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Event: 2042
Key Event Title
Orofacial clefting
Short name
Biological Context
Level of Biological Organization |
---|
Individual |
Key Event Components
Process | Object | Action |
---|---|---|
Cleft palate | increased | |
cleft upper lip | increased |
Key Event Overview
AOPs Including This Key Event
AOP Name | Role of event in AOP | Point of Contact | Author Status | OECD Status |
---|---|---|---|---|
Antagonism SMO leads to OFC | AdverseOutcome | Arthur Author (send email) | Under development: Not open for comment. Do not cite | Under Development |
Decrease, GLI1/2 target gene expression leads to OFC | AdverseOutcome | Agnes Aggy (send email) | Under development: Not open for comment. Do not cite | Under Development |
Decrease, cholesterol synthesis leads to OFC | AdverseOutcome | Arthur Author (send email) | Under development: Not open for comment. Do not cite | Under Development |
Taxonomic Applicability
Term | Scientific Term | Evidence | Link |
---|---|---|---|
Vertebrates | Vertebrates | NCBI |
Life Stages
Life stage | Evidence |
---|---|
Embryo | High |
Sex Applicability
Term | Evidence |
---|---|
Unspecific |
Key Event Description
Orofacial clefts (OFC) are one of the most common birth defects. Orofacial clefts are commonly divided on the anatomy they affect by clefts of the lip and/or palate (CL/P) and those of the palate only (CPO) (Murray 2002). Clefts can also be classified as either syndromic when they occur with other physical or developmental anomalies or nonsydromic in the absence of other symptoms (Stanier and Moore 2004). Like most births, the etiology of OFCs are complex and include a combination of genetic and chemical factors (Lipinski and Bushman 2010, Heyne, Melberg et al. 2015). Orofacial development is tightly regulated by multiple signaling pathways and genes including: fibroblast growth factors (Fgfs), Sonic Hedgehog (shh), bone morphogenic protein (Bmp), transforming growth factor beta (Tgf- β) and transcription factors including Dlx, Pitx, Hox, Gli and T-box (Stanier and Moore 2004). Orofacial development requires precise cell migration, growth, differentiation and apoptosis to create the needed orofacial structures from the oropharyngeal membrane (Jugessur and Murray 2005). During the sixth week of human embryogenesis the medial nasal prominences merge to form the primary palate and the upper lip. The mandibular prominences merge across the midline to produce the lower jaw and lip. Development of the secondary palate begins in the sixth week where the palatal shelves extend internally to the maxillary processes. The shelves then elevate above the tongue and grow towards each other until contact occurs. During weeks 7-8 the medial edges of the palatal shelves fuse through as series of epithelial-mesenchyme transition (EMT) and apoptosis(Jugessur and Murray 2005, Zhang, Tian et al. 2016). Disruption to the complex processes required for proper orofacial development can occur both through genetic factors and environmental (i.e. chemical) exposure by causing disruption to one or multiple steps of orofacial development resulting in OFC.
How It Is Measured or Detected
- OFC can be visually observed both in humans and in animals. It can be classified by which tissues (e.g.cleft lip and palate) are effected and its’ severity (complete/incomplete, unilateral/bilateral). Techniques such as the revised Smith-modified Kernahan ‘Y’ classification can be used describe the type, location, and extent of OFC deformities (Khan, Ullah et al. 2013).
Domain of Applicability
- Sex- OFC can occur for all sexes. Differences in incidence between males and females have been found however a clear understanding of what causes this difference is not understood. Cleft lip with or without cleft palate is more common in males while cleft palate only is more common for females (Barbosa Martelli, Machado et al. 2012).
- Life stages- Orofacial development and any disruption leading to clefting occurs early in embryonic development. This begins between the 6th and 12th week of pregnancy in humans and between day 10.0 and 15 in mice (Okuhara and Iseki 2012).
- Taxonomic- Orofacial development occurs in all vertebrates.
Regulatory Significance of the Adverse Outcome
OFC is one of the most common birth defects occurring in approximately 1 in 700 live births. The etiology of OFC is poorly understood and is believed to be a combination of genetic and environmental factors. Understanding the genetic and environmental factors that can lead to OFC is the first step in preventing this birth defect.
References
Barbosa Martelli, D. R., R. A. Machado, M. S. Oliveira Swerts, L. A. Mendes Rodrigues, S. N. de Aquino and H. M. Júnior (2012). "Non sindromic cleft lip and palate: relationship between sex and clinical extension." Brazilian Journal of Otorhinolaryngology 78(5): 116-120.
Heyne, G. W., C. G. Melberg, P. Doroodchi, K. F. Parins, H. W. Kietzman, J. L. Everson, L. J. Ansen-Wilson and R. J. Lipinski (2015). "Definition of critical periods for Hedgehog pathway antagonist-induced holoprosencephaly, cleft lip, and cleft palate." PLoS One 10(3): e0120517.
Jugessur, A. and J. C. Murray (2005). "Orofacial clefting: recent insights into a complex trait." Curr Opin Genet Dev 15(3): 270-278.
Khan, M., H. Ullah, S. Naz, T. Iqbal, T. Ullah, M. Tahir and O. Ullah (2013). "A revised classification of the cleft lip and palate." Can J Plast Surg 21(1): 48-50.
Lipinski, R. J. and W. Bushman (2010). "Identification of Hedgehog signaling inhibitors with relevant human exposure by small molecule screening." Toxicol In Vitro 24(5): 1404-1409.
Murray, J. C. (2002). "Gene/environment causes of cleft lip and/or palate." Clin Genet 61(4): 248-256.
Okuhara, S. and S. Iseki (2012). "Epithelial integrity in palatal shelf elevation." Japanese Dental Science Review 48(1): 18-22.
Stanier, P. and G. E. Moore (2004). "Genetics of cleft lip and palate: syndromic genes contribute to the incidence of non-syndromic clefts." Hum Mol Genet 13 Spec No 1: R73-81.
Zhang, J., X.-J. Tian and J. Xing (2016). "Signal Transduction Pathways of EMT Induced by TGF-β, SHH, and WNT and Their Crosstalks." Journal of clinical medicine 5(4): 41.