AOP: 510

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

Demethylation of PPAR promotor leading to vascular disrupting effects

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 v2.6

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

Yanhong Wei

Department of Toxicology, School of Public Health

Sun Yat-sen University, Guangdong, China

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

Yanhong Wei (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

Yanhong Wei

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

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 July 04, 2024 16:22

Revision dates for related pages

Page	Revision Date/Time
peroxisome proliferator activated receptor promoter demethylation	September 16, 2017 10:14
Activation of PPAR	August 20, 2023 22:14
Abnormal expression of NO	August 20, 2023 22:18
Activation of MMP-2 MMP-9	August 20, 2023 22:20
Activation of angiopoietin like protein 4	August 20, 2023 22:23
Activation of Angiogenic cytokines	August 20, 2023 22:24
increased，Vascular endothelial dysfunction	September 01, 2021 20:37
Increase, Vascular disrupting effects	August 19, 2023 20:12
Angiogenesis dysfunction	August 28, 2023 05:00
Oxidative Stress	August 26, 2024 10:26
demethylation, PPARg promoter leads to Activation of PPAR	August 20, 2023 23:11
Activation of PPAR leads to Oxidative Stress	July 04, 2024 16:07
Activation of PPAR leads to Activation of MMP-2 MMP-9	August 20, 2023 23:12
Activation of PPAR leads to Activation of angiopoietin like protein 4	August 20, 2023 23:12
Activation of PPAR leads to Activation of Angiogenic cytokines	August 20, 2023 23:13
Oxidative Stress leads to Abnormal expression of NO	July 04, 2024 16:07
Activation of MMP-2 MMP-9 leads to increased，Vascular endothelial dysfunction	August 20, 2023 23:14
Activation of angiopoietin like protein 4 leads to increased，Vascular endothelial dysfunction	August 20, 2023 23:14
Activation of Angiogenic cytokines leads to increased，Vascular endothelial dysfunction	August 20, 2023 23:15
Abnormal expression of NO leads to increased，Vascular endothelial dysfunction	August 20, 2023 23:15
increased，Vascular endothelial dysfunction leads to Angiogenesis dysfunction	August 28, 2023 05:01
Angiogenesis dysfunction leads to Increase, Vascular disrupting effects	August 28, 2023 05:03

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

BACKGROUND: CVDs are the main cause of morbidity and mortality worldwide. Vascular network is an important channel of chemical’s ADME process and an important target of toxic effect. However, evidence inference information on the AOPs frameworks for the vascular toxic mechanisms remains limited. We collect toxicological information in literature from the following aspects: (1) In the screening of model organisms, aquatic organisms were mainly selected in vivo, supplemented by chicken embryos and mice, while cell lines were mainly selected in vitro. (2) The study focused on vascular toxicology, which are all closely related to human health hazards. (3) Molecular events and apical endpoint (MIEs, KEs, and AOs) contained changes in cellular function, pathways, transcription and expression, or organ status. In this hypothetical AOP network, the postulated molecular initiating event (MIE) may be invoked by effects on the inhibition of Nrf2. Downstream key events (KE) include Activation of PPAR, Oxidative stress, Abnormal expression of NO, Activation of MMP-2 MMP-9, Activation of angiopoietin like protein 4, Activation of Angiogenic cytokines, Vascular endothelial dysfunction. KE relationships (KERs) leading to Angiogenesis dysfunction. The severity of adverse outcomes (vascular disrupting effects) would ultimately vary by anatomical region, organ system, and physiological state when an MIE is invoked. In addition, it was considered that the results obtained in this investigation may potentially guide future vascular toxicological studies and enhance risk assessment.

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

This AOP focuses on the vascular disrupting effect. The demethylation of PPAR promotor plays an important role in the vasculogenesis and angiogenesis. The postulated AOP may be invoked by effects on the demethylation of PPAR promotor. Downstream key events (KE) include Activation of PPAR, Oxidative stress, Abnormal expression of NO, Activation of MMP-2 MMP-9, Activation of angiopoietin like protein 4, Activation of Angiogenic cytokines, Vascular endothelial dysfunction. KE relationships (KERs) lead to Angiogenesis dysfunction. The severity of adverse outcomes (vascular disrupting effects) would ultimately vary by anatomical region, organ system, and physiological state when an MIE is invoked. Furthermore, to better elucidate the AOP of vascular disrupting effect better, the established AOPs are included.

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

228

peroxisome proliferator activated receptor promoter demethylation

demethylation, PPARg promoter

KE	2165	Activation of PPAR	Activation of PPAR
KE	1392	Oxidative Stress	Oxidative Stress
KE	2166	Abnormal expression of NO	Abnormal expression of NO
KE	2167	Activation of MMP-2 MMP-9	Activation of MMP-2 MMP-9
KE	2168	Activation of angiopoietin like protein 4	Activation of angiopoietin like protein 4
KE	2169	Activation of Angiogenic cytokines	Activation of Angiogenic cytokines
KE	1928	increased，Vascular endothelial dysfunction	increased，Vascular endothelial dysfunction
KE	2181	Angiogenesis dysfunction	Angiogenesis dysfunction

