NFE2/Nrf2 repression

WCS_9606

common toxicological species human

10090

NCBI mouse

WCS_7955

common ecological species zebrafish

NFE2/Nrf2 repression

Molecular

AOPWiki 2017-06-02T16:27:39

2017-06-02T16:27:39

Activation, HIF1α

Cellular

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Activation Sema6A

Cellular

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Activation, Dll4-Notch pathway

Cellular

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increased，Vascular endothelial dysfunction

Tissue

AOPWiki 2021-08-19T11:45:28

2021-09-01T20:37:06

Increase, Vascular disrupting effects

Individual

AOPWiki 2023-08-19T20:12:04

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Angiogenesis dysfunction

Organ

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AOPWiki 2023-08-28T05:01:05

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AOPWiki 2023-08-28T05:03:20

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Nrf2 inhibition leading to vascular disrupting effects through activating HIF1α, Semaphorin 6A, and Dll4-Notch pathway

Nrf2 inhibition leading to vascular disrupting effects

Yanhong Wei

Yanhong Wei Department of Toxicology, School of Public Health Sun Yat-sen University, Guangdong, China

2.6

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.<a name="_Hlk136427273"></a> This AOP focuses on the <a name="_Hlk136152466">vascular disrupting effect</a> via inhibiting the <a name="_Hlk139144228">Nrf2</a>-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.

adjacent

High

High adjacent

Moderate

High adjacent

Moderate

Moderate adjacent

High

High adjacent

High

High adjacent

High

High Mixed

Moderate

All life stages

Low High High

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.  <ol> <li style="text-align:justify"><a name="_Hlk139480582">Life Stage</a> Applicability</li> </ol> The AOPs are not life stage specific <ol start="2"> <li style="text-align:justify">Taxonomic Applicability</li> </ol> <table align="center" cellspacing="0" class="MsoTableGrid" style="border-collapse:collapse; border:none"> <tbody> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:75px"> Term </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; width:85px"> Scientific Term </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; width:76px"> Evidence </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; width:317px"> Links </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; width:75px"> Human </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; width:85px"> Homo sapiens </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; width:76px"> Low </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; width:317px"> https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=9606 </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; width:75px"> Mouse </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; width:85px"> Mus musculus </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; width:76px"> High </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; width:317px"> https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=10090 </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; width:75px"> Zebrafish </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; width:85px"> Danio rerio </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; width:76px"> High </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; width:317px"> https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=7955 </td> </tr> </tbody> </table>   <ol start="3"> <li style="text-align:justify">Sex Applicability</li> </ol> Mixed

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.

