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Relationship: 2765

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

Activation, AhR leads to Altered, Cardiovascular development/function

Upstream event

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

Activation, AhR

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

AOP Name	Adjacency	Weight of Evidence	Quantitative Understanding	Point of Contact	Author Status	OECD Status
Aryl hydrocarbon receptor activation leading to early life stage mortality via sox9 repression induced cardiovascular toxicity	non-adjacent	High	Low	Prarthana Shankar (send email)	Under development: Not open for comment. Do not cite	Under Review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

Term	Scientific Term	Evidence	Link
zebrafish	Danio rerio	High	NCBI
mouse	Mus musculus	High	NCBI
Salmo salar	Salmo salar	High	NCBI
rainbow trout	Oncorhynchus mykiss	High	NCBI
medaka	Oryzias latipes	High	NCBI
human	Homo sapiens	Moderate	NCBI

Sex Applicability

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

Sex	Evidence
Unspecific	High

Life Stage Applicability

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

Term	Evidence
Embryo	High
Development	High

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

The Ahr signaling pathway has been shown to have critical functions in the heart, including development of the heart and angiogenesis in a variety of organisms (See “Activation, AhR” Key event 18 page for references).

Further, disruption of the Ahr signaling pathway has been associated with cardiovascular toxicity in animals including birds and fish (Heid et al. 2001; Incardona et al. 2009).

This KER page provides some highlights of the evidence relating Ahr activation and cardiovascular development and function.

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

KER 2765 concordance table: https://aopwiki.org/system/dragonfly/production/2022/10/21/7su9acuq5b_Concordance_Table_AHR_to_cardiovascular_clean.pdf

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

Ahr mRNA and protein expression (along with Ahr signaling pathways genes, such as cyp1a) have been detected in the developing heart of a number of organisms including mice (Abbott et al. 1995) and zebrafish (Andreasen et al. 2002). Ahr activating chemicals (such as, TCDD) increase expression of these genes in the heart (Andreasen et al. 2002) providing biological plausibility evidence for the role of Ahr in cardiotoxicity.

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 and essentiality of KE_up for KE_down to occur

Zebrafish embryos exposed during development to a number of Ahr activating chemicals cause concentration-dependent cardiovascular toxicity, indicated as pericardial edema (area, severity, or percent animals), inhibition of cardiac looping, among other cardiac-specific measurements. Examples include, but are not limited to, TCDD and the PAH, Benzo[a]pyrene (Bugiak and Weber 2010; Knecht et al. 2017), Aroclor 1254 (Li et al. 2014), PCB-126 (Jonsson et al. 2007; Liu et al. 2016), and cyprodinil (Tang et al. 2020).

Additionally, several morpholino knockdown (Jayasundara et al. 2015; Jonsson et al. 2007) and CRISPR-Cas9 knockout (Fu et al. 2019) studies, in addition to Ahr chemical inhibitor (McGee et al. 2013) studies have definitively demonstrated Ahr’s role in cardiotoxicity induced by several Ahr activating chemicals.

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

Abbott BD, Birnbaum LS, Perdew GH. 1995. Developmental expression of two members of a new class of transcription factors: I. Expression of aryl hydrocarbon receptor in the c57bl/6n mouse embryo. Dev Dyn. 204(2):133-143.

Andreasen EA, Spitsbergen JM, Tanguay RL, Stegeman JJ, Heideman W, Peterson RE. 2002. Tissue-specific expression of ahr2, arnt2, and cyp1a in zebrafish embryos and larvae: Effects of developmental stage and 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure. Toxicol Sci. 68(2):403-419.

Bugiak BJ, Weber LP. 2010. Phenotypic anchoring of gene expression after developmental exposure to aryl hydrocarbon receptor ligands in zebrafish. Aquat Toxicol. 99(3):423-437.

Fu H, Wang L, Wang J, Bennett BD, Li JL, Zhao B, Hu G. 2019. Dioxin and ahr impairs mesoderm gene expression and cardiac differentiation in human embryonic stem cells. Sci Total Environ. 651(Pt 1):1038-1046.

Heid SE, Walker MK, Swanson HI. 2001. Correlation of cardiotoxicity mediated by halogenated aromatic hydrocarbons to aryl hydrocarbon receptor activation. Toxicol Sci. 61(1):187-196.

Incardona JP, Carls MG, Day HL, Sloan CA, Bolton JL, Collier TK, Scholz NL. 2009. Cardiac arrhythmia is the primary response of embryonic pacific herring (clupea pallasi) exposed to crude oil during weathering. Environ Sci Technol. 43(1):201-207.

Jayasundara N, Van Tiem Garner L, Meyer JN, Erwin KN, Di Giulio RT. 2015. Ahr2-mediated transcriptomic responses underlying the synergistic cardiac developmental toxicity of pahs. Toxicol Sci. 143(2):469-481.

Jonsson ME, Jenny MJ, Woodin BR, Hahn ME, Stegeman JJ. 2007. Role of ahr2 in the expression of novel cytochrome p450 1 family genes, cell cycle genes, and morphological defects in developing zebra fish exposed to 3,3',4,4',5-pentachlorobiphenyl or 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicol Sci. 100(1):180-193.

Knecht AL, Truong L, Marvel SW, Reif DM, Garcia A, Lu C, Simonich MT, Teeguarden JG, Tanguay RL. 2017. Transgenerational inheritance of neurobehavioral and physiological deficits from developmental exposure to benzo[a]pyrene in zebrafish. Toxicol Appl Pharmacol. 329:148-157.

Li M, Wang X, Zhu J, Zhu S, Hu X, Zhu C, Guo X, Yu Z, Han S. 2014. Toxic effects of polychlorinated biphenyls on cardiac development in zebrafish. Mol Biol Rep. 41(12):7973-7983.

Liu H, Nie FH, Lin HY, Ma Y, Ju XH, Chen JJ, Gooneratne R. 2016. Developmental toxicity, erod, and cyp1a mrna expression in zebrafish embryos exposed to dioxin-like pcb126. Environmental toxicology. 31(2):201-210.

McGee SP, Konstantinov A, Stapleton HM, Volz DC. 2013. Aryl phosphate esters within a major pentabde replacement product induce cardiotoxicity in developing zebrafish embryos: Potential role of the aryl hydrocarbon receptor. Toxicol Sci. 133(1):144-156.

Tang C, Shen C, Zhu K, Zhou Y, Chuang YJ, He C, Zuo Z. 2020. Exposure to the ahr agonist cyprodinil impacts the cardiac development and function of zebrafish larvae. Ecotoxicol Environ Saf. 201:110808.