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Relationship: 2689

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 Smaller and morphologically distorted facial cartilage structures

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

Smaller and morphologically distorted facial cartilage structures

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 impeded craniofacial development	non-adjacent	High	High	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 Do not cite	Under Review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
American mink	Neovison vison	High	NCBI
human	Homo sapiens	Moderate	NCBI
chicken	Gallus gallus	High	NCBI
Japanese quail	Coturnix japonica	High	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

This KER provides some highlights for the relationship between Ahr signaling activation and craniofacial formation disruptions, including those directly associated with cartilage structure malformation.

Several Ahr activating chemicals have been associated with the disruption of jaw formation in animals such as fish and mink (Hornung et al. 1999; Render et al. 2000), providing evidence for the KER.

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 2689 concordance table: https://aopwiki.org/system/dragonfly/production/2022/10/20/14h2wanxmd_Concordance_Table_AHR_to_craniofacial_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

Primary biological plausibility evidence comes from studies using techniques such as in situ hybridization and immunohistochemistry to identify Ahr and Ahr-related gene and protein expression in lower jaw structures of a variety of animals. For example, Ahr mRNA and protein are present in mouse craniofacial tissue (Abbott et al. 1994a; Abbott et al. 1998), Ahr and Arnt protein are expressed in human embryonic palatal cells (Abbott et al. 1994b), and Ahr2 and cyp1a are expressed in the craniofacial region (including the Meckel’s cartilage) of zebrafish (Mattingly et al. 2001; Teraoka et al. 2002).

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

Some examples for empirical evidence from exposures to known Ahr activators:

TCDD exposure to developing mice causes cleft plate and negative effects on cell proliferation in the jaw region (Tao et al. 2020).

Beta-naphthoflavone (BNF) exposure to mink decreased squamous epithelial proliferation and caused lesions in mink jaws (Matz et al. 2019).

In zebrafish, PCB-126 exposure caused impaired lower jaw growth, and TCDD exposure decreased craniofacial cartilage size, chondrocyte size and number, and tended to decrease chondrocyte proliferation, while also causing the Meckel’s and palatoquadrate cartilages to be malformed (Burns et al. 2015; Grimes et al. 2008; Liu et al. 2016; Xiong et al. 2008).

Chick embryos exposed to mono-ortho-chlorinated chlorobiphenyls at high concentrations led to mortality of the embryos, with the surviving embryos displaying shortened beaks (as well as microphthalmia, degenerative hepatic lesions and edema) (Brunstrom 1990).

Japanese Quail and Common Pheasant embryos exposed to TCDD, 2,3,4,7,8-pentachlorodibenzofuran (PeCDF), and 2,3,7,8-tetrachlorodibenzofuran (TCDF), and White Leghorn Chicken embryos exposed to TCDD and PeCDF all displayed bill deformities including incomplete or lack of upper/lower beak or crossbill (Cohen-Barnhouse et al., 2011). Japanese Quail in particular had % deformities that increased in a concentration-depedent manner (0.42 - 23 g/egg) for each chemical.

Some examples for essentiality evidence:

Ahr2 morpholino knockdown in zebrafish exposed to 0.4 ng/mL TCDD provided partial protection from TCDD-induced jaw length shortening (Prasch et al. 2003).

Ahr-null mice were protected from TCDD-induced cleft palate (Mimura et al. 1997).

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, Perdew GH, Buckalew AR, Birnbaum LS. 1994a. Interactive regulation of ah and glucocorticoid receptors in the synergistic induction of cleft palate by 2,3,7,8-tetrachlorodibenzo-p-dioxin and hydrocortisone. Toxicol Appl Pharmacol. 128(1):138-150.

Abbott BD, Probst MR, Perdew GH. 1994b. Immunohistochemical double-staining for ah receptor and arnt in human embryonic palatal shelves. Teratology. 50(5):361-366.

Abbott BD, Probst MR, Perdew GH, Buckalew AR. 1998. Ah receptor, arnt, glucocorticoid receptor, egf receptor, egf, tgf alpha, tgf beta 1, tgf beta 2, and tgf beta 3 expression in human embryonic palate, and effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (tcdd). Teratology. 58(2):30-43.

