The authors have designated this AOP as all rights reserved. Re-use in any form requires advanced permission from the authors.
AOP: 460
Title
Antagonism of Smoothened receptor leading to orofacial clefting
Short name
Graphical Representation
Point of Contact
Contributors
- Jacob Reynolds
- Arthur Author
Coaches
Status
Handbook Version | OECD status | OECD project |
---|---|---|
v2.0 |
This AOP was last modified on April 29, 2023 13:02
Revision dates for related pages
Page | Revision Date/Time |
---|---|
Antagonism, Smoothened receptor | July 28, 2022 12:17 |
Decrease, GLI1/2 translocation to nucleus | October 28, 2022 15:22 |
Decrease, GLI1/2 target gene expression | March 22, 2023 10:38 |
Decrease, Cell proliferation | December 07, 2020 06:55 |
Decrease, palatal shelf outgrowth | August 05, 2022 11:20 |
Ororofacial clefting | August 08, 2022 15:15 |
Decrease, Sonic Hedgehog second messenger production | March 22, 2023 12:09 |
Decrease, Smoothend relocation and activation | October 27, 2022 09:14 |
Apoptosis | December 20, 2022 08:33 |
Antagonism Smoothened leads to OFC | April 14, 2023 10:48 |
Antagonism Smoothened leads to Decrease, SMO relocation | January 23, 2023 15:43 |
Decrease, SMO relocation leads to Decrease, GLI1/2 translocation | January 23, 2023 15:46 |
Decrease, GLI1/2 translocation leads to Decrease, GLI1/2 target gene expression | January 27, 2023 15:34 |
Decrease, GLI1/2 target gene expression leads to Decrease, SHH second messenger production | February 06, 2023 11:18 |
Decrease, SHH second messenger production leads to Decrease, Cell proliferation | February 10, 2023 09:43 |
Decrease, Cell proliferation leads to Decrease, outgrowth | March 10, 2023 09:51 |
Decrease, outgrowth leads to OFC | March 13, 2023 13:45 |
Apoptosis leads to Decrease, outgrowth | April 11, 2023 10:25 |
Decrease, GLI1/2 target gene expression leads to Apoptosis | April 06, 2023 12:47 |
Vismodegib | July 14, 2022 13:04 |
Cyclopamine | August 03, 2022 09:21 |
SANT-1 | October 04, 2022 13:17 |
SANT-2 | October 04, 2022 13:17 |
SANT-3 | October 04, 2022 13:17 |
SANT-4 | October 04, 2022 13:18 |
Piperonyl butoxide | March 23, 2023 10:19 |
Abstract
The Sonic Hedgehog (SHH) is a major signaling pathway of intercellular signaling during embryonic development. Disruption of SHH during critical periods of development can lead to orofacial clefts (OFCs). In canonical SHH signaling, the SHH ligand binds to the Patched1 (PTCH1) receptor and relieves its’ suppression of Smoothened (SMO) receptor. Antagonism of SMO results in disruption the downstream SHH signaling cascade. Disruption to the signaling cascade causes a decrease in the translocation of the GLI1/2 transcription factors to the nucleus resulting in a decrease in expression of the GLI1/2 target genes. This decrease in gene expression which causes a reduction in production of SHH secondary messengers, namely Fgf10 and members of the BMP family. This reduction in secondary messengers leads to a decrease in cellular proliferation in the palatal shelves. This reduction in cellular proliferation lead to a decrease in palatal shelf outgrowth which ultimately results in a cleft. This AOP is intended to serve as a tool for risk assessment for drug and chemical exposures during embryonic development when disruption to SHH through antagonism of SMO occurs.
AOP Development Strategy
Context
Orofacial clefts (OFCs), encompassing cleft lip with or without palate (CL/P), and cleft palate only (CPO) represent the second most common birth defect in humans with a prevalence of 1-2/1,000 births (Lidral, Moreno et al. 2008). The etiology of OFCs is complex with approximately 50% of CPO and 70% of CL/P considered non-syndromic (2011). SHH signaling is required for normal facial development and plays a critical role in the growth of the facial processes that form the upper palate and lip (Bush and Jiang 2012, Kurosaka 2015). The epithelial derived SHH drives orofacial development through an induced gradient in the underlying mesenchyme (Lan and Jiang 2009, Kurosaka 2015). This gradient of SHH induces cellular proliferation and outgrowth of the mesenchyme (Lan and Jiang 2009). The SHH pathway is sensitive to chemical disruption and can be disrupted at multiple places along the signaling cascade during critical windows for exposure and has been shown to cause OFCs (Lipinski and Bushman 2010, Heyne, Melberg et al. 2015). The targets of this disruption include ligand modification, ligand secretion, downstream sensing, and signal transduction (Jeong and McMahon 2002, Lauth, Bergström et al. 2007, Petrova, Rios-Esteves et al. 2013). Chemical modulators of the SHH pathway have been identified including the natural alkaloid cyclopamine, both natural and synthetic pharmaceuticals, and a chemical commonly found in pesticides (Lipinski, Dengler et al. 2007, Lipinski, Song et al. 2010, Wang, Lu et al. 2012, Everson, Sun et al. 2019, Rivera-González, Beames et al. 2021).
