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Relationship: 2727

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

Increase, slincR expression leads to Altered, Cardiovascular development/function

Upstream event

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

Increase, slincR expression

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	Moderate	Moderate	Prarthana Shankar (send email)	Under development: Not open for comment. Do not cite	WPHA/WNT Endorsed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

Term	Scientific Term	Evidence	Link
zebrafish	Danio rerio	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
Development	High
Embryo	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

Cardiovascular toxicity is a common phenotypic endpoint detected in a variety of animals including fishes and birds upon exposure to Ahr activating environmental chemicals such as PAHs and dioxin (Incardona et al., 2009; Kopf and Walker 2009; Marris et al., 2020).

This KER describes one molecular player (slincR) that seems to be involved in some aspect of Ahr activation-induced cardiovascular toxicity.

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

Individual exposures to the PAHs, retene, dibenzo[a,h]pyrene, and dibenzo[a,i]pyrene cause cyp1a vascular expression as well as a significant induction of slincR at 48 hours post fertilization (hpf) (Garcia et al., 2018; Geier et al., 2018), suggesting the possibility of slincR involved in some aspect of cardiovascular function.

Knockdown of slincR expression in developing zebrafish, alters expression of sox9b (a critical transcription factor that has been shown to be involved in cardiovascular development (Akiyama et al., 2004; Gawdzik et al., 2018)), as well as certain downstream targets of sox9, such as notch3, adamts3, fabp2, sfrp2, and fgfr3 (Garcia et al., 2017).

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_downto occur

Knockdown of slincR in zebrafish using a morpholino technique was utilized in (Garcia et al., 2018) to study possible functions of slincR during development. The study found that several processes related to angiogenesis and vasculature development were highly enriched in the transcriptomics dataset comparing slincR morphants and control animals.

SlincR morphants exposed to 1ng/mL TCDD had a reduced percentage of blood hemorrhaging compared to control zebrafish exposed to the same concentration of TCDD (Garcia et al., 2018).

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

Impact of absence of slincR has only been studied with morpholino knockdown experiments (Garcia et al., 2017; Garcia et al., 2018), which have two relevant drawbacks: 1. Inability to maintain slincR repression by 72 hpf since morpholinos are transient in nature, and 2. Incomplete functional knockout which prevents us from understanding the true impact of the absence of slincR. Future studies using CRISPR-Cas-generated knockout lines, for example, will help overcome both limitations.

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

Morpholino knockdown of slincR reduced slincR expression by 98% in DMSO-treated zebrafish, and 81% in TCDD-treated zebrafish at 48 hpf (Garcia et al., 2017). The knockdown was sufficient to cause differences in the blood hemorrhaging phenotype by 72 hpf when the zebrafish were exposed to 1ng/mL TCDD.

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

Evidence for this KER comes from zebrafish studies.

References

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

Akiyama H, Chaboissier MC, Behringer RR, Rowitch DH, Schedl A, Epstein JA, de Crombrugghe B. 2004. Essential role of sox9 in the pathway that controls formation of cardiac valves and septa. Proc Natl Acad Sci U S A. 101(17):6502-6507.

Garcia GR, Goodale BC, Wiley MW, La Du JK, Hendrix DA, Tanguay RL. 2017. In vivo characterization of an ahr-dependent long noncoding rna required for proper sox9b expression. Mol Pharmacol. 91(6):609-619.

Garcia GR, Shankar P, Dunham CL, Garcia A, La Du JK, Truong L, Tilton SC, Tanguay RL. 2018. Signaling events downstream of ahr activation that contribute to toxic responses: The functional role of an ahr-dependent long noncoding rna (slincr) using the zebrafish model. Environ Health Perspect. 126(11):117002.

Gawdzik JC, Yue MS, Martin NR, Elemans LMH, Lanham KA, Heideman W, Rezendes R, Baker TR, Taylor MR, Plavicki JS. 2018. Sox9b is required in cardiomyocytes for cardiac morphogenesis and function. Sci Rep. 8(1):13906.

Geier MC, Chlebowski AC, Truong L, Massey Simonich SL, Anderson KA, Tanguay RL. 2018. Comparative developmental toxicity of a comprehensive suite of polycyclic aromatic hydrocarbons. Arch Toxicol. 92(2):571-586.

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.

Kopf PG, Walker MK. 2009. Overview of developmental heart defects by dioxins, pcbs, and pesticides. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev. 27(4):276-285.

Marris CR, Kompella SN, Miller MR, Incardona JP, Brette F, Hancox JC, Sorhus E, Shiels HA. 2020. Polyaromatic hydrocarbons in pollution: A heart-breaking matter. J Physiol. 598(2):227-247.