Aop: 209

Title

A descriptive phrase which references both the Molecular Initiating Event and Adverse Outcome.It should take the form “MIE leading to AO”. For example, “Aromatase inhibition leading to reproductive dysfunction” where Aromatase inhibition is the MIE and reproductive dysfunction the AO. In cases where the MIE is unknown or undefined, the earliest known KE in the chain (i.e., furthest upstream) should be used in lieu of the MIE and it should be made clear that the stated event is a KE and not the MIE. More help

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

Short name
A name that succinctly summarises the information from the title. This name should not exceed 90 characters. More help
Cholesterol and glutathione leading to hepatotoxicity: Multi-OMICS approach

Graphical Representation

A graphical representation of the AOP.This graphic should list all KEs in sequence, including the MIE (if known) and AO, and the pair-wise relationships (links or KERs) between those KEs. More help
Click to download graphical representation template Explore AOP in a Third Party Tool
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Authors

The names and affiliations of the individual(s)/organisation(s) that created/developed the AOP. More help

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

The user responsible for managing the AOP entry in the AOP-KB and controlling write access to the page by defining the contributors as described in the next section.   More help
Allie Always   (email point of contact)

Contributors

Users with write access to the AOP page.  Entries in this field are controlled by the Point of Contact. More help
  • Jinhee Choi
  • Allie Always

Status

Provides users with information concerning how actively the AOP page is being developed, what type of use or input the authors feel comfortable with given the current level of development, and whether it is part of the OECD AOP Development Workplan and has been reviewed and/or endorsed. OECD Status - Tracks the level of review/endorsement the AOP has been subjected to. OECD Project Number - Project number is designated and updated by the OECD. SAAOP Status - Status managed and updated by SAAOP curators. More help
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 16, 2022 18:37

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

A concise and informative summation of the AOP under development that can stand-alone from the AOP page. The aim is to capture the highlights of the AOP and its potential scientific and regulatory relevance. More help

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).

AOP Development Strategy

Context

Used to provide background information for AOP reviewers and users that is considered helpful in understanding the biology underlying the AOP and the motivation for its development.The background should NOT provide an overview of the AOP, its KEs or KERs, which are captured in more detail below. More help

Strategy

Provides a description of the approaches to the identification, screening and quality assessment of the data relevant to identification of the key events and key event relationships included in the AOP or AOP network.This information is important as a basis to support the objective/envisaged application of the AOP by the regulatory community and to facilitate the reuse of its components.  Suggested content includes a rationale for and description of the scope and focus of the data search and identification strategy/ies including the nature of preliminary scoping and/or expert input, the overall literature screening strategy and more focused literature surveys to identify additional information (including e.g., key search terms, databases and time period searched, any tools used). More help

Summary of the AOP

This section is for information that describes the overall AOP. The information described in section 1 is entered on the upper portion of an AOP page within the AOP-Wiki. This is where some background information may be provided, the structure of the AOP is described, and the KEs and KERs are listed. More help

Events:

Molecular Initiating Events (MIE)
An MIE is a specialised KE that represents the beginning (point of interaction between a prototypical stressor and the biological system) of an AOP. More help
Key Events (KE)
A measurable event within a specific biological level of organisation. More help
Adverse Outcomes (AO)
An AO is a specialized KE that represents the end (an adverse outcome of regulatory significance) of an AOP. More help
Type Event ID Title Short name
KE 1284 Up Regulation, SREBF2 Up Regulation, SREBF2
KE 1285 Up Regulation, Unsaturated fatty acid Up Regulation, Unsaturated fatty acid
KE 1286 Down Regulation, GSS and GSTs gene Down Regulation, GSS and GSTs gene
KE 1287 Glutathione synthesis Glutathione synthesis
KE 1288 Activation, 3-hydroxy-3-methylglutaryl-CoA reductase gene Activation, 3-hydroxy-3-methylglutaryl-CoA reductase gene
KE 1289 Perturbation of cholesterol Perturbation of cholesterol
KE 1290 Glutathione homeostasis Glutathione homeostasis
AO 1291 Hepatotoxicity Hepatotoxicity

Relationships Between Two Key Events (Including MIEs and AOs)

This table summarizes all of the KERs of the AOP and is populated in the AOP-Wiki as KERs are added to the AOP.Each table entry acts as a link to the individual KER description page. More help

Network View

This network graphic is automatically generated based on the information provided in the MIE(s), KEs, AO(s), KERs and Weight of Evidence (WoE) summary tables. The width of the edges representing the KERs is determined by its WoE confidence level, with thicker lines representing higher degrees of confidence. This network view also shows which KEs are shared with other AOPs. More help

Prototypical Stressors

A structured data field that can be used to identify one or more “prototypical” stressors that act through this AOP. Prototypical stressors are stressors for which responses at multiple key events have been well documented. More help

Life Stage Applicability

The life stage for which the AOP is known to be applicable. More help
Life stage Evidence
All life stages

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available. More help

Sex Applicability

The sex for which the AOP is known to be applicable. More help
Sex Evidence
Unspecific

Overall Assessment of the AOP

Addressess the relevant biological domain of applicability (i.e., in terms of taxa, sex, life stage, etc.) and Weight of Evidence (WoE) for the overall AOP as a basis to consider appropriate regulatory application (e.g., priority setting, testing strategies or risk assessment). More help

Domain of Applicability

Addressess the relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context. More help

Essentiality of the Key Events

The essentiality of KEs can only be assessed relative to the impact of manipulation of a given KE (e.g., experimentally blocking or exacerbating the event) on the downstream sequence of KEs defined for the AOP. Consequently, evidence supporting essentiality is assembled on the AOP page, rather than on the independent KE pages that are meant to stand-alone as modular units without reference to other KEs in the sequence. The nature of experimental evidence that is relevant to assessing essentiality relates to the impact on downstream KEs and the AO if upstream KEs are prevented or modified. This includes: Direct evidence: directly measured experimental support that blocking or preventing a KE prevents or impacts downstream KEs in the pathway in the expected fashion. Indirect evidence: evidence that modulation or attenuation in the magnitude of impact on a specific KE (increased effect or decreased effect) is associated with corresponding changes (increases or decreases) in the magnitude or frequency of one or more downstream KEs. More help

Evidence Assessment

Addressess the biological plausibility, empirical support, and quantitative understanding from each KER in an AOP. More help

Known Modulating Factors

Modulating factors (MFs) may alter the shape of the response-response function that describes the quantitative relationship between two KES, thus having an impact on the progression of the pathway or the severity of the AO.The evidence supporting the influence of various modulating factors is assembled within the individual KERs. More help

Quantitative Understanding

Optional field to provide quantitative weight of evidence descriptors.  More help

Considerations for Potential Applications of the AOP (optional)

Addressess potential applications of an AOP to support regulatory decision-making.This may include, for example, possible utility for test guideline development or refinement, development of integrated testing and assessment approaches, development of (Q)SARs / or chemical profilers to facilitate the grouping of chemicals for subsequent read-across, screening level hazard assessments or even risk assessment. More help

References

List of the literature that was cited for this AOP. More help