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AOP: 423

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

Toxicological mechanisms of hepatocyte apoptosis through the PARP1 dependent cell death pathway

Short name

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

hepatocyte apoptosis

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

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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

Xiaoqing Wang, Fei Li, Jialin Liu, Qiongyu Li, Chenglong Ji, Huifeng Wu

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

Fei Li (email point of contact)

Contributors

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Fei Li

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

This AOP was last modified on April 29, 2023 16:03

Revision dates for related pages

Page	Revision Date/Time
Activation, PARP1	July 18, 2022 05:23
Releasing, Apoptosis-Inducing Factor (AIF)	July 18, 2022 05:25
Mitochondrial dysfunction	April 17, 2024 08:26
Increase, DNA damage	May 08, 2019 12:28
Apoptotic cell death	November 02, 2020 07:11
ROS formation	September 16, 2017 10:17
PARP1 leads to Mitochondrial dysfunction	July 28, 2022 03:36

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 changes of PARP1 activity were considered as the molecular initial event. The activated PARP1 affected the downstream key events, such as the damage of mitochondrial structure and function, apoptotic factors AIF release and ROS production and DNA damage. These key events finally induced cell death through PARP1 dependent pathway. Mitochondrial PARP1 was a vital target to illuminate the early mechanism of apoptosis induced by typical organophosphate ester.

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

Triphenyl phosphate (TPP), as a typical aryl organophosphate ester, has drew much attention to its adverse effects (Du et al., 2016; Mendelsohn et al., 2016; Su et al., 2014; Zhang et al., 2016). It was also considered as a mitochondrial toxicant that could alter mitochondrial function and disorder mitochondria metabolism to exert severe cytotoxicity (Bowen et al., 2020). Further research is necessary to explore how TPP affects mitochondrial PARP1 activation in the early stage to cause cell death pathway.

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

In this study, the cell viability assay aimed to determine the effective dose of TPP on L02 cells. Docking analysis was performed to explore the structural characteristics and interaction between TPP and PARP1. The activity of PARP1 enzyme in mitochondria was determined to confirm the effects of TPP on PARP1. In addition, mitochondrial membrane potential (MMP), apoptotic induction factor (AIF) and reactive oxygen species (ROS) production, DNA damage, cell apoptosis, and PJ34 hydrochloride (PARP1 inhibitor) assay were conducted to further reveal the underlying toxicological effect.

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	2030	Activation, PARP1	PARP1
MIE	1278	ROS formation	ROS formation

KE	2031	Releasing, Apoptosis-Inducing Factor (AIF)	AIF release
KE	177	Mitochondrial dysfunction	Mitochondrial dysfunction
KE	1194	Increase, DNA damage	Increase, DNA Damage

1817

Apoptotic cell death

Relationships Between Two Key Events (Including MIEs and AOs)

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Title	Adjacency	Evidence	Quantitative Understanding

PARP1 leads to Mitochondrial dysfunction

adjacent

Moderate

Network View

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Prototypical Stressors

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Life Stage Applicability

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

Taxonomic Applicability

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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

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Essentiality of the Key Events

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Evidence Assessment

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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

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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