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AOP: 325

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

Excessive reactive oxygen species leading to growth inhibition via uncoupling of oxidative phosphorylation and reduced cell growth

Short name

A name that succinctly summarises the information from the title. This name should not exceed 90 characters. More help

ROS leading to growth inhibition via OXPHOS uncoupling and reduced cell growth

The current version of the Developer's Handbook will be automatically populated into the Handbook Version field when a new AOP page is created.Authors have the option to switch to a newer (but not older) Handbook version any time thereafter. More help

Handbook Version v2.0

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

Authors

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

You Song^a

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

You Song (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

You Song

Coaches

This field is used to identify coaches who supported the development of the AOP.Each coach selected must be a registered author. More help

Shihori Tanabe

OECD Information Table

Provides users with information concerning how actively the AOP page is being developed and whether it is part of the OECD Workplan and has been reviewed and/or endorsed. OECD Project: Assigned upon acceptance onto OECD workplan. This project ID is managed and updated (if needed) by the OECD. OECD Status: For AOPs included on the OECD workplan, ‘OECD status’ tracks the level of review/endorsement of the AOP . This designation is managed and updated by the OECD. Journal-format Article: The OECD is developing co-operation with Scientific Journals for the review and publication of AOPs, via the signature of a Memorandum of Understanding. When the scientific review of an AOP is conducted by these Journals, the journal review panel will review the content of the Wiki. In addition, the Journal may ask the AOP authors to develop a separate manuscript (i.e. Journal Format Article) using a format determined by the Journal for Journal publication. In that case, the journal review panel will be required to review both the Wiki content and the Journal Format Article. The Journal will publish the AOP reviewed through the Journal Format Article. OECD iLibrary published version: OECD iLibrary is the online library of the OECD. The version of the AOP that is published there has been endorsed by the OECD. The purpose of publication on iLibrary is to provide a stable version over time, i.e. the version which has been reviewed and revised based on the outcome of the review. AOPs are viewed as living documents and may continue to evolve on the AOP-Wiki after their OECD endorsement and publication. More help

OECD Project #	OECD Status	Reviewer's Reports	Journal-format Article	OECD iLibrary Published Version

This AOP was last modified on September 05, 2025 05:46

Revision dates for related pages

Page	Revision Date/Time
Increase, Reactive oxygen species	June 12, 2025 01:27
Increase, Oxidative Stress	February 11, 2026 07:05
Decrease, Coupling of oxidative phosphorylation	November 07, 2025 05:15
Decrease, Adenosine triphosphate pool	June 14, 2021 13:40
Decrease, Cell growth	May 23, 2025 05:31
Decrease, Growth	July 06, 2022 07:36
Increase, ROS leads to Increase, Oxidative Stress	August 02, 2024 15:40
Increase, Oxidative Stress leads to Decrease, Coupling of OXPHOS	August 21, 2025 08:44
Decrease, Coupling of OXPHOS leads to Decrease, ATP pool	July 06, 2022 07:39
Decrease, ATP pool leads to Decrease, Cell growth	August 21, 2025 08:50
Decrease, Cell growth leads to Decrease, Growth	August 21, 2025 08:50
Heavy metals (cadmium, lead, copper, iron, nickel)	October 25, 2021 03:21

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

A wide variety of chemicals can induce the formation of reactive oxygen species (ROS), disrupting the cellular redox balance. These chemicals interact with cellular components, including mitochondria and enzymes like cytochrome P450, leading to the generation of superoxide anions, hydrogen peroxide, and hydroxyl radicals. Once produced, ROS can oxidize lipids, proteins, and nucleic acids, resulting in cellular damage and contributing to oxidative stress. The extent of ROS production is influenced by factors such as the chemical structure, the efficiency of cellular defense mechanisms, and the presence of metal ions that can catalyze ROS formation.

Over time, excessive ROS generation can overwhelm antioxidant defenses, causing oxidative damage to essential macromolecules, including DNA, lipids, and proteins, as well as critical cellular components like the plasma membrane and mitochondria. Oxidative DNA damage is a direct consequence of excessive ROS formation. One of the most common oxidative modifications, 8-oxoguanine (8-oxoG), can mispair with adenine during DNA replication, leading to G to T transversions, a specific type of mutation.

Moreover, oxidative DNA damage can trigger cell death through several interconnected mechanisms, such as apoptosis (programmed cell death) and necrosis (uncontrolled cell death). Cell population dynamics plays a crucial role in regulating tissue and organismal growth.

As part of a large AOP network linking ROS to growth inhibition, this AOP mainly describes how excessive ROS formation leads to growth inhibtion via induction of lipid peroxidation and 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

MIE

1115

Increase, Reactive oxygen species

Increase, ROS

KE	1392	Increase, Oxidative Stress	Increase, Oxidative Stress
KE	1446	Decrease, Coupling of oxidative phosphorylation	Decrease, Coupling of OXPHOS
KE	1771	Decrease, Adenosine triphosphate pool	Decrease, ATP pool
KE	2327	Decrease, Cell growth	Decrease, Cell growth

1521

Decrease, Growth

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

Title	Adjacency	Evidence	Quantitative Understanding

Increase, ROS leads to Increase, Oxidative Stress	adjacent
Increase, Oxidative Stress leads to Decrease, Coupling of OXPHOS	adjacent
Decrease, Coupling of OXPHOS leads to Decrease, ATP pool	adjacent
Decrease, ATP pool leads to Decrease, Cell growth	adjacent
Decrease, Cell growth leads to Decrease, Growth	adjacent

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

Name
Heavy metals (cadmium, lead, copper, iron, nickel)

Life Stage Applicability

The life stage for which the AOP is known to be applicable. More help

Life stage	Evidence
Not Otherwise Specified
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

Term	Scientific Term	Evidence	Link
fish	fish		NCBI

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

Modulating Factor (MF)	Influence or Outcome	KER(s) involved

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