Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_4533_Библиотеки_им_академика_М_И_Перельмана

have been utilized in the laboratory to chemically induce cleft palate or to study the effect of reti­noids on palatogenesis. Sufcient maternal dos­age of tretinoin, or all-trans retinoic acid (ATRA), can induce cleft palate in mouse embryos at a high frequency [189].

sis by interfering with Wnt, FGF, and BMP sig­naling [197–199].

Pesticides represent a broad category of insecti­cides, herbicides, fungicides, and other biocides that span a large range of chemical classes. Exposure to pesticides in general, as well as spe­cic chemicals, has been associated with increased OFC risk. Meta-analysis of 19 studies examining an association between occupational pesticide exposure and OFCs indicated a small yet elevated risk (OR= 1.37, 95% CI = 1.04,

is often regarded as the most toxic compound made by humans and has no utility outside of chemical exposure research [232–234]. TCDD is perhaps best known as a contaminant in the syn­thesis of chlorophenoxyacetic acid herbicides, such as those used as defoliants in Agent Orange during the Vietnam War. Along with other diox­ins, TCDD may also be generated during fossil fuel combustion, waste incineration, metal pro­duction, and paper bleaching [31, 235–242].

1.62) [280]. Using data from the Taiwanese Birth Registry from 2001 to 2003, a study found an increased association between CL/P and elevated ozone levels at the rst gestational month (OR= 1.20 95% CI: 1.02, 1.39) as well as the second (OR=1.25; 95% CI: 1.03, 1.52). Ozone may be teratogenic by creating oxidative stress through the generation of superoxide, hydrogen peroxide, and hydroxyl radicals [281]. A study in the United States examined the association of OFCs and air pollutants at different periods of maternal exposure [282]. At 3months preconcep­tion, elevated SO2 was associated with increased

was

Tobacco smoke consists of thousands of chemicals including many combustion products [301]. Aside from nicotine, these include carbon monoxide, dioxins, PAHs, heavy metals, pesti­cides, and many others. Because so many terato­gens are present in tobacco smoke, it is possible that the causation for OFCs is multifactorial. However, exposure to the individual chemicals listed above is sufcient to induce OFCs. Nicotine can induce hypoxia by impairing uterine vascular function, while carbon monoxide may also increase OFC risk through hypoxic effects [302–

305]. Heavy metals like cadmium can cause oxi-

dative stress and possibly affect redox-sensitive signaling pathways [265].

Population genetics studies have shown that the smoking-related risk for OFCs can be modi­ed by variants of genes involved in developmen­tal signaling and detoxication. Developmental GxE interactions appear to specically affect fusion events in orofacial development. Polymorphisms in TGFA, which encodes an EGF signaling ligand expressed in the medial edge epithelium during fusion, increased the GxE risk for OFCs in population samples from Maryland, California, Washington D.C., Taiwan, Singapore, South Korea, Iran, and India [290, 306–310]. Meta-analysis identied an increased risk for CPO specically [311]. Variation of TGFB3, which is required for fusion of the MES, has been associated with GxE risk in samples from Maryland, Washington D.C., Iowa, and China [308, 312–314]. TGFB3 polymorphism is also associated with SMCP in a German population [4]. Variation of BMP4, which is necessary for appropriate fusion of medial and lateral nasal processes, is associated with increased GxE risk for CL/P in China [313].

2), preventing synthesis of RA [335]. This hypothesis has been corroborated in a study using the Xenopus model [339]. Supplementation with folic acid in mouse embryos and co-exposure with RA or folic acid during larval zebrash development are protective against the terato­genic effects of ethanol [334, 336].

adopting a Western lifestyle are also facing increased incidence of these metabolic diseases [342]. Studies have linked maternal metabolic health status associated with weight and diabetes to OFCs. In these studies, pregestational diabetes mellitus (PGDM) refers to a diagnosis of type I or II diabetes before pregnancy, while gestation diabetes mellitus (GDM) refers to insulin de­ciency and resistance induced by pregnancy. Notably, data in birth defect studies may be con­founded since some cases of GDM are actually a latent diagnosis of type 2 diabetes [343, 344]. In 2008, a US study using data from the National Birth Defects Prevention Study (1997–2003) linked PGDM with increased risk of isolated CL/P (OR=2.92, 95% CI: 1.45, 5.87) and GDM with isolated CL/P (OR =1.45, 95% CI: 1.03,

Maternal obesity has been linked with NTDs and cardiac defects, and it likely increases the risk of OFCs as well [350–352]. Analysis of data from a Swedish population identied an increased

the Netherlands. European OFC prevalence was generally higher in northern and lower in south­ern countries [360]. In Asia, PRs in the highest quartile had also been observed in the Philippines, Japan, and regions of China, although CPO prev­alence was reportedly lower in the latter two countries [1, 361, 362]. In South America, the highest global CL/P PR quartile was observed in several countries including Bolivia, Brazil, Argentina, and Paraguay, while Mexico and the Canadian province Alberta represented regions of high CL/P in North America [1, 360]. The CL/P PRs of Oceana and Australasia were rela­tively high at 18.5 and 20.1, respectively [363]. In African regions including north and sub­Saharan, OFC PRs ranged between 3.8 and 5.4 [363]. The PR in the Middle East was roughly twice that of African regions at 10.5.

