This AOP is licensed under a Creative Commons Attribution 4.0 International License.

Aop: 455

Title

A descriptive phrase which references both the Molecular Initiating Event and Adverse Outcome.It should take the form “MIE leading to AO”. For example, “Aromatase inhibition leading to reproductive dysfunction” where Aromatase inhibition is the MIE and reproductive dysfunction the AO. In cases where the MIE is unknown or undefined, the earliest known KE in the chain (i.e., furthest upstream) should be used in lieu of the MIE and it should be made clear that the stated event is a KE and not the MIE. More help

Aryl hydrocarbon receptor activation leading to early life stage mortality via impeded craniofacial development

Short name

A name that succinctly summarises the information from the title. This name should not exceed 90 characters. More help

Ahr mediated early stage mortality via craniofacial malformations

Graphical Representation

A graphical representation of the AOP.This graphic should list all KEs in sequence, including the MIE (if known) and AO, and the pair-wise relationships (links or KERs) between those KEs. More help

Click to download graphical representation template Explore AOP in a Third Party Tool

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Authors

The names and affiliations of the individual(s)/organisation(s) that created/developed the AOP. More help

Prarthana Shankar, Ph.D., US EPA Mid-Continent Ecology Division, Duluth, MN, USA (shankar.prarthana@epa.gov)

Dan Villeneueve, Ph.D., US EPA Mid-Continent Ecology Division, Duluth, MN, USA (villeneuve.dan@epa.gov)

Point of Contact

The user responsible for managing the AOP entry in the AOP-KB and controlling write access to the page by defining the contributors as described in the next section. More help

Prarthana Shankar (email point of contact)

Contributors

Users with write access to the AOP page. Entries in this field are controlled by the Point of Contact. More help

Prarthana Shankar

Status

Provides users with information concerning how actively the AOP page is being developed, what type of use or input the authors feel comfortable with given the current level of development, and whether it is part of the OECD AOP Development Workplan and has been reviewed and/or endorsed. OECD Status - Tracks the level of review/endorsement the AOP has been subjected to. OECD Project Number - Project number is designated and updated by the OECD. SAAOP Status - Status managed and updated by SAAOP curators. More help

Author status	OECD status	OECD project	SAAOP status
Under development: Not open for comment. Do not cite

This AOP was last modified on August 11, 2022 19:28

Revision dates for related pages

Page	Revision Date/Time
Activation, AhR	March 22, 2018 14:00
dimerization, AHR/ARNT	September 16, 2017 10:14
Decrease, sox9 expression	August 11, 2022 15:09
Increase, Early Life Stage Mortality	March 22, 2018 10:23
Facial cartilage structures are reduced in size and morphologically distorted	December 20, 2018 04:16
Increase, slincR expression	August 01, 2022 13:37
Activation, AhR leads to dimerization, AHR/ARNT	March 22, 2018 11:02
dimerization, AHR/ARNT leads to Increase, slincR expression	July 29, 2022 13:26
Activation, AhR leads to Decrease, sox9 expression	August 11, 2022 13:04
Increase, slincR expression leads to Decrease, sox9 expression	August 11, 2022 14:28
Decrease, sox9 expression leads to Smaller and morphologically distorted facial cartilage structures	August 11, 2022 12:57
Smaller and morphologically distorted facial cartilage structures leads to Increase, Early Life Stage Mortality	June 30, 2022 16:32
Increase, slincR expression leads to Smaller and morphologically distorted facial cartilage structures	August 01, 2022 11:54
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)	February 09, 2017 14:32

Abstract

A concise and informative summation of the AOP under development that can stand-alone from the AOP page. The aim is to capture the highlights of the AOP and its potential scientific and regulatory relevance. More help

The Aryl Hydrocarbon Receptor (Ahrs) are evolutionarily conserved ligand-dependent transcription factors that can be activated by structurally diverse compounds such as halogenated aromatic hydrocarbons, polycyclic aromatic hydrocarbons, and polychlorinated biphenyls. Ahr activation can cause developmental toxicity, including craniofacial malformations, that can lead to early-stage mortality. The current AOP describes a novel adverse outcome pathway (AOP) which describe how Ahr activation (molecular initiating event; MIE) can lead to early-stage mortality (adverse outcome; AO), via craniofacial malformations. The AOP includes two novel key events (KEs), increase in slincR expression, a newly characterized long non-coding RNA that has regulatory functions, and decrease in sox9 expression, a critical transcription factor implicated in several processes including chondrogenesis. Using a key event relationship (KER)-by-KER approach, we collected evidence using both relevant zebrafish literature as well as through broader key word searches in the AbstractSifter tool. Weight of evidence for each KER was assessed to inform overall assessment of the two AOPs which is presented here. Overall confidence levels ranged between medium and strong, with few inconsistencies as well several opportunities for future research identified. While the AOP has only been demonstrated in zebrafish with TCDD as an Ahr activator, we provide lines of evidence for the AOP to apply to majority of animals, as well as many Ahr activating chemicals. The addition of the AOP into the AOP-Wiki helps expand the growing Ahr-related AOP network.

