Folic acid and orofacial clefts: a review of the evidence

Wehby, George L.; Murray, Jeffrey C.

doi:10.1111/j.1601-0825.2009.01587.x

Cited by 166 publications

(103 citation statements)

References 104 publications

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“…Certainly, changes in folate metabolism have been shown to affect both DNA synthesis and histone methylation during neurulation, heart development, and in diseases such as cancer (Beaudin and Stover, 2009; Momb et al, 2013; Sun et al, 2011; Tang et al, 2005; Wang et al, 2014). Folate deficiency and mutations to genes involved in the folate pathway cause orofacial defects in model vertebrates and humans (Li et al, 2011; Momb et al, 2013; Tang et al, 2005; Wehby and Murray, 2010; Wilcox et al, 2007) (Burgoon et al, 2002; Kao et al, 2014; Lee et al, 2012). However, it is less clear if these results are due to similar processes during orofacial development.…”

Section: Introductionmentioning

confidence: 99%

The role of folate metabolism in orofacial development and clefting

Wahl

Kennedy

Wyatt

et al. 2015

Developmental Biology

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Folate deficiency has been associated with numerous diseases and birth defects including orofacial defects. However, whether folate has a role in the face during early orofacial development has been unclear. The present study reveals that pharmacological and antisense oligonucleotide mediated inhibition of DHFR, an integral enzyme in the folate pathway, results in specific changes in the size and shape of the midface and embryonic mouth. Such defects are accompanied by a severe reduction in the muscle and cartilage jaw elements without significant change in neural crest pattern or global levels of methylation. We propose that the orofacial defects associated with DHFR deficient function are the result of decreased cell proliferation and increased cell death via DNA damage. In particular, localized apoptosis may also be depleting the cells of the face that express crucial genes for the differentiation of the jaw structures. Folate supplementation is widely known to reduce human risk for orofacial clefts. In the present study, we show that activating folate metabolism can reduce median oral clefts in the primary palate by increasing cell survival. Moreover, we demonstrate that a minor decrease in DHFR function exacerbates median facial clefts caused by RAR inhibition. This work suggests that folate deficiencies could be a major contributing factor to multifactorial orofacial defects.

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Section: Introductionmentioning

confidence: 99%

The role of folate metabolism in orofacial development and clefting

Wahl

Kennedy

Wyatt

et al. 2015

Developmental Biology

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“…It is suggested that such a benefit exists for both OFC and NTDs but that it only occurs at very high intakes of folic acid. This and other aspects of OFC and NTDs are reviewed by Wehly and Murray [14. ]…”

Section: Resultsmentioning

confidence: 99%

Folic Acid Consumption throughout Pregnancy – Differentiation between Trimesters

Scott

2011

Ann Nutr Metab

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Intervention trials have demonstrated conclusively that oral ingestion of extra folic acid can prevent the majority of cases of spina bifida and other neural tube defects (NTDs). Data from these studies offer conclusive evidence that the intake of 400 µg/day folic acid provides this benefit. The big problem has remained that the neural plate closes to form the neural tube between day 21 and day 28 postconception, at which point most women do not even realize that they are pregnant. This, coupled with the fact that over half of all pregnancies are unplanned, has resulted in many studies showing that less than one-fifth of pregnancies have followed the recommendation for prevention. However, where compliance has been good or where folic acid has been added mandatorily, there has been the expected reduction in NTDs. Clarity regarding what is recommended for early pregnancy does not carry through to the second or third trimester of pregnancy where practices vary widely not only from country to country but even from clinician to clinician within particular countries.

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“…8 Smoking, alcohol consumption, and lack of vitamins during pregnancy are among the mostly studied environmental risk factors to date. [9][10][11] It is well documented that maternal smoking during pregnancy is associated with a wide variety of adverse reproductive outcomes, such as increased rates of spontaneous abortion, premature birth, smaller head size, and low birth weight (LBW) in newborns. 12,13 Among smoke products, nicotine is considered to be the main teratogenic substance that alters and delays embryonic development.…”

Section: Nicotine Exposure During Pregnancy Results In Persistent Midmentioning

confidence: 99%

Nicotine Exposure During Pregnancy Results in Persistent Midline Epithelial Seam With Improper Palatal Fusion

Öztürk

Sheldon

Sharma

et al. 2015

NICTOB

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Introduction: Nonsyndromic cleft palate is a common birth defect (1:700) with a complex etiology involving both genetic and environmental risk factors. Nicotine, a major teratogen present in tobacco products, was shown to cause alterations and delays in the developing fetus. Methods: To demonstrate the postpartum effects of nicotine on palatal development, we delivered three different doses of nicotine (1.5, 3.0, and 4.5 mg/kg/d) and sterile saline (control) into pregnant BALB/c mice throughout their entire pregnancy using subcutaneous micro-osmotic pump. Dams were allowed to deliver (~day 21 of pregnancy) and neonatal assessments (weight, length, nicotine levels) were conducted, and palatal tissues were harvested for morphological and molecular analyses, as well as transcriptional profiling using microarrays. Results: Consistent administration of nicotine caused developmental retardation, still birth, low birth weight, and significant palatal size and shape abnormality and persistent midline epithelial seam in the pups. Through microarray analysis, we detected that 6232 genes were up-regulated and 6310 genes were down-regulated in nicotine-treated groups compared to the control. Moreover, 46% of the cleft palate-causing genes were found to be affected by nicotine exposure. Alterations of a subset of differentially expressed genes were illustrated with hierarchal clustering and a series of formal pathway analyses were performed using the bioinformatics tools. Conclusions: We concluded that nicotine exposure during pregnancy interferes with normal growth and development of the fetus, as well results in persistent midline epithelial seam with type B and C patterns of palatal fusion. Implications: Although there are several studies analyzing the genetic and environmental causes of palatal deformities, this study primarily shows the morphological and large-scale genomic outcomes of gestational nicotine exposure in neonatal mice palate.

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Folic acid and orofacial clefts: a review of the evidence

Cited by 166 publications

References 104 publications

The role of folate metabolism in orofacial development and clefting

The role of folate metabolism in orofacial development and clefting

Folic Acid Consumption throughout Pregnancy – Differentiation between Trimesters

Nicotine Exposure During Pregnancy Results in Persistent Midline Epithelial Seam With Improper Palatal Fusion

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