Stratied analyses of population samples demonstrate that ethnicity is a major driver of PR variation in OFCs between regions, although environmental factors may still contribute to these geographical differences [1]. A general observation is that African ethnicity presents the lowest risk for OFCs, Caucasian ancestry pres­ents an intermediate risk, and Mongolian ethnic­ity presents the greatest risk. It has been proposed that the increased risk for OFCs in the Bolivian population is due to the Mongolian background of Indigenous peoples in the region. Notably, data in the Bolivian registry is primarily derived from La Paz, which lies at a 4km elevation. This may generate hypoxic conditions during preg­nancy that could contribute to increased OFC risk [302]. The WHO report compared the Bolivian data to that of a Tibetan population of Mongolian ethnicity, who also live at a similar altitude and experience high OFC prevalence [1]. It is unclear whether the ethnicity, elevation, or an interaction of these factors contributed to the increased risk. In North America, populations of Indigenous peoples, Indigenous people of mixed race, or mestizo ancestry also had an increased OFC prevalence in British Columbia, California, and Mexico [1, 364, 365]. A similar trend was also observed in South American countries like Bolivia, Chile, and Argentina [360]. Venezuela and Santo Domingo had lower frequencies of

including varicella, rubella, rubeola, Epstein­Barr virus, herpesvirus, cytomegalovirus, com­mon cold, and inuenza [253, 369–371,

study from a hospital in Mexico City reported an infant with oblique oro-orbital cleft attributed to congenital toxoplasmosis [5]. In latent infections, T. gondii likely poses no hazard to the fetus since it is generally present as acystic, non-migratory bradyzoite. In fact, a study in 2001 found that 15% of women of childbearing age in the United States show signs of toxoplasmosis [386]. Risk for congenital toxoplasmosis is greatly elevated when pregnant women accidentally ingest oocytes. The oocyte transforms into the migra­tory tachyzoite stage, which is the only form that can cross the placenta and infect the fetus. Because cats are the denitive hosts for T. gondii, it is recommended that pregnant women avoid any exposure to used cat litter to avoid congenital toxoplasmosis.

During craniofacial development, gene expres­sion is tightly controlled through several mech­anisms. Among these are covalent modications to the genome (including DNA and histone pro­teins) that are conserved during cell prolifera­tion. Such epigenetic modications are crucial to the normal development of orofacial struc­tures, and their disruption has been associated with OFCs. Epigenetic mechanisms can pre­vent or allow transcriptional machinery to access the gene promoters or enhancers, thereby permitting spatiotemporal control over gene expression. In the context of orofacial develop­ment, the best described epigenetic mecha­nisms include DNA methylation and histone modication. Environmental exposures are believed to affect orofacial development at least partly through epigenetic mechanisms. In fact, maternal smoking during pregnancy is known to alter DNA methylation of genes previously associated with OFCs [387]. Here we describe DNA methylation and histone modications during orofacial development, as well as how their disruption may contribute toward OFC risk.

In mammals, cytosine (C) residues may be meth­ylated at the 5C position to yield 5- methylcytosine. These modications are carried out by DNA meth­yltransferases (DNMTs) that catalyze the transfer of a methyl group from the donor molecule, SAM [388]. Consequently, DNA methylationis strongly associated with folate metabolism. Methylation occurs at specic sequence motifs involving an adjacent guanine (G) residue. This ensures that both DNA strands are methylated at the same posi­tion and the modication is conserved during rep­lication. The best studied motif is 5′-CpG-3′, which are enriched in regions known as CpG islands [389]. Another motif is 5′-CCWGG-3′, where W is either adenine or thymine [390]. While gene promoter elements may be enriched with CpG islands, enhancers are known to harbor both CpG and CCWGG motifs. Methylation may pre­vent the binding of transcriptional machinery through spatial hindrance [391]. Methylation can also recruit CpG-binding proteins, which them­selves recruit histone deacetylases that modify chromatin to an inaccessible conformation.

In the cell nucleus, DNA is organized by wrapping around histone proteins to form chromatin. Histone proteins can be post-translationally modied at specic amino acid residues to make DNA acces­sible or inaccessible to transcriptional machinery and may also recruit protein complexes that remodel chromatin [411, 412]. Many studies have focused on histone methylation and acetylation, although several other modications may also be important [413, 414]. Methylation is known to occur on both arginine (R) and lysine (K) residues, while acetylation occurs on K residues. These modications are catalyzed by specic enzymes whose mutation or inhibition is associated with OFCs. Dysfunction of these enzymes can affect several developmental processes and consequently often lead to syndromic effects.