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

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 Tom Knudsen (send email) Open for citation & comment EAGMST Under Review

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

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].

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
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.