This Key Event Relationship is licensed under the Creative Commons BY-SA license. This license allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use. If you remix, adapt, or build upon the material, you must license the modified material under identical terms.

Relationship: 1036

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Insufficiency, Vascular leads to Increased, Developmental Defects

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

Insufficiency, Vascular

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

Increased, Developmental Defects

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name	Adjacency	Weight of Evidence	Quantitative Understanding	Point of Contact	Author Status	OECD Status
Disruption of VEGFR Signaling Leading to Developmental Defects	non-adjacent	High	Moderate	Undefined (send email)	Open for citation & comment	WPHA/WNT Endorsed

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER. More help

Sex Applicability

An indication of the the relevant sex for this KER. More help

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER. More help

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

Blood vessels in a developing embryo change to accommodate rapid growth, morphogenesis and differentiation. The importance of development and maintenance of the vasculature is evident in the association between developmental defects and vascular insufficiency, particularly arterial dysgenesis, derived by experimental teratogenesis and inferred in clinical teratology [Vargesson and Hootnick, 2017]. Several known anti-angiogenic compounds have been shown to cause dose-dependent developmental defects in various animal models (e.g., zebrafish, frog, chick, mouse, rat) [Therapontos et al. 2009; Jang et al. 2009; Rutland et al. 2009; Tal et al. 2014; Vargesson, 2015; Beedie et al. 2016; Ellis-Hutchings et al. 2017; Kotini et al. 2020]. Human studies of malformations showed a correlation with genetic and/or environmental factors that target vascular development [Husain et al. 2008; Gold et al. 2011]. Broad analysis of medicinal compounds to which women of reproductive age were exposed identified ‘vascular disruption’ as one of six potential mechanisms of teratogenesis [van Gelder et al. 2010].

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings. Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

Biological Plausibility: A failure of correct vessel patterning, vessel occlusion in the embryo, or placental defects limiting maternal-fetal nutrition could result in tissue damage to an embryo invoking malformations and other developmental defects at critical periods of development. This perhaps best known for limb reduction defects (e.g., phocomelia) following thalidomide exposure during early limb development, when the critical response coincides with nascent vascular patterning prior to innervation [Therapontos et al. 2009]. At this stage, the early limb-bud receives its blood supply from a single axial artery at which time the undifferentiated mesenchyme is perfused by a simple capillary network. Susceptibility to thalidomide-induced dysmorphogenesis declines as the vascular pattern transitions to a more complex and definitive system of maturing vessels and emergence of the skeletal elements [Vargesson and Hootnick, 2017].

Biological Plausibility

Addresses the biological rationale for a connection between KEupstream and KEdownstream. This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured. More help

Empirical Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

Empirical Evidence: Two lines of evidence support this KER for developmental vascular toxicity: (i) spatial correlation between altered vascular patterning and dysmorphogenesis; and (ii) concentration-dependent developmental toxicity with known anti-angiogenic compounds. Therapontos et al. [2009] determined that loss of immature blood vessels was the primary cause of thalidomide-induced teratogenesis in the chick limb, an effect phenocopied by anti-angiogenic but not anti-inflammatory metabolites/analogues of thalidomide. The thalidomide analog CPS49 suppressed chick limb-bud outgrowth only when the vasculature was at an immature stage of development; CPS49 did not suppress limb development post-innervation [Mahony et al. 2018]. Eight mechanistically diverse angiogenesis inhibitors (sunitinib, sorafenib, TNP-470, axitinib, pazopanib, vandetanib, everolimus, CPS49) suppressed vascularization and invoked dysmorphogenesis in a concentration-dependent manner in both the chick limb-bud and zebrafish embryo models [Beedie et al. 2016]. Vatalanib, a selective VEGFR2 antagonist, suppressed vascular development in zebrafish embryos at 0.07 µM leading to vascular insufficiency by 72 hours post-fertilization (hpf), foreshadowing dysmorphogenesis at 0.22 µM by 120 hpf reduced survival of 10-day adults at 0.70 µM [Tal et al. 2014]. A tiered study evaluated two anti-angiogenic agents, 5HPP-33, a synthetic Thalidomide analog [Noguchi et al. 2005] and TNP-470, a synthetic Fumagillan analog [Ingber et al. 1990] across several complex in vitro functional assays: rat aortic explant assay, rat whole embryo culture, and zebrafish embryotoxicity [Ellis-Hutchngs et al. 2017]. Both compounds disrupted angiogenesis and embryogenesis but with modal differences: 5HPP-33 was embryolethal, and TNP-470 dysmorphic. The former blocks tubulin polymerization [Yeh et al. 2000; Inatsuki et al. 2005; Kizaki et al. 2008; Rashid et al. 2015] and the latter is a methionine aminopeptidase II inhibitor that suppresses non-canonical Wnt signals for endothelial proliferation [Ingber et al. 1990]. Transcriptomic profiles of exposed embryos pathways unique to each and in common to both, strongest being the TP53 pathway [Saili et al. 2019]. In mouse, TNP-470 reduced fetal intraocular microvasculature and induced microphthalmia [Rutland et al. 2009], which is a TP53-dependent phenotype [Wubah et al. 1996].

