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Methotrexate-induced decrease in embryonic 5-methyl-tetrahydrofolate is irreversible with leucovorin supplementation.

ABSTRACT: Folate is a nutrient crucial for rapidly growing tissues, including developing embryos and cancer cells. Folate participates in the biosynthesis of nucleic acids, proteins, amino acids, S-adenosylmethionine, many neurotransmitters, and some vitamins. The intracellular folate pool consists of different folate adducts, which carry one-carbon units at three different oxidative states and participate in distinct biochemical reactions. Therefore, the content and dynamics of folate adducts will affect the homeostasis of the metabolites generated in these folate-mediated reactions. Currently, the knowledge on the level of each individual folate adduct in developing embryos is limited. With an improved high-performance liquid chromatography protocol, we found that tetrahydrofolate (THF), the backbone of one-carbon carrier, gradually increased and became dominant in developing zebrafish embryos. 5-methyl-tetrahydrofolate (5-CH3-THF) was abundant in unfertilized eggs but decreased rapidly when embryos started to proliferate and differentiate. 10-formyltetrahydrofolate at first increased after fertilization, and then dropped dramatically before reaching a sustained level at later stages. Dihydrofolate (DHF) slightly decreased initially and remained low throughout embryogenesis. Exposure to methotrexate significantly decreased 5-CH3-THF levels and increased DHF pools, besides causing brain ventricle anomaly. Rescuing with leucovorin partly reversed the abnormal phenotype. Unexpectedly, the level of 5-CH3-THF remained low even when leucovorin was added for rescue. Our results show that different folate adducts fluctuated significantly and differentially in concert with the physiological requirement specific for the corresponding developmental stages. Furthermore, methotrexate lowered the level of 5-CH3-THF in developing embryos, which could not be reversed with folate supplementation and might be more substantial to cellular methylation potential and epigenetic control than to nucleotide synthesis.

SUBMITTER: Kao TT

PROVIDER: S-EPMC3760077 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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Methotrexate-induced decrease in embryonic 5-methyl-tetrahydrofolate is irreversible with leucovorin supplementation.

Kao Tseng-Ting TT Lee Gang-Hui GH Fu Chi-Chang CC Chen Bing-Hung BH Chen Li-Ting LT Fu Tzu-Fun TF

Zebrafish 20130612 3

Folate is a nutrient crucial for rapidly growing tissues, including developing embryos and cancer cells. Folate participates in the biosynthesis of nucleic acids, proteins, amino acids, S-adenosylmethionine, many neurotransmitters, and some vitamins. The intracellular folate pool consists of different folate adducts, which carry one-carbon units at three different oxidative states and participate in distinct biochemical reactions. Therefore, the content and dynamics of folate adducts will affect ...[more]

PMID: 23758124

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Project description:BackgroundDespite decades of public education about dire consequences of prenatal alcohol exposure (PAE), drinking alcohol during pregnancy remains prevalent. As high as 40% of live-born infants exposed to alcohol during gestation and diagnosed with fetal alcohol syndrome have congenital heart defects that can be life-threatening. In animal models, the methyl donor betaine, found in foods such as wheat bran, quinoa, beets, and spinach, ameliorated neurobehavioral deficits associated with PAE, but effects on heart development are unknown.MethodsPreviously, we modeled a binge drinking episode during the first trimester in avian embryos. Here, we investigated whether betaine could prevent adverse effects of alcohol on heart development. Embryos exposed to ethanol (EtOH) with and without an optimal dose of betaine (5 μM) were analyzed at late developmental stages. Cardiac morphology parameters were rapidly analyzed and quantified using optical coherence tomography. DNA methylation at early stages was detected by immunofluorescent staining for 5-methylcytosine in sections of embryos treated with EtOH or cotreated with betaine.ResultsCompared to EtOH-exposed embryos, betaine-supplemented embryos had higher late-stage survival rates and fewer gross head and body defects than seen after alcohol exposure alone. Betaine also reduced the incidence of late-stage cardiac defects such as absent vessels, abnormal atrioventricular (AV) valves, and hypertrophic ventricles. Furthermore, betaine cotreatment brought measurements of great vessel diameters, interventricular septum thickness, and AV leaflet volumes in betaine-supplemented embryos close to control values. Early-stage 5-methycytosine staining revealed that DNA methylation levels were reduced by EtOH exposure and normalized by co-administration with betaine.ConclusionsThis is the first study demonstrating efficacy of the methyl donor betaine in alleviating cardiac defects associated with PAE. These findings highlight the therapeutic potential of low-concentration betaine doses in mitigating PAE-induced birth defects and have implications for prenatal nutrition policies, especially for women who may not be responsive to folate supplementation.

Dataset Information

Methotrexate-induced decrease in embryonic 5-methyl-tetrahydrofolate is irreversible with leucovorin supplementation.

Publications

Methotrexate-induced decrease in embryonic 5-methyl-tetrahydrofolate is irreversible with leucovorin supplementation.

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