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Demethylation of PPAR promotor leading to vascular disrupting effects
Point of Contact
- Yanhong Wei
|Handbook Version||OECD status||OECD project|
This AOP was last modified on August 28, 2023 07:21
|peroxisome proliferator activated receptor promoter demethylation||September 16, 2017 10:14|
|Activation of PPAR||August 20, 2023 22:14|
|Increase, Oxidative Stress||March 03, 2022 10:40|
|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|
|demethylation, PPARg promoter leads to Activation of PPAR||August 20, 2023 23:11|
|Activation of PPAR leads to Increase, Oxidative Stress||August 20, 2023 23:11|
|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|
|Increase, Oxidative Stress leads to Abnormal expression of NO||August 20, 2023 23:13|
|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|
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
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.
Summary of the AOP
Molecular Initiating Events (MIE)
Key Events (KE)
Adverse Outcomes (AO)
|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||1969||Increase, Oxidative Stress||Increase, 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|
|AO||2161||Increase, Vascular disrupting effects||Increase, Vascular disrupting effects|
Relationships Between Two Key Events (Including MIEs and AOs)
Life Stage Applicability
|All life stages||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. 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
- Life Stage Applicability
The AOPs are not life stage specific
- Taxonomic Applicability
- Sex Applicability
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. 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.
The QWOE approach is an analytical method that utilizes causality criteria to assess the evidence-supported postulated AOP. 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|
|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|
Known Modulating Factors
|Modulating Factor (MF)||Influence or Outcome||KER(s) involved|
Optional field to provide quantitative weight of evidence descriptors.
Considerations for Potential Applications of the AOP (optional)
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