Editing Cleft lip and cleft palate (section)

===Environmental factors===
Environmental influences may also cause, or interact with genetics to produce, orofacial clefts. An example of the link between environmental factors and genetics comes from a research on mutations in the gene ''[[PHF8]]''. The research found that ''PHF8'' encodes for a [[histone]] lysine demethylase,<ref name= "PMID19843542">{{cite journal | vauthors = Loenarz C, Ge W, Coleman ML, Rose NR, Cooper CD, Klose RJ, Ratcliffe PJ, Schofield CJ | title = PHF8, a gene associated with cleft lip/palate and mental retardation, encodes for an Nepsilon-dimethyl lysine demethylase | journal = Human Molecular Genetics | volume = 19 | issue = 2 | pages = 217–222 | date = January 2010 | pmid = 19843542 | pmc = 4673897 | doi = 10.1093/hmg/ddp480 | author-link8 = Christopher J. Schofield }}</ref> and is involved in [[epigenetic regulation]]. The catalytic activity of ''PHF8'' depends on molecular [[oxygen]],<ref name= "PMID19843542" /> a factor considered important from reports on increased incidence of cleft lip/palate in mice that have been exposed to [[Hypoxia (medical)|hypoxia]] early during pregnancy.<ref>{{cite journal | vauthors = Millicovsky G, Johnston MC | title = Hyperoxia and hypoxia in pregnancy: simple experimental manipulation alters the incidence of cleft lip and palate in CL/Fr mice | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 78 | issue = 9 | pages = 5722–5723 | date = September 1981 | pmid = 6946511 | pmc = 348841 | doi = 10.1073/pnas.78.9.5722 | doi-access = free | bibcode = 1981PNAS...78.5722M }}</ref>

Cleft lip and other [[congenital abnormalities]] have also been linked to maternal hypoxia caused by [[Smoking and pregnancy|maternal smoking]],<ref>{{cite journal | vauthors = Shi M, Wehby GL, Murray JC | title = Review on genetic variants and maternal smoking in the etiology of oral clefts and other birth defects | journal = Birth Defects Research. Part C, Embryo Today | volume = 84 | issue = 1 | pages = 16–29 | date = March 2008 | pmid = 18383123 | pmc = 2570345 | doi = 10.1002/bdrc.20117 }}</ref> with the estimated attributable fraction of orofacial clefts due to smoking in early pregnancy being 6.1%. Orofacial clefts occur very early in pregnancy and so smoking cessation right after recognition of pregnancy is unlikely to reduce the exposure during the critical time period.<ref>{{cite journal | vauthors = Honein MA, Devine O, Grosse SD, Reefhuis J | title = Prevention of orofacial clefts caused by smoking: implications of the Surgeon General's report | journal = Birth Defects Research. Part A, Clinical and Molecular Teratology | volume = 100 | issue = 11 | pages = 822–825 | date = November 2014 | pmid = 25045059 | pmc = 4559232 | doi = 10.1002/bdra.23274 }}</ref>

Maternal [[Alcohol use disorder|alcohol use]] has also been linked to cleft lip and palate due to the effects on the cranial [[neural crest]] cells. The degree of the effect, however, is unknown and requires further research.<ref>{{cite journal | vauthors = Bell JC, Raynes-Greenow C, Turner RM, Bower C, Nassar N, O'Leary CM | title = Maternal alcohol consumption during pregnancy and the risk of orofacial clefts in infants: a systematic review and meta-analysis | journal = Paediatric and Perinatal Epidemiology | volume = 28 | issue = 4 | pages = 322–332 | date = July 2014 | pmid = 24800624 | doi = 10.1111/ppe.12131 }}</ref> Some forms of maternal [[hypertension]] treatment have been linked to cleft lip and palate.<ref name="pmid8574428">{{cite journal | vauthors = Hurst JA, Houlston RS, Roberts A, Gould SJ, Tingey WG | title = Transverse limb deficiency, facial clefting and hypoxic renal damage: an association with treatment of maternal hypertension? | journal = Clinical Dysmorphology | volume = 4 | issue = 4 | pages = 359–363 | date = October 1995 | pmid = 8574428 | doi = 10.1097/00019605-199510000-00013 | s2cid = 6330050 }}</ref> Other environmental factors that have been studied include seasonal causes (such as pesticide exposure); maternal diet and vitamin intake; [[retinoid]]s (members of the vitamin A family); [[anticonvulsant]] drugs; nitrate compounds; organic solvents; parental exposure to lead; alcohol; cigarette use; and a number of other psychoactive drugs (e.g. [[cocaine]], [[crack cocaine]], [[heroin]]).

Current research continues to investigate the extent to which [[folic acid]] can reduce the incidence of clefting.<ref>{{cite journal | vauthors = Boyles AL, Wilcox AJ, Taylor JA, Meyer K, Fredriksen A, Ueland PM, Drevon CA, Vollset SE, Lie RT | title = Folate and one-carbon metabolism gene polymorphisms and their associations with oral facial clefts | journal = American Journal of Medical Genetics. Part A | volume = 146A | issue = 4 | pages = 440–449 | date = February 2008 | pmid = 18203168 | pmc = 2366099 | doi = 10.1002/ajmg.a.32162 }}</ref> Folic acid alone or in combination with vitamins and minerals prevents neural tube defects but does not have a clear effect on cleft lip palate incidence.<ref>{{cite journal | vauthors = De-Regil LM, Peña-Rosas JP, Fernández-Gaxiola AC, Rayco-Solon P | title = Effects and safety of periconceptional oral folate supplementation for preventing birth defects | journal = The Cochrane Database of Systematic Reviews | volume = 2015 | issue = 12 | pages = CD007950 | date = December 2015 | pmid = 26662928 | pmc = 8783750 | doi = 10.1002/14651858.CD007950.pub3 }}</ref> The mechanism behind beneficial folate supplementation is due to folate playing a pivotal role in DNA synthesis and methylation and contributes to both development and gene expression.<ref>{{cite journal | vauthors = Wehby GL, Goco N, Moretti-Ferreira D, Felix T, Richieri-Costa A, Padovani C, Queiros F, Guimaraes CV, Pereira R, Litavecz S, Hartwell T, Chakraborty H, Javois L, Murray JC | title = Oral cleft prevention program (OCPP) | journal = BMC Pediatrics | volume = 12 | issue = 1 | pages = 184 | date = November 2012 | pmid = 23181832 | pmc = 3532199 | doi = 10.1186/1471-2431-12-184 | doi-access = free }}</ref>