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AOP: 508
Title
Nrf2 inhibition leading to vascular disrupting effects through activating HIF1α, Semaphorin 6A, and Dll4-Notch pathway
Short name
Graphical Representation
Point of Contact
Contributors
- Yanhong Wei
Coaches
OECD Information Table
OECD Project # | OECD Status | Reviewer's Reports | Journal-format Article | OECD iLibrary Published Version |
---|---|---|---|---|
This AOP was last modified on August 28, 2023 06:42
Revision dates for related pages
Page | Revision Date/Time |
---|---|
NFE2/Nrf2 repression | June 02, 2017 16:27 |
Activation, HIF1α | August 20, 2023 07:16 |
Activation Sema6A | August 20, 2023 07:17 |
Activation, Dll4-Notch pathway | August 20, 2023 07:18 |
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 |
NFE2/Nrf2 repression leads to Activation, HIF1α | August 20, 2023 07:20 |
Activation, HIF1α leads to Activation Sema6A | August 20, 2023 07:20 |
Activation Sema6A leads to Activation, Dll4-Notch pathway | August 20, 2023 07:21 |
Activation, Dll4-Notch pathway leads to increased,Vascular endothelial dysfunction | August 20, 2023 07:21 |
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
CVDs are the leading cause of morbidity and mortality worldwide. Vascular network is an important channel of chemical’s ADME process and an essential target of toxic effect. Therefore, it is necessary to elucidate the AOP of vascular disrupting effects. Past studies showed that nuclear factor (erythroid-derived 2)-like 2 (Nrf2) inhibition could regulate the response of key events and the activation of downstream pathways including the activation of HIF1α, activation of Sema6A, activation of Dll4-Notch pathway, vascular endothelial dysfunction and Angiogenesis disfunction, which ultimately leads to vascular disrupting effects. Collectively, As part of an integrated assessment of toxicity, this AOP can identify useful information for assessing adverse outcomes relevant to risk assessment and efficient use of resources for validation through predictive models related to vascular toxicity. In future, AOP-based computer models that simulate vascular disrupting effects can usher-in new virtual screening techniques to predict what might happen to the vascular when exposed to chemicals across different dose-time-stage scenarios.
AOP Development Strategy
Context
This AOP focuses on the vascular disrupting effect via inhibiting the Nrf2-signaling pathway. The abnormal expression of Nrf2 plays an important role in the vasculogenesis and angiogenesis. The postulated molecular initiating event (MIE) for this AOP may be invoked by effects on the inhibition of Nrf2. Downstream key events (KE) include activation, HIF1α, activation Sema6A, activation, Dll4-Notch pathway, 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. Furthermore, to better elucidate the AOP of vascular disrupting effect, the established AOPs are included.
Strategy
Summary of the AOP
Events:
Molecular Initiating Events (MIE)
Key Events (KE)
Adverse Outcomes (AO)
Type | Event ID | Title | Short name |
---|
MIE | 1417 | NFE2/Nrf2 repression | NFE2/Nrf2 repression |
KE | 2162 | Activation, HIF1α | Activation, HIF1α |
KE | 2163 | Activation Sema6A | Activation Sema6A |
KE | 2164 | Activation, Dll4-Notch pathway | Activation, Dll4-Notch pathway |
KE | 1928 | increased,Vascular endothelial dysfunction | increased,Vascular endothelial dysfunction |
KE | 2181 | Angiogenesis dysfunction | Angiogenesis dysfunction |
AO | 2161 | Increase, Vascular disrupting effects | Increase, Vascular disrupting effects |
Relationships Between Two Key Events (Including MIEs and AOs)
Title | Adjacency | Evidence | Quantitative Understanding |
---|
NFE2/Nrf2 repression leads to Activation, HIF1α | adjacent | High | High |
Activation, HIF1α leads to Activation Sema6A | adjacent | High | Moderate |
Activation Sema6A leads to Activation, Dll4-Notch pathway | adjacent | Moderate | Moderate |
Activation, Dll4-Notch pathway 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
Prototypical Stressors
Life Stage Applicability
Life stage | Evidence |
---|---|
All life stages | Moderate |
Taxonomic Applicability
Sex Applicability
Sex | Evidence |
---|---|
Mixed | High |
Overall Assessment of the AOP
The biological plausibility of KERs is strong due to the available mechanistic evidence present in studies from a wide variety of taxa. Support for the essentiality of the key events can be obtained from a wide diversity of taxonomic groups, with lab rats, mice, and cell lines. Wei et al provided some 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. More studies are needed to explore the dose concordance, incidence concordance, and temporal concordance.
Domain of Applicability
- Life Stage Applicability
The AOPs are not life stage specific
- Taxonomic Applicability
Term |
Scientific Term |
Evidence |
Links |
Human |
Homo sapiens |
Low |
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 biological plausibility of KERs is strong due to the available mechanistic evidence present in studies from a wide variety of taxa. Nrf2 inhibition causes a variety of cellular responses. The essentiality of KERs is strong due to many evidence from different controlled experimental designs with controls. Support for the essentiality of the key events can be obtained from a wide diversity of taxonomic groups, with lab 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.
Evidence Assessment
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 | ||
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 |
Dose and incidence concordance | 0.2 | 3 | 3 | 3 | 2 | 3 |
Empirical support temporal concordance | 0.2 | 3 | 3 | 3 | 2 | 3 |
Consistency across test systems | 0.1 | 3 | 3 | 3 | 2 | 3 |
Analogy mutiple studies support KE and KER | 0.1 | 3 | 3 | 3 | 3 | 3 |
Score | 1 | 2.2 | 2.2 | 2.2 | 1.7 | 2.2 |
AOP Score | 0.7 |
Known Modulating Factors
Modulating Factor (MF) | Influence or Outcome | KER(s) involved |
---|---|---|
Quantitative Understanding
Optional field to provide quantitative weight of evidence descriptors.
Considerations for Potential Applications of the AOP (optional)
References
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