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Relationship: 2684

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 Decrease, sox9 expression

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
Aryl hydrocarbon receptor activation leading to early life stage mortality via impeded craniofacial development adjacent High High Prarthana Shankar (send email) Under development: Not open for comment. Do not cite
Aryl hydrocarbon receptor activation leading to early life stage mortality via cardiovascular toxicity adjacent High High Prarthana Shankar (send email) Under development: Not open for comment. Do not cite

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 Moderate 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
  • Sox9b (one of two paralogs of the sox9 gene in zebrafish) is one of the most reduced transcripts in the jaw upon TCDD exposure in zebrafish (Xiong et al., 2008).
  • One question that remained unanswered was the possible mechanisms by which Ahr was regulating sox9b expression, given that even though there are eight putative AHREs near the sox9b promoter, its repression in zebrafish does not occur immediately after TCDD exposure (Xiong et al. 2008).
  • slincR is a long non-coding RNA (lncRNA) that was recently discovered in zebrafish. Multiple lines of evidence from zebrafish experiments point to slincR being the intermediate between Ahr activation and sox9b repression (Garcia et al., 2017; Garcia et al., 2018).

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
  • The nature of lncRNAs is such that they have diverse functions and can regulate gene expression at multiple levels, including by interacting with DNA, RNA, proteins, and altering transcription of both neighboring and distant genes (Statello et al., 2021).
  • slincR (in situ hybridization) and sox9b (immunohistochemistry for sox9b-eGFP) are expressed in adjacent and overlapping tissues through multiple stages of zebrafish development, such as in the eye, otic vesicle, and in the lower jaw (Garcia et al., 2017).
  • A capture hybridization analysis of RNA targets (CHART) experiment in both DMSO- and TCDD-exposed 48 hpf zebrafish identified enrichment of slincR in the 5’UTR of the sox9b locus (Garcia et al., 2018) suggesting possible interaction between slincR and sox9b.
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
  • Six individual PAHs, retene, benzo[j]fluoranthene, benzo[k]fluoranthene, dibenzo[a,h]pyrene, dibenzo[a,i]pyrene, and benzo[b]fluoranthene, significantly induced slincR expression in whole-animal zebrafish, however no repression of sox9b was detected in any of the PAHs (Garcia et al., 2018).
  • Morpholino knockdown of sox9b in zebrafish led to a significant increase in slincR expression suggesting that slincR and sox9b may share overlapping regulatory networks that is not fully understood (Garcia et al., 2018). 
  • We note that slincR is not the only mechanism of regulation of sox9. Other studies have found evidence for different regulatory mechanisms of sox9, but the circumstances under which different pathways are turned on is still unknown (Dash et al., 2021; Fu et al., 2018).

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
  • The interaction between SlincR and sox9 (sox9b, specifically) has only been investigated in zebrafish. 

References

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

Dash S, Bhatt S, Falcon KT, Sandell LL, Trainor PA. 2021. Med23 regulates sox9 expression during craniofacial development. J Dent Res. 100(4):406-414.

Fu R, Wang X, Xia L, Tan Y, Liu J, Yuan L, Yang Z, Fang B. 2018. Adam10 modulates sox9 expression via n1icd during chondrogenesis at the cranial base. RSC Adv. 8(67):38315-38323.

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.

Statello L, Guo CJ, Chen LL, Huarte M. 2021. Gene regulation by long non-coding rnas and its biological functions. Nat Rev Mol Cell Biol. 22(2):96-118.

Xiong KM, Peterson RE, Heideman W. 2008. Aryl hydrocarbon receptor-mediated down-regulation of sox9b causes jaw malformation in zebrafish embryos. Mol Pharmacol. 74(6):1544-1553.