Uncertainties and Inconsistencies

Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

Uncertainties and Inconsistencies: The cellular basis of tissue damage linked to vascular insufficiency is not well and represents a gap in understanding. During limb development, programmed cell death (PCD) contributes to separation of the digits. The onset of PCD is preceded by a genetically programmed increase of vascular density that directly determines with the extent of PCD and oxygen-dependent generation of reactive oxygen species (ROS) [Eshkar-Oren et al. 2015]. While many human and animal phenotypes associate with genetic signals and responses that control circulatory development, the causal relationship between vascular insufficiency and dysmorphogenesis is less understood due to various modes of tissue damage that may follow insufficient blood support (e.g., slow or weak heartbeat, poor vascularization, vessel occlusion, or reperfusion injury).

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references. More help

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

Concentration-dependent linkages reported for at least 9 anti-angiogenic compounds in chick limb and/or zebrafish embryos with regards to both vascular suppression and dysmorphogenesis [Tal et al. 2014; Beedie et al. 2016]. The general response on endothelial cells preceded effects on morphogenesis. Potential modulating factors include species susceptibility and stage dependency. Developmental buffering (canalization) systems may support resilience to exposure via angio-adaptative recovery mechanisms that are spatially and temporally differentiated.

Response-response Relationship

Provides sources of data that define the response-response relationships between the KEs. More help

Time-scale

Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

Known Feedforward/Feedback loops influencing this KER

Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

Wilson's Principles of Teratology (circa 1977) support the taxonomic applicability of teratogenesis. According to these long-standing Wilson's principles, the first on "Susceptibility to Teratogenesis Depends on the Genotype of the Conceptus and a Manner in which this Interacts with Adverse Environmental Factors". This principle has four main tenets: (i) species differences account for the fact that certain species respond to particular teratogens where others do not, or at least not to the same extent (e.g., humans and other primates are vulnerable to thalidomide induced phocomelia whereas rodents are not); (ii) strain and individual differences account for the fact that some lineages of the same species with different genetic backgrounds can differ in teratogenic susceptibility; (iii) gene-environment interplay results in different patterns of abnormalities between organisms with the same genome raised in different environments, and between organisms with different genomes raised in the same environment; and (iv) multifactorial causation accounts for the complex interactions involving more than one gene and/or more than one environmental factor.

References

List of the literature that was cited for this KER description. More help

Gold NB, Westgate MN, Holmes LB. Anatomic and etiological classification of congenital limb deficiencies. American journal of medical genetics Part A. 2011 Jun;155A(6):1225-35. PubMed PMID: 21557466.

Husain T, Langlois PH, Sever LE, Gambello MJ. Descriptive epidemiologic features shared by birth defects thought to be related to vascular disruption in Texas, 1996-2002. Birth defects research Part A, Clinical and molecular teratology. 2008 Jun;82(6):435-40. PubMed PMID: 18383510.

Kleinstreuer NC, Judson RS, Reif DM, Sipes NS, Singh AV, Chandler KJ, et al. Environmental impact on vascular development predicted by high-throughput screening. Environmental health perspectives. 2011 Nov;119(11):1596-603. PubMed PMID: 21788198. Pubmed Central PMCID: PMC3226499.

Knudsen TB, Kleinstreuer NC. Disruption of embryonic vascular development in predictive toxicology. Birth defects research Part C, Embryo today : reviews. 2011 Dec;93(4):312-23. PubMed PMID: 22271680.

Therapontos C, Erskine L, Gardner ER, Figg WD, Vargesson N. Thalidomide induces limb defects by preventing angiogenic outgrowth during early limb formation. Proceedings of the National Academy of Sciences of the United States of America. 2009 May 26;106(21):8573-8. PubMed PMID: 19433787. Pubmed Central PMCID: 2688998.

van Gelder MM, van Rooij IA, Miller RK, Zielhuis GA, de Jong-van den Berg LT, Roeleveld N. Teratogenic mechanisms of medical drugs. Human reproduction update. 2010 Jul-Aug;16(4):378-94. PubMed PMID: 20061329.