Burns FR, Peterson RE, Heideman W. 2015. Dioxin disrupts cranial cartilage and dermal bone development in zebrafish larvae. Aquat Toxicol. 164:52-60.

Brunström B. 1990. Mono-ortho-chlorinated chlorobiphenyls: Toxicity and induction of 7-ethoxyresorufino-deethylase (erod) activity in chick embryos. Archives of Toxicology. 64(3):188-192.

Cohen‐Barnhouse AM, Zwiernik MJ, Link JE, Fitzgerald SD, Kennedy SW, Giesy JP, Wiseman S, Jones PD, Newsted JL, Kay D. 2011. Developmental and posthatch effects of in ovo exposure to 2, 3, 7, 8‐tcdd, 2, 3, 4, 7, 8‐pecdf, and 2, 3, 7, 8‐tcdf in japanese quail (coturnix japonica), common pheasant (phasianus colchicus), and white leghorn chicken (gallus gallus domesticus) embryos. Environmental Toxicology and Chemistry. 30(7):1659-1668.

Grimes AC, Erwin KN, Stadt HA, Hunter GL, Gefroh HA, Tsai HJ, Kirby ML. 2008. Pcb126 exposure disrupts zebrafish ventricular and branchial but not early neural crest development. Toxicol Sci. 106(1):193-205.

Hornung MW, Spitsbergen JM, Peterson RE. 1999. 2,3,7,8-tetrachlorodibenzo-p-dioxin alters cardiovascular and craniofacial development and function in sac fry of rainbow trout (oncorhynchus mykiss). Toxicol Sci. 47(1):40-51.

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.

Mattingly CJ, McLachlan JA, Toscano WA, Jr. 2001. Green fluorescent protein (gfp) as a marker of aryl hydrocarbon receptor (ahr) function in developing zebrafish (danio rerio). Environ Health Perspect. 109(8):845-849.

Matz DK, Chuck J, Hosmer RJ, Piper HC, Link JE, Fitzgerald SD, Steibel JP, Bursian SJ. 2019. Induction of maxillary and mandibular squamous epithelial cell proliferation in mink (neovison vison) by β-naphthoflavone. Environ Toxicol Chem. 38(2):460-463.

Mimura J, Yamashita K, Nakamura K, Morita M, Takagi TN, Nakao K, Ema M, Sogawa K, Yasuda M, Katsuki M et al. 1997. Loss of teratogenic response to 2,3,7,8-tetrachlorodibenzo-p-dioxin (tcdd) in mice lacking the ah (dioxin) receptor. Genes Cells. 2(10):645-654.

Prasch AL, Teraoka H, Carney SA, Dong W, Hiraga T, Stegeman JJ, Heideman W, Peterson RE. 2003. Aryl hydrocarbon receptor 2 mediates 2,3,7,8-tetrachlorodibenzo-p-dioxin developmental toxicity in zebrafish. Toxicol Sci. 76(1):138-150.

Render JA, Aulerich RJ, Bursian SJ, Nachreiner RF. 2000. Proliferation of maxillary and mandibular periodontal squamous cells in mink fed 3,3',4,4',5-pentachlorobiphenyl (pcb 126). J Vet Diagn Invest. 12(5):477-479.

Tao Y, Liu X, Cui L, Liu X, Chen Y, He Z, Ji M, Gao Z, Li N, Wan Z et al. 2020. Oct4 plays a role in 2, 3, 7, 8 - tetrachlorobenzo-p-dioxin (tcdd) inducing cleft palate and inhibiting mesenchymal proliferation. Toxicology. 438:152444.

Teraoka H, Dong W, Ogawa S, Tsukiyama S, Okuhara Y, Niiyama M, Ueno N, Peterson RE, Hiraga T. 2002. 2,3,7,8-tetrachlorodibenzo-p-dioxin toxicity in the zebrafish embryo: Altered regional blood flow and impaired lower jaw development. Toxicol Sci. 65(2):192-199.

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.