AOP Development Strategy

Context

Used to provide background information for AOP reviewers and users that is considered helpful in understanding the biology underlying the AOP and the motivation for its development.The background should NOT provide an overview of the AOP, its KEs or KERs, which are captured in more detail below. More help

Strategy

Provides a description of the approaches to the identification, screening and quality assessment of the data relevant to identification of the key events and key event relationships included in the AOP or AOP network.This information is important as a basis to support the objective/envisaged application of the AOP by the regulatory community and to facilitate the reuse of its components. Suggested content includes a rationale for and description of the scope and focus of the data search and identification strategy/ies including the nature of preliminary scoping and/or expert input, the overall literature screening strategy and more focused literature surveys to identify additional information (including e.g., key search terms, databases and time period searched, any tools used). More help

Summary of the AOP

This section is for information that describes the overall AOP. The information described in section 1 is entered on the upper portion of an AOP page within the AOP-Wiki. This is where some background information may be provided, the structure of the AOP is described, and the KEs and KERs are listed. More help

Events:

Molecular Initiating Events (MIE)

An MIE is a specialised KE that represents the beginning (point of interaction between a prototypical stressor and the biological system) of an AOP. More help

Key Events (KE)

A measurable event within a specific biological level of organisation. More help

Adverse Outcomes (AO)

An AO is a specialized KE that represents the end (an adverse outcome of regulatory significance) of an AOP. More help

Type	Event ID	Title	Short name

MIE

Activation, AhR

KE	944	dimerization, AHR/ARNT	dimerization, AHR/ARNT
KE	2021	Increase, slincR expression	Increase, slincR expression
KE	2020	Decrease, sox9 expression	Decrease, sox9 expression
KE	1559	Facial cartilage structures are reduced in size and morphologically distorted	Smaller and morphologically distorted facial cartilage structures

947

Increase, Early Life Stage Mortality

Relationships Between Two Key Events (Including MIEs and AOs)

This table summarizes all of the KERs of the AOP and is populated in the AOP-Wiki as KERs are added to the AOP.Each table entry acts as a link to the individual KER description page. More help

Title	Adjacency	Evidence	Quantitative Understanding

Activation, AhR leads to dimerization, AHR/ARNT	adjacent	High	High
dimerization, AHR/ARNT leads to Increase, slincR expression	adjacent	High	High
Increase, slincR expression leads to Decrease, sox9 expression	adjacent	High	High
Decrease, sox9 expression leads to Smaller and morphologically distorted facial cartilage structures	adjacent	High	High
Smaller and morphologically distorted facial cartilage structures leads to Increase, Early Life Stage Mortality	adjacent

Activation, AhR leads to Decrease, sox9 expression	non-adjacent	High	High
Increase, slincR expression leads to Smaller and morphologically distorted facial cartilage structures	non-adjacent	High	High

Network View

This network graphic is automatically generated based on the information provided in the MIE(s), KEs, AO(s), KERs and Weight of Evidence (WoE) summary tables. The width of the edges representing the KERs is determined by its WoE confidence level, with thicker lines representing higher degrees of confidence. This network view also shows which KEs are shared with other AOPs. More help

Prototypical Stressors

A structured data field that can be used to identify one or more “prototypical” stressors that act through this AOP. Prototypical stressors are stressors for which responses at multiple key events have been well documented. More help

Name
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)

Life Stage Applicability

The life stage for which the AOP is known to be applicable. More help

Life stage	Evidence
Embryo	High
Development	High

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available. More help

Sex Applicability

The sex for which the AOP is known to be applicable. More help

Sex	Evidence
Unspecific	High

Overall Assessment of the AOP

Addressess the relevant biological domain of applicability (i.e., in terms of taxa, sex, life stage, etc.) and Weight of Evidence (WoE) for the overall AOP as a basis to consider appropriate regulatory application (e.g., priority setting, testing strategies or risk assessment). More help

Domain of Applicability

Addressess the relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context. More help

Essentiality of the Key Events

The essentiality of KEs can only be assessed relative to the impact of manipulation of a given KE (e.g., experimentally blocking or exacerbating the event) on the downstream sequence of KEs defined for the AOP. Consequently, evidence supporting essentiality is assembled on the AOP page, rather than on the independent KE pages that are meant to stand-alone as modular units without reference to other KEs in the sequence. The nature of experimental evidence that is relevant to assessing essentiality relates to the impact on downstream KEs and the AO if upstream KEs are prevented or modified. This includes: Direct evidence: directly measured experimental support that blocking or preventing a KE prevents or impacts downstream KEs in the pathway in the expected fashion. Indirect evidence: evidence that modulation or attenuation in the magnitude of impact on a specific KE (increased effect or decreased effect) is associated with corresponding changes (increases or decreases) in the magnitude or frequency of one or more downstream KEs. More help

Evidence Assessment

Addressess the biological plausibility, empirical support, and quantitative understanding from each KER in an AOP. More help

Known Modulating Factors

Modulating factors (MFs) may alter the shape of the response-response function that describes the quantitative relationship between two KES, thus having an impact on the progression of the pathway or the severity of the AO.The evidence supporting the influence of various modulating factors is assembled within the individual KERs. More help

Quantitative Understanding

Optional field to provide quantitative weight of evidence descriptors. More help

Considerations for Potential Applications of the AOP (optional)

Addressess potential applications of an AOP to support regulatory decision-making.This may include, for example, possible utility for test guideline development or refinement, development of integrated testing and assessment approaches, development of (Q)SARs / or chemical profilers to facilitate the grouping of chemicals for subsequent read-across, screening level hazard assessments or even risk assessment. More help

References

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