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AOP: 447

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

Kidney failure induced by inhibition of mitochondrial electron transfer chain through apoptosis, inflammation and oxidative stress pathways

Short name

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

Kidney failure induced by inhibition of mitochondrial ETC

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

Institut de Radioprotection et de Sûreté Nucléaire (IRSN), PSE-SANTE, SESANE, Fontenay-aux-Roses, France

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

Brendan Ferreri-Hanberry (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

Yann GUEGUEN
Marie FREREJACQUES
Brendan Ferreri-Hanberry

Coaches

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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

Handbook Version	OECD status	OECD project
v2.0

This AOP was last modified on April 29, 2023 13:02

Revision dates for related pages

Page	Revision Date/Time
Inhibition, Mitochondrial Electron Transport Chain Complexes	March 22, 2023 11:04
Increase, Mitochondrial Dysfunction	February 09, 2022 11:48
Decrease, Mitochondrial membrane potential	April 30, 2020 12:41
Altered gene expression, NRF2 dependent antioxidant pathway	August 19, 2021 07:35
Inhibition, Nuclear factor kappa B (NF-kB)	March 02, 2023 01:58
Activation of ER stress	November 02, 2020 07:09
Increased, Oxidative Stress	February 03, 2022 14:20
Increase, Apoptosis	April 15, 2017 16:17
Increase in inflammation	May 03, 2019 14:27
Occurrence, renal proximal tubular necrosis	September 16, 2017 10:16
Occurrence, Kidney toxicity	March 04, 2022 10:58
Increased, Kidney Failure	January 16, 2019 08:57
Inhibition, ETC complexes of the respiratory chain leads to Decrease, MMP	April 08, 2022 08:27
Decrease, MMP leads to Increase, Mt Dysfunction	April 08, 2022 08:28
Increase, Mt Dysfunction leads to Altered expression of NRF2 pathway-dependent genes	April 08, 2022 08:29
Increase, Mt Dysfunction leads to Inhibition, Nuclear factor kappa B (NF-kB)	April 08, 2022 08:30
Increase, Mt Dysfunction leads to Increase, Apoptosis	April 08, 2022 08:31
Altered expression of NRF2 pathway-dependent genes leads to ER stress	April 08, 2022 08:31
Altered expression of NRF2 pathway-dependent genes leads to Increased, Oxidative Stress	April 08, 2022 08:32
ER stress leads to Increase, Apoptosis	April 08, 2022 08:32
Inhibition, Nuclear factor kappa B (NF-kB) leads to Increase in inflammation	April 08, 2022 08:32
Increased, Oxidative Stress leads to Occurrence, renal proximal tubular necrosis	December 03, 2016 16:38
Increase, Apoptosis leads to Occurrence, renal proximal tubular necrosis	April 08, 2022 08:34
Increase in inflammation leads to Occurrence, renal proximal tubular necrosis	April 08, 2022 08:34
Occurrence, renal proximal tubular necrosis leads to Occurrence, Kidney toxicity	April 08, 2022 08:35
Occurrence, Kidney toxicity leads to Increased, Kidney Failure	April 08, 2022 08:35
Uranium	August 05, 2021 14:28
Uranium, soluble salts	April 08, 2022 08:55

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

U metal-ions are filtered through the glomerular membrane of the kidneys, then concentrate in cortical and juxtaglomerular areas and bind to the brush border membrane of the proximal convoluted tubules. U uptake by epithelial cells occurs through endocytosis and the sodium-dependent phosphate co-transporter (NaPi-IIa). Molecular key events start with U induce mitochondrial ETC inhibition (KE1), decrease MMP (KE2) and mitochondrial disruption (KE3). The collapse of mitochondrial membrane potential triggers the Nrf2 (KE3), NF-κB (KE4) or endoplasmic reticulum-stress (KE5) pathways. The resulting cellular key events include oxidative stress (KE6), apoptosis (KE7), and pro-inflammatory effects (KE8). Finally, the main adverse outcome is tubular cell necrosis (KE9), leading to kidney toxicity (KE10) and then kidney failure (AO).

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

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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	105	Inhibition, Mitochondrial Electron Transport Chain Complexes	Inhibition, ETC complexes of the respiratory chain
KE	1770	Decrease, Mitochondrial membrane potential	Decrease, MMP
KE	1968	Increase, Mitochondrial Dysfunction	Increase, Mt Dysfunction
KE	1917	Altered gene expression, NRF2 dependent antioxidant pathway	Altered expression of NRF2 pathway-dependent genes
KE	202	Inhibition, Nuclear factor kappa B (NF-kB)	Inhibition, Nuclear factor kappa B (NF-kB)
KE	1815	Activation of ER stress	ER stress
KE	1088	Increased, Oxidative Stress	Increased, Oxidative Stress
KE	1365	Increase, Apoptosis	Increase, Apoptosis
KE	1633	Increase in inflammation	Increase in inflammation
KE	1097	Occurrence, renal proximal tubular necrosis	Occurrence, renal proximal tubular necrosis
KE	814	Occurrence, Kidney toxicity	Occurrence, Kidney toxicity

759

Increased, Kidney Failure

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

Inhibition, ETC complexes of the respiratory chain leads to Decrease, MMP	adjacent
Decrease, MMP leads to Increase, Mt Dysfunction	adjacent
Increase, Mt Dysfunction leads to Altered expression of NRF2 pathway-dependent genes	adjacent
Increase, Mt Dysfunction leads to Inhibition, Nuclear factor kappa B (NF-kB)	adjacent
Increase, Mt Dysfunction leads to Increase, Apoptosis	adjacent
Altered expression of NRF2 pathway-dependent genes leads to ER stress	adjacent
Altered expression of NRF2 pathway-dependent genes leads to Increased, Oxidative Stress	adjacent
ER stress leads to Increase, Apoptosis	adjacent
Inhibition, Nuclear factor kappa B (NF-kB) leads to Increase in inflammation	adjacent
Increased, Oxidative Stress leads to Occurrence, renal proximal tubular necrosis	adjacent
Increase, Apoptosis leads to Occurrence, renal proximal tubular necrosis	adjacent
Increase in inflammation leads to Occurrence, renal proximal tubular necrosis	adjacent
Occurrence, renal proximal tubular necrosis leads to Occurrence, Kidney toxicity	adjacent
Occurrence, Kidney toxicity leads to Increased, Kidney Failure	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
Uranium
Uranium, soluble salts

Life Stage Applicability

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

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

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