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Relationship: 2690
Title
Increase, slincR expression leads to Smaller and morphologically distorted facial cartilage structures
Upstream event
Downstream event
Key Event Relationship Overview
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 | Moderate | Moderate | Prarthana Shankar (send email) | Under development: Not open for comment. Do not cite | Under Review |
Taxonomic Applicability
Term | Scientific Term | Evidence | Link |
---|---|---|---|
zebrafish | Danio rerio | High | NCBI |
Sex Applicability
Sex | Evidence |
---|---|
Unspecific | High |
Life Stage Applicability
Term | Evidence |
---|---|
Embryo | High |
Development | High |
Key Event Relationship Description
- Craniofacial malformations, including due to small and distorted facial cartilage structures, are a common phenotypic endpoint detected upon exposure to a variety of environmental chemicals (Huang et al., 2021).
- Craniofacial development is a highly complex and coordinated process involving both environmental and genetic factors, and thus the mechanisms leading up to its disruption are expected to be complicated (Raterman et al., 2020).
- This KER describes one molecular player (slincR) that is involved in both normal craniofacial development as well as chemical exposure-induced facial cartilage structures.
Evidence Collection Strategy
Evidence Supporting this KER
Biological Plausibility
- Across multiple stages of zebrafish development, slincR is expressed in the jaw/snout region, as well as in the eye and otic vesicle (Garcia et al., 2017).
- Upon exposure to TCDD (a strong Ahr activating chemical), slincR expression increases in both the otic vesicle, as well as the lower jaw/snout region (Garcia et al., 2017).
- Knockdown of slincR expression in developing zebrafish, alters expression of sox9b (a critical transcription factor that regulates cartilage development (Lefebvre et al., 2017)), as well as certain downstream targets of sox9, such as notch3, adamts3, fabp2, sfrp2, and fgfr3 (Garcia et al., 2017).
Empirical Evidence
Empirical evidence and essentiality of KEup for KEdown to occur
- While both control and slincR morphant zebrafish exposed to TCDD displayed cartilage structure defects, the slincR morphants had an abnormal junction between hyosymplectic and ceratohyal cartilages in comparison to the control morphants (Garcia et al., 2018), suggesting slincR’s role in the craniofacial malformation caused due to TCDD exposure.
Uncertainties and Inconsistencies
- DMSO-treated slincR morphants did not show any changes to craniofacial cartilage structure (Garcia et al., 2018).
- 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
Quantitative Understanding of the Linkage
- 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 cartilage structure by 72 hpf only in TCDD-exposed slincR morphants.
Response-response Relationship
Time-scale
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Evidence for this KER comes from zebrafish studies.
References
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.
Huang W, Wang X, Zheng S, Wu R, Liu C, Wu K. 2021. Effect of bisphenol a on craniofacial cartilage development in zebrafish (danio rerio) embryos: A morphological study. Ecotoxicol Environ Saf. 212:111991.
Lefebvre V, Dvir-Ginzberg M. 2017. Sox9 and the many facets of its regulation in the chondrocyte lineage. Connect Tissue Res. 58(1):2-14.
Raterman ST, Metz JR, Wagener F, Von den Hoff JW. 2020. Zebrafish models of craniofacial malformations: Interactions of environmental factors. Front Cell Dev Biol. 8:600926.