Strategy
This AOP was developed as part of a larger network of AOPs linking disruption of SHH signaling with OFCs (EAGMST workplan project 1.101.). Orofacial clefts (OFCs) are one of the most common human birth defects and occur in approximately 1 in 700 live births (Mossey, Little et al. 2009, Dixon, Marazita et al. 2011). Early orofacial development involves epithelial ectoderm derived SHH ligand driving tissue outgrowth through an induced gradient of SHH dependent transcription in the underlying mesenchyme, which is thought to drive mesenchymal proliferation (Lan and Jiang 2009, Kurosaka 2015). The SHH pathway is sensitive to chemical disruption at multiple molecular targets along the signaling cascade, with exposure during critical windows in development leading to OFCs (Lipinski and Bushman 2010, Heyne, Melberg et al. 2015). The molecular targets of this disruption include SHH ligand modification with cholesterol and palmitoylate, ligand secretion, mesenchymal reception, and signal transduction (Jeong and McMahon 2002, Lauth, Bergström et al. 2007, Petrova, Rios-Esteves et al. 2013). This AOP focuses on the disruption to SHH signaling resulting in antagonism of the SMO receptor. To select the key events for the AOP, we used existing knowledge of the pathway along with reviews of the SHH pathway to assemble a path that was physiologically plausible. Care was taken to select events that would be of direct regulatory relevance (i.e. a method to quantify exists). To identify sources and data for each KER, Pubmed was used. Initially results were screened for relevance off title/abstract and any of suspected relevance were reviewed in full to determine their applicability for the KER. Each KER includes a table of relevant search information (date, search terms, citations, etc). It is the hope of the authors that this AOP is used as a tool for risk assessment for drug and chemical exposures during embryonic development when disruption to SHH through antagonism of SMO occurs.
Summary of the AOP
Events:
Molecular Initiating Events (MIE)
Key Events (KE)
Adverse Outcomes (AO)
Type | Event ID | Title | Short name |
---|
MIE | 2027 | Antagonism, Smoothened receptor | Antagonism Smoothened |
KE | 2044 | Decrease, Smoothend relocation and activation | Decrease, SMO relocation |
KE | 2028 | Decrease, GLI1/2 translocation to nucleus | Decrease, GLI1/2 translocation |
KE | 2040 | Decrease, GLI1/2 target gene expression | Decrease, GLI1/2 target gene expression |
KE | 1262 | Apoptosis | Apoptosis |
KE | 2043 | Decrease, Sonic Hedgehog second messenger production | Decrease, SHH second messenger production |
KE | 1821 | Decrease, Cell proliferation | Decrease, Cell proliferation |
KE | 2041 | Decrease, palatal shelf outgrowth | Decrease, outgrowth |
AO | 2042 | Ororofacial clefting | OFC |
Relationships Between Two Key Events (Including MIEs and AOs)
Title | Adjacency | Evidence | Quantitative Understanding |
---|
Antagonism Smoothened leads to Decrease, SMO relocation | adjacent | Moderate | Low |
Decrease, SMO relocation leads to Decrease, GLI1/2 translocation | adjacent | Moderate | Low |
Decrease, GLI1/2 translocation leads to Decrease, GLI1/2 target gene expression | adjacent | Low | Low |
Decrease, GLI1/2 target gene expression leads to Decrease, SHH second messenger production | adjacent | Low | Low |
Decrease, SHH second messenger production leads to Decrease, Cell proliferation | adjacent | Low | Low |
Decrease, Cell proliferation leads to Decrease, outgrowth | adjacent | Low | Low |
Decrease, outgrowth leads to OFC | adjacent | Moderate | Low |
Apoptosis leads to Decrease, outgrowth | adjacent | Low | Low |
Decrease, GLI1/2 target gene expression leads to Apoptosis | adjacent | Low | Low |
Antagonism Smoothened leads to OFC | non-adjacent | High | High |
Network View
Prototypical Stressors
Life Stage Applicability
Life stage | Evidence |
---|---|
Embryo | High |
Taxonomic Applicability
Term | Scientific Term | Evidence | Link |
---|---|---|---|
mouse | Mus musculus | NCBI |
Sex Applicability
Sex | Evidence |
---|---|
Unspecific | High |
Overall Assessment of the AOP
Domain of Applicability
Essentiality of the Key Events
Evidence Assessment
Known Modulating Factors
Modulating Factor (MF) | Influence or Outcome | KER(s) involved |
---|---|---|