several published and unpublished assays covering different aspects of the angiogenic cycle were generated for a test set of 38 chemicals representing a range of putative vascular disrupting compounds (pVDCs). Results boost confidence in the capacity to predict adverse developmental outcomes from HTS in vitro data and model computational dynamics for in silico reconstruction of developmental systems biology. Finally, we demonstrate the integration of the AOP and developmental systems toxicology to investigate the unique modes of action of two angiogenesis inhibitors.

2019-06-08 | GSE132375 | GEO

Whole organism transcriptomic analysis provides mechanistic insight into the acute toxicity of emamectin benzoate in Daphnia magna

Project description:This experiment was conducted to study the short-term (12h) transcriptional responses in Daphnia magna after exposure to the anti-sea lice chemical emamectin benzoate (EMB). The microarray results were further vefiried using qPCR. The gene exression responses were linked to adverse effects after 48h exposure, in order to supply knowledge for environmental hazard assessment of this chemical in non-target crustaceans.

2016-06-30 | GSE83859 | GEO

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