Difference between revisions of "Relationship:125"

From AOP-Wiki
Jump to: navigation, search
(Quantitative Understanding of the Linkage)
(Quantitative Understanding of the Linkage)
Line 78: Line 78:
 
</em>
 
</em>
  
This is not well established for mammalian systems; however, a clear concentration-dependent relationship
+
This is not well established for mammalian systems; however, a clear concentration- and time-dependent relationship has been demonstrated in transgenic zebrafish embryos exposed to a VEGFR2 inhibitor (Vatalanib). Quantitative effects on angiogenesis forshadowed, both in concntration and time, the morphological effects on larva and this extended even to survival curves at 30 days post-hatching. [Tal et al. 2014].
  
 
== Evidence Supporting Taxonomic Applicability ==
 
== Evidence Supporting Taxonomic Applicability ==

Revision as of 17:05, 16 June 2016



Key Event Relationship Overview

Please follow link to widget page to edit this section.

If you manually enter text in this section, it will get automatically altered or deleted in subsequent edits using the widgets.

Description of Relationship

Upstream Event Downstream Event/Outcome
Endothelial network, Impairment Vascular, Insufficiency

AOPs Referencing Relationship

AOP Name Type of Relationship Weight of Evidence Quantitative Understanding
VEGF Signaling and Vascular Disruption Leading to Adverse Developmental Outcomes Indirectly Leads to Moderate Weak

Taxonomic Applicability

Name Scientific Name Evidence Links

How Does This Key Event Relationship Work

In utero vascular disruptions are thought to be associated with a variety of developmental defects [Husain et al. 2008]. Vascular disruption was identified as one of 6 teratogenic mechanisms linked with medications [van Gelder et al. 2010].

Weight of Evidence

Biological Plausibility

In humans, the most common apparent cause of limb deficiencies was found to be vascular disruption defects [Gold et al. 2011]. Many genetic and environmental factors alter molecular pathways regulating angiogenesis [Knudsen and Kleinstreuer, 2011].

Empirical Support for Linkage

Include consideration of temporal concordance here

Susceptibility to Thalidomide linked to the disruption of immature angiogenic network at time of exposure [Therapontos et al. 2009]. Predicted vascular disrupting chemicals in ToxCast correlate with developmental toxicity [Kleinstreuer et al. 2011].

Uncertainties or Inconsistencies

Quantitative Understanding of the Linkage

Is it known how much change in the first event is needed to impact the second? Are there known modulators of the response-response relationships? Are there models or extrapolation approaches that help describe those relationships?

This is not well established for mammalian systems; however, a clear concentration- and time-dependent relationship has been demonstrated in transgenic zebrafish embryos exposed to a VEGFR2 inhibitor (Vatalanib). Quantitative effects on angiogenesis forshadowed, both in concntration and time, the morphological effects on larva and this extended even to survival curves at 30 days post-hatching. [Tal et al. 2014].

Evidence Supporting Taxonomic Applicability

References


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.