2161

Increase, Vascular disrupting effects

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

demethylation, PPARg promoter leads to Activation of PPAR	adjacent	High	High
Activation of PPAR leads to Oxidative Stress	adjacent	High	High
Activation of PPAR leads to Activation of MMP-2 MMP-9	adjacent	High	High
Activation of PPAR leads to Activation of angiopoietin like protein 4	adjacent	High	High
Activation of PPAR leads to Activation of Angiogenic cytokines	adjacent	High	High
Oxidative Stress leads to Abnormal expression of NO	adjacent	High	High
Activation of MMP-2 MMP-9 leads to increased，Vascular endothelial dysfunction	adjacent	Moderate	Moderate
Activation of angiopoietin like protein 4 leads to increased，Vascular endothelial dysfunction	adjacent	High	High
Activation of Angiogenic cytokines leads to increased，Vascular endothelial dysfunction	adjacent	High	High
Abnormal expression of NO leads to increased，Vascular endothelial dysfunction	adjacent	High	High
increased，Vascular endothelial dysfunction leads to Angiogenesis dysfunction	adjacent	High	High
Angiogenesis dysfunction leads to Increase, Vascular disrupting effects	adjacent	High	High

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	High

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
human	Homo sapiens	High	NCBI
mouse	Mus musculus	High	NCBI
zebrafish	Danio rerio	High	NCBI

Sex Applicability

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

Sex	Evidence
Mixed	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

The biological plausibility of KERs is strong due to the available mechanistic evidence present in studies from a wide variety of taxa. The postulated molecular initiating event (MIE) for this AOP may be invoked by effects on the inhibition of Nrf2, and the key events (KEs) including Activation of PPAR, Oxidative stress, Abnormal expression of NO, Activation of MMP-2 MMP-9, Activation of angiopoietin like protein 4, Activation of Angiogenic cytokines, Vascular endothelial dysfunction. KE relationships (KERs) lead to Angiogenesis dysfunction, which is consistent with established biological understanding. Support for the essentiality of the key events can be obtained from a wide diversity of taxonomic groups, with lab rats, mice, cell lines, and zebrafish. Some studies provided evidence such as antagonism, knock-outs, or knock-ins to probe the necessity of MIE and KE. Furthermore, the AOP can be anticipated based on broader chemical-specific knowledge. However, more studies are needed to explore dose concordance, incidence concordance, and temporal concordance.

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

Life Stage Applicability

The AOPs are not life stage specific

Taxonomic Applicability

Term	Scientific Term	Evidence	Links
Human	Homo sapiens	High	https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=9606
Mouse	Mus musculus	High	https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=10090
Zebrafish	Danio rerio	High	https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=7955

Sex Applicability

Mixed

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

The biological plausibility of KERs is strong due to the available mechanistic evidence present in studies from a wide variety of taxa. The demethylation of PPAR promotor causes oxidative stress and a variety of cellular responses. The essentiality of KERs is strong due to many evidence from different controlled experimental designs with controls. Exposure to a various of chemical stressors has induced oxidative stress from PPAR activation. Support for the essentiality of the key events can be obtained from a wide diversity of taxonomic groups, with lab rats, mice, cell lines, and zebrafish. The empirical support of KERs is largely found in toxicological studies derived from reference chemicals with dose-response and temporal concordance assessed. Furthermore, weight of evidence for the MIE and AO are strong, the intermediate KEs have in some cases strong evidence but in other cases, weaker evidence, due to the lack of quantitative information.

Evidence Assessment

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

The QWOE approach is an analytical method that utilizes causality criteria to assess the evidence-supported postulated AOP^[4]. Firstly, the hypothesis of action was presented and the quantitative evaluation of evidence ranging from no evidence (0) to strong for each category (3, strong and −3, strong counter) utilizing the evolved MIEs, KEs, and KERs. Subsequently, a ranked importance-based numerical weight was assigned to Bradford Hill causal considerations, and the composite score and confidence score for MIEs, KEs, and entire AOP were evaluated.


	Assigned weight	Qualitative rating
		MIE	KE1	KE2	KE3	KE4	KE5	KE6	KE7
Biological plausibility	Some in vivo and in vitro evidence suggest that the chemicals can cause the vascular toxicity
Essentiality empirical support	0.4	1	1	1	1	1	1	1	1
Dose and incidence concordance	0.2	3	3	3	3	2	2	2	3
Empirical support temporal concordance	0.2	3	3	3	3	2	2	2	3
Consistency across test systems	0.1	3	3	3	3	2	2	2	3
Analogy mutiple studies support KE and KER	0.1	3	3	3	3	3	3	3	3
Score	1	2.2	2.2	2.2	2.2	1.7	1.7	1.7	2.2
AOP Score	0.670833

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

Optional field to provide quantitative weight of evidence descriptors.

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

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[2] CHEN C A, WANG T Y, VARADHARAJ S, et al. S-glutathionylation uncouples eNOS and regulates its cellular and vascular function [J]. Nature, 2010, 468(7327): 1115-8.

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[30] QIAN Y, DUCATMAN A, WARD R, et al. Perfluorooctane sulfonate (PFOS) induces reactive oxygen species (ROS) production in human microvascular endothelial cells: role in endothelial permeability [J]. Journal of toxicology and environmental health Part A, 2010, 73(12): 819-36.

[31] MARINELLO W P, MOHSENI Z S, CUNNINGHAM S J, et al. Perfluorobutane sulfonate exposure disrupted human placental cytotrophoblast cell proliferation and invasion involving in dysregulating preeclampsia related genes [J]. FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2020, 34(11): 14182-99.

[32] DANGUDUBIYYAM S V, MISHRA J S, ZHAO H, et al. Perfluorooctane sulfonic acid (PFOS) exposure during pregnancy increases blood pressure and impairs vascular relaxation mechanisms in the adult offspring [J]. Reproductive toxicology (Elmsford, NY), 2020, 98: 165-73.

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