API XML

Aop: 209

AOP Title

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Perturbation of cholesterol and glutathione homeostasis leading to hepatotoxicity: Integrated multi-OMICS approach for building AOP

Short name:

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Cholesterol and glutathione leading to hepatotoxicity: Multi-OMICS approach

Graphical Representation

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Authors

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Jinhee Choi, University of Seoul, Republic of Korea

Nivedita Chatterjee, University of Seoul, India

Jaeseong Jeong, University of Seoul, Republic of Korea

Point of Contact

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Jinhee Choi   (email point of contact)

Contributors

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  • Jinhee Choi

Status

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Author status OECD status OECD project SAAOP status
Under development: Not open for comment. Do not cite Under Development


This AOP was last modified on July 02, 2018 22:10

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Revision dates for related pages

Page Revision Date/Time
Up Regulation, SREBF2 September 16, 2017 10:17
Up Regulation, Unsaturated fatty acid September 16, 2017 10:17
Down Regulation, GSS and GSTs gene September 16, 2017 10:17
Glutathione synthesis September 16, 2017 10:17
Activation, 3-hydroxy-3-methylglutaryl-CoA reductase gene September 16, 2017 10:17
Perturbation of cholesterol September 16, 2017 10:17
Glutathione homeostasis September 16, 2017 10:17
Hepatotoxicity February 15, 2017 04:11
Up Regulation, SREBF2 leads to Up Regulation, Unsaturated fatty acid February 15, 2017 04:11
Up Regulation, Unsaturated fatty acid leads to Perturbation of cholesterol February 15, 2017 04:12
Down Regulation, GSS and GSTs gene leads to Glutathione synthesis February 15, 2017 04:12
Glutathione synthesis leads to Activation, 3-hydroxy-3-methylglutaryl-CoA reductase gene February 15, 2017 04:12
Activation, 3-hydroxy-3-methylglutaryl-CoA reductase gene leads to Perturbation of cholesterol February 15, 2017 04:13
Down Regulation, GSS and GSTs gene leads to Glutathione homeostasis February 15, 2017 04:13
Perturbation of cholesterol leads to Hepatotoxicity February 15, 2017 04:13
Glutathione homeostasis leads to Hepatotoxicity February 15, 2017 04:13
Silica nanoparticles February 15, 2017 04:01

Abstract

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The system toxicology approach using ‘multi-OMICS-profiling-techniques’ (transcriptomics, proteomics and metabolomics) have proven to be robust tool for unraveling complex molecular machinery underlying various physiological, as well as, pathophysiological processes and have been successfully utilized in various fields including stress biology and toxicology. The application of multi-OMICS approaches are gaining acceptance in the regulatory community to provide information on a chemical’s hazard and risks though their mode-of-action (MOA), however, its utility in a AOP building context are still limited. This AOP is constituted the MIE as sterol regulatory element binding transcription factor 2 (SREBF2) gene activation and repressions of glutathione synthetase (GSS) and glutathione S-transferases (GSTA1, GSTA2, GSTA3, GSTA5) genes and the KEs as perturbation of cholesterol, though up regulated unsaturated fatty acid concentration, and glutathione homeostasis leading to oxidative stress, DNA damage and AO as hepatotoxicity (HepG2 cell death).


Background (optional)

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Summary of the AOP

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Events: Molecular Initiating Events (MIE)

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Key Events (KE)

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Adverse Outcomes (AO)

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Sequence Type Event ID Title Short name
1 KE 1284 Up Regulation, SREBF2 Up Regulation, SREBF2
2 KE 1285 Up Regulation, Unsaturated fatty acid Up Regulation, Unsaturated fatty acid
3 KE 1286 Down Regulation, GSS and GSTs gene Down Regulation, GSS and GSTs gene
4 KE 1287 Glutathione synthesis Glutathione synthesis
5 KE 1288 Activation, 3-hydroxy-3-methylglutaryl-CoA reductase gene Activation, 3-hydroxy-3-methylglutaryl-CoA reductase gene
6 KE 1289 Perturbation of cholesterol Perturbation of cholesterol
7 KE 1290 Glutathione homeostasis Glutathione homeostasis
8 AO 1291 Hepatotoxicity Hepatotoxicity

Relationships Between Two Key Events
(Including MIEs and AOs)

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Title Adjacency Evidence Quantitative Understanding
Up Regulation, SREBF2 leads to Up Regulation, Unsaturated fatty acid adjacent
Up Regulation, Unsaturated fatty acid leads to Perturbation of cholesterol adjacent
Down Regulation, GSS and GSTs gene leads to Glutathione synthesis adjacent
Glutathione synthesis leads to Activation, 3-hydroxy-3-methylglutaryl-CoA reductase gene adjacent
Activation, 3-hydroxy-3-methylglutaryl-CoA reductase gene leads to Perturbation of cholesterol adjacent
Down Regulation, GSS and GSTs gene leads to Glutathione homeostasis adjacent
Perturbation of cholesterol leads to Hepatotoxicity adjacent
Glutathione homeostasis leads to Hepatotoxicity adjacent

Network View

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Stressors

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Name Evidence Term
Silica nanoparticles

Life Stage Applicability

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Life stage Evidence
All life stages

Taxonomic Applicability

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Sex Applicability

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Sex Evidence
Unspecific

Overall Assessment of the AOP

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Domain of Applicability

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Essentiality of the Key Events

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Evidence Assessment

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Quantitative Understanding

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Considerations for Potential Applications of the AOP (optional)

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References

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