5-mehtyltetrahydrofolate rescues alcohol-induced neural crest cell migration abnormalities

Abstract

BackgroundAlcohol is detrimental to early development. Fetal alcohol spectrum disorders (FASD) due to maternal alcohol abuse results in a series of developmental abnormalities including cranial facial dysmorphology, ocular anomalies, congenital heart defects, microcephaly and intellectual disabilities. Previous studies have been shown that ethanol exposure causes neural crest (NC) apoptosis and perturbation of neural crest migration. However, the underlying mechanism remains elusive. In this report we investigated the fetal effect of alcohol on the process of neural crest development in the Xenopus leavis.ResultsPre-gastrulation exposure of 2-4% alcohol induces apoptosis in Xenopus embryo whereas 1% alcohol specifically impairs neural crest migration without observing discernible apoptosis. Additionally, 1% alcohol treatment considerably increased the phenotype of small head (43.4% ± 4.4%, total embryo n = 234), and 1.5% and 2.0% dramatically augment the deformation to 81.2% ± 6.5% (n = 205) and 91.6% ± 3.0% (n = 235), respectively (P < 0.05). Significant accumulation of Homocysteine was caused by alcohol treatment in embryos and 5-mehtyltetrahydrofolate restores neural crest migration and alleviates homocysteine accumulation, resulting in inhibition of the alcohol-induced neurocristopathies.ConclusionsOur study demonstrates that prenatal alcohol exposure causes neural crest cell migration abnormality and 5-mehtyltetrahydrofolate could be beneficial for treating FASD.

Supplementation with the Methyl Donor Betaine Prevents Congenital Defects Induced by Prenatal Alcohol Exposure

“…Folate or folic acid is already present in prenatal supplements and as a food supplement in North America for protection against congenital neural tube defects, including those associated with alcohol exposure (Bailey et al., ; Serrano et al., ; Shi et al., ). However, current recommended supplement levels may not be sufficient to prevent alcohol‐induced congenital heart defects (CHDs) (Huhta and Linask, ).…”

Effects of 13 developmentally toxic chemicals on the migration of rat cephalic neural crest cells in vitro

“…Ethanol is a well-known teratogen causing craniofacial malformations (Schardein and Macina 2006) and its toxic effects on NCCs have often been investigated. It was previously shown that ethanol caused apoptotic cell death (Yan et al 2010) and inhibited migration (Shi et al 2014) of NCCs. In the present study, both reduced cell number and inhibited migration of cNCCs were observed as the effects of ethanol, although the effective concentration of ethanol was relatively higher than those reported in previous studies, probably because of species and strain differences in the susceptibility to ethanol (Wentzel and Eriksson 2008).…”

“…) and inhibited migration (Shi et al. ) of NCCs. In the present study, both reduced cell number and inhibited migration of cNCCs were observed as the effects of ethanol, although the effective concentration of ethanol was relatively higher than those reported in previous studies, probably because of species and strain differences in the susceptibility to ethanol (Wentzel and Eriksson ).…”

Modeling Human Craniofacial Disorders in Xenopus

“…While 1% ethanol exposure did not affect NPB ( msx1 , pax3 and zic1 ) and NC ( snai2 ) specifier genes, it more specifically impaired the expression of genes involved in NCCs migration at a later stage, which has been proposed to be the cause of reduced craniofacial cartilages [41]. Because alcohol consumption reduces folic acid uptake, the same group examined a possible link between the two pathways.…”

“…Because alcohol consumption reduces folic acid uptake, the same group examined a possible link between the two pathways. Microinjection of 5-mehtyltetrahydrofolate (5-MTHF), the most bioactive form of folic acid, prior to ethanol exposure was able to partially rescue the expression of genes associated with NCCs migration in these embryos [41], suggesting that 5-MTHF could be beneficial for treating FAS. However, the authors did not directly evaluate whether the treatment could also rescue craniofacial structures in these tadpoles.…”