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.   <table cellspacing="0" style="border-collapse:collapse; width:901px"> <tbody> <tr> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; height:20px; text-align:center; vertical-align:middle; white-space:nowrap; width:293px"> </td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap; width:101px"> </td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap; width:101px"> </td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap; width:101px"> </td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap; width:101px"> </td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap; width:101px"> </td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap; width:101px"> </td> </tr> <tr> <td style="border-bottom:none; border-left:none; border-right:none; border-top:1px solid black; height:20px; text-align:center; vertical-align:middle; white-space:nowrap">　</td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:1px solid black; text-align:center; vertical-align:middle; white-space:nowrap">Assigned weight</td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:1px solid black; text-align:center; vertical-align:middle; white-space:nowrap"> Qualitative rating</td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:1px solid black; text-align:center; vertical-align:middle; white-space:nowrap">　</td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:1px solid black; text-align:center; vertical-align:middle; white-space:nowrap">　</td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:1px solid black; text-align:center; vertical-align:middle; white-space:nowrap">　</td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:1px solid black; text-align:center; vertical-align:middle; white-space:nowrap">　</td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:none; border-right:none; border-top:none; height:20px; text-align:center; vertical-align:middle; white-space:nowrap">　</td> <td style="border-bottom:1px solid black; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap">　</td> <td style="border-bottom:1px solid black; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap">MIE</td> <td style="border-bottom:1px solid black; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap">KE1</td> <td style="border-bottom:1px solid black; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap">KE2</td> <td style="border-bottom:1px solid black; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap">KE3</td> <td style="border-bottom:1px solid black; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap">KE4</td> </tr> <tr> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; height:20px; text-align:center; vertical-align:middle; white-space:nowrap">Biological plausibility</td> <td colspan="6" style="border-bottom:none; border-left:none; border-right:none; border-top:1px solid black; text-align:center; vertical-align:middle; white-space:nowrap">Some in vivo and in vitro evidence suggest that the chemicals can cause the vascular toxicity</td> </tr> <tr> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; height:20px; text-align:center; vertical-align:middle; white-space:nowrap">Essentiality empirical support</td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap">0.4</td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap">1</td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap">1</td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap">1</td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap">1</td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap">1</td> </tr> <tr> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; height:20px; text-align:center; vertical-align:middle; white-space:nowrap">Dose and incidence concordance</td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap">0.2</td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap">3</td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap">3</td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap">3</td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap">2</td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap">3</td> </tr> <tr> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; height:20px; text-align:center; vertical-align:middle; white-space:nowrap">Empirical support temporal concordance</td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap">0.2</td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap">3</td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap">3</td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap">3</td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap">2</td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap">3</td> </tr> <tr> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; height:20px; text-align:center; vertical-align:middle; white-space:nowrap">Consistency across test systems</td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap">0.1</td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap">3</td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap">3</td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap">3</td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap">2</td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap">3</td> </tr> <tr> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; height:20px; text-align:center; vertical-align:middle; white-space:nowrap">Analogy mutiple studies support KE and KER</td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap">0.1</td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap">3</td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap">3</td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap">3</td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap">3</td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap">3</td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:none; border-right:none; border-top:none; height:20px; text-align:center; vertical-align:middle; white-space:nowrap">Score</td> <td style="border-bottom:1px solid black; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap">1</td> <td style="border-bottom:1px solid black; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:bottom; white-space:nowrap">2.2</td> <td style="border-bottom:1px solid black; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:bottom; white-space:nowrap">2.2</td> <td style="border-bottom:1px solid black; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap">2.2</td> <td style="border-bottom:1px solid black; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap">1.7</td> <td style="border-bottom:1px solid black; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap">2.2</td> </tr> <tr> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; height:41px; text-align:center; vertical-align:middle; white-space:nowrap">AOP Score</td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap">0.7</td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap"> </td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap"> </td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap"> </td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap"> </td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap"> </td> </tr> </tbody> </table>

<div> <table class="table table-bordered table-fullwidth"> <thead> <tr> <th>Modulating Factor (MF)</th> <th>Influence or Outcome</th> <th>KER(s) involved</th> </tr> </thead> <tbody> <tr> <td> </td> <td> </td> <td> </td> </tr> </tbody> </table> </div>

Optional field to provide quantitative weight of evidence descriptors.

[1]        ELLIS-HUTCHINGS R G, SETTIVARI R S, MCCOY A T, et al. Embryonic vascular disruption adverse outcomes: Linking high throughput signaling signatures with functional consequences [J]. Reproductive toxicology (Elmsford, NY), 2017, 70: 82-96. [2]        KLEINSTREUER N C, JUDSON R S, REIF D M, et al. Environmental impact on vascular development predicted by high-throughput screening [J]. Environ Health Perspect, 2011, 119(11): 1596-603. [3]        LIND L, ARAUJO J A, BARCHOWSKY A, et al. Key Characteristics of Cardiovascular Toxicants [J]. Environ Health Perspect, 2021, 129(9): 95001. [4]        BECKER R A, DELLARCO V, SEED J, et al. Quantitative weight of evidence to assess confidence in potential modes of action [J]. Regulatory toxicology and pharmacology : RTP, 2017, 86: 205-20. [5]        HE F, RU X, WEN T. NRF2, a Transcription Factor for Stress Response and Beyond [J]. International journal of molecular sciences, 2020, 21(13). [6]        REY S, SEMENZA G L. 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