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AOP: 258

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

Renal protein alkylation leading to kidney toxicity

Short name

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

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 v1.0

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

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Prof. Dr. Angela Mally Department of Toxicology University of Würzburg Versbacher Str. 9 97078 Würzburg Germany Phone: +49 931 31-81194 Email: mally@toxi.uni-wuerzburg.de (mailto:mally@toxi.uni-wuerzburg.de)

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

Angela Mally (email point of contact)

Contributors

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Angela Mally

Coaches

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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
1.43	Under Development

This AOP was last modified on February 28, 2024 14:59

Revision dates for related pages

Page	Revision Date/Time
Alkylation, Protein	September 16, 2017 10:14
Decrease, Mitochondrial ATP production	September 16, 2017 10:14
Increase, Cytotoxicity (renal tubular cell)	March 03, 2022 15:14
Occurrence, Kidney toxicity	March 04, 2022 10:58
Mitochondrial dysfunction	April 17, 2024 08:26
Alkylation, Protein leads to Mitochondrial dysfunction	February 28, 2024 14:58
Mitochondrial dysfunction leads to Decrease, Mitochondrial ATP production	January 05, 2023 07:47
Decrease, Mitochondrial ATP production leads to Increase, Cytotoxicity (renal tubular cell)	October 25, 2017 09:24
Increase, Cytotoxicity (renal tubular cell) leads to Occurrence, Kidney toxicity	March 08, 2022 11:46

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

It is well established that bioactivation of xenobiotics to reactive intermediates that covalently bind to proteins presents a major mechanism by which xenobiotics may cause proximal tubule injury. Examples for compounds that form covalent protein adducts in proximal tubule cells include haloalkenes (e.g. trichloroethylene, tetrachloroethylene, hexachloro-1,3-butadiene, chloroform), quinones (derived from e.g. hydroquinone, bromobenzene, 4-aminophenol), cephalosporins, and N-(3,5-dichlorophenyl)succinimide [1-6]. Covalent interaction of a chemical or a metabolite with cellular proteins represents the molecular initiating event (MIE) that triggers perturbation of cellular functions, of which mitochondrial dysfunction (KE1) leading to ATP depletion (KE2) appears to be most critical for proximal tubule cell death (KE3) by apoptosis and/or necrosis [5, 7-10]. Tubular obstruction and inflammatory responses to proximal tubule injury including activation of complement may cause secondary toxicity and thus amplify kidney injury, resulting in a progressive decline in kidney function (evidenced by e.g. rise in serum creatinine and blood urea nitrogen) (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

MIE

244

Alkylation, Protein

KE	177	Mitochondrial dysfunction	Mitochondrial dysfunction
KE	40	Decrease, Mitochondrial ATP production	Decrease, Mitochondrial ATP production
KE	709	Increase, Cytotoxicity (renal tubular cell)	Increase, Cytotoxicity (renal tubular cell)

814

Occurrence, Kidney toxicity

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

Alkylation, Protein leads to Mitochondrial dysfunction	adjacent	Not Specified	Low
Mitochondrial dysfunction leads to Decrease, Mitochondrial ATP production	adjacent	High	Low
Decrease, Mitochondrial ATP production leads to Increase, Cytotoxicity (renal tubular cell)	adjacent	High	Low
Increase, Cytotoxicity (renal tubular cell) leads to Occurrence, Kidney toxicity	adjacent	High	Moderate

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	Not Specified

Taxonomic Applicability

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Term	Scientific Term	Evidence	Link
Human, rat, mouse	Human, rat, mouse	High	NCBI

Sex Applicability

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

Sex	Evidence
Unspecific	High

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

Concordance of dose-response relationships

This is still a qualitiative description of the pathway. There is at present no quantitative information on dose-response relationships. Experiments are underway to provide quantitative understanding of dose-response relationships and response-response relationships between upstream and downstream KEs.

