07 May 2019 : Animal Research
Low Maternal Dietary Folate Alters Retrotranspose by Methylation Regulation in Intrauterine Growth Retardation (IUGR) Fetuses in a Mouse Model
Baiyi Li1BCF, Shaoyan Chang2BC, Chi Liu2B, Min Zhang2C, Lianfeng Zhang3D, Liang Liang3F, Rui Li2D, Xiuwei Wang2F, Chuan Qin3C, Ting Zhang2B, Bo Niu2AEG*, Li Wang2ADEGDOI: 10.12659/MSM.914292
Med Sci Monit 2019; 25:3354-3365