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Relationship: 16

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

Altered expression of AHR/ARNT pathway-dependent genes leads to Altered, Cardiovascular development/function

Upstream event

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

Altered expression of AHR/ARNT pathway-dependent genes

Downstream event

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

Altered, Cardiovascular development/function

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

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

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

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

Include consideration of temporal concordance here

Another proposed mechanism for the observed effects of DLCs on heart development is that sustained AHR/ARNT dimerization induced by DLCs may sequester ARNT from its other dimerization partners at inappropriate times during embryonic cardiomorphogenesis, disrupting ARNT-dependent cellular functions^[1]^[2]. Co-treatment of a human hepatoma cell line with CoCl2 or desferrioxamine, which are known to induce hypoxia-like responses, and TCDD resulted in inhibited HIF-1 mediated gene expression in a luciferase reporter gene assay system^[3]. HIF-1 binding to DNA was increased by desferrioxamine in Hepa 1 cells, however pre-incubation of cells with TCDD prior to desferrioxamine treatment significantly reduced DNA binding activity to HIF-1^[3].

Exposure to TCDD reduces myocardial hypoxia, VEGF expression and endothelial cell responsiveness to angiogenic stimuli in the chicken embryo (Ivnitski-Steele et al., 2004; 2005)^[4]. A dose-dependent decrease in nuclear-localized HIF-1α and overall levels of HIF-1α signaling was observed in chicken embryos exposed to TCDD. Embryos exposed to TCDD also experienced increased mortality, hemorrhaging and coronary anomalies. These results support the hypothesis that TCDD-induced AHR activation competes with HIF-1α for ARNT, which prevents nuclear translocation of the HIF-1 complex and results in abnormal coronary vasculature development^[5].

These studies indicate that the effects of DLCs can be explained by crosstalk between the AHR and hypoxia pathways involving ARNT. Sequestration of ARNT from HIF-1α may impair hypoxia-stimulated coronary angiogenesis through inhibition of VEGF expression^[3], which would explain some DLC-induced effects on vascular development in chicken embryos^[6]^[2]^[5].

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

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

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

References

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

↑ Heid, S. E., Walker, M. K., and Swanson, H. I. (2001). Correlation of cardiotoxicity mediated by halogenated aromatic hydrocarbons to aryl hydrocarbon receptor activation. Toxicol.Sci 61, 187-196.
↑ ^2.0 ^2.1 Walker, M. K., Pollenz, R. S., and Smith, S. M. (1997). Expression of the aryl hydrocarbon receptor (AhR) and AhR nuclear translocator during chick cardiogenesis is consistent with 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced heart defects. Toxicol.Appl.Pharmacol. 143, 407-419.
↑ ^3.0 ^3.1 ^3.2 Nie, M., Blankenship, A. L., and Giesy, J. P. (2001). Interactions between aryl hydrocarbon receptor (AhR) and hypoxia signaling pathways. Environ.Toxicol.Pharmacol. 10, 17-27.
↑ Full Reference?
↑ ^5.0 ^5.1 Wikenheiser, J., Karunamuni, G., Sloter, E., Walker, M. K., Roy, D., Wilson, D. L., and Watanabe, M. (2012). Altering HIF-1alpha Through 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (TCDD) Exposure Affects Coronary Vessel Development. Cardiovasc.Toxicol.
↑ Walker, M. K., and Catron, T. F. (2000). Characterization of cardiotoxicity induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin and related chemicals during early chick embryo development. Toxicol.Appl.Pharmacol. 167, 210-221.