Temporal concordance among the key events and adverse outcome

The individual KEs are shown to occur prior to or concomitant with the onset of nephrotoxicity.

Strength, consistency, and specificity of association of adverse outcome and initiating event

The scientific evidence on the association between protein alkylation by reactive intermediates and kidney toxicity (AO) is strong and consistent. The MIE is not specific for kidney toxicity and is well established to lead to damage to other organs, whereby the site of toxicity is largely determined by the toxicokinetics of the parent compound or active metabolite.

Biological plausibility, coherence, and consistency of the experimental evidence

The described AOP is biologically plausible, coherent and well supported by experimental data.

Alternative mechanism(s) that logically present themselves and the extent to which they may distract from the postulated AOP

There are no alternative mechanism(s) that logically present themselves, although a contribution of other mechanisms such as generation of oxidative stress to the overall AO is possible.

Uncertainties, inconsistencies and data gaps

This AOP is plausible and consistent with general biological knowledge. However, there is currently little understanding as to which target proteins are critical to toxicity mediated by alkalation damage. Quantitative information on dose response-relationships as well as response-response relationships for upstream and downstream KEs is needed to support its applicability for the development of alternative in vitro tests for nephrotoxicity testing.

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

Quantitative data on KERs between upstream and downstream KE are still lacking.

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

The described AOP is intended to provide a mechanistic framework for the development of in vitro bioactivity assays capable of predicting quantitative points of departure for safety assessment with regard to nephrotoxicity. Such assays may form part of an integrated testing strategy to reduce the need for repeated dose toxicity studies (e.g. OECD Guideline 407; OECD Guideline 407).

References

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

1. Birner, G., et al., Metabolism of tetrachloroethene in rats: identification of N epsilon-(dichloroacetyl)-L-lysine and N epsilon-(trichloroacetyl)-L-lysine as protein adducts. Chem Res Toxicol, 1994. 7(6): p. 724-32.

2. Pahler, A., et al., Generation of antibodies to Di- and trichloroacetylated proteins and immunochemical detection of protein adducts in rats treated with perchloroethene. Chem Res Toxicol, 1998. 11(9): p. 995-1004.

3. Kleiner, H.E., et al., Immunochemical detection of quinol--thioether-derived protein adducts. Chem Res Toxicol, 1998. 11(11): p. 1283-90.

4. Lau, S.S., Quinone-thioether-mediated nephrotoxicity. Drug Metab Rev, 1995. 27(1-2): p. 125-41.

5. Tune, B.M., Nephrotoxicity of beta-lactam antibiotics: mechanisms and strategies for prevention. Pediatr Nephrol, 1997. 11(6): p. 768-72.

6. Griffin, R.J. and P.J. Harvison, In vivo metabolism and disposition of the nephrotoxicant N-(3, 5-dichlorophenyl)succinimide in Fischer 344 rats. Drug Metab Dispos, 1998. 26(9): p. 907-13.

7. Groves, C.E., et al., Pentachlorobutadienyl-L-cysteine (PCBC) toxicity: the importance of mitochondrial dysfunction. J Biochem Toxicol, 1991. 6(4): p. 253-60.

8. Chen, Y., et al., Role of mitochondrial dysfunction in S-(1,2-dichlorovinyl)-l-cysteine-induced apoptosis. Toxicol Appl Pharmacol, 2001. 170(3): p. 172-80.

9. Hill, B.A., T.J. Monks, and S.S. Lau, The effects of 2,3,5-(triglutathion-S-yl)hydroquinone on renal mitochondrial respiratory function in vivo and in vitro: possible role in cytotoxicity. Toxicol Appl Pharmacol, 1992. 117(2): p. 165-71.

10. Aleo, M.D., et al., Toxicity of N-(3,5-dichlorophenyl)succinimide and metabolites to rat renal proximal tubules and mitochondria. Chem Biol Interact, 1991. 78(1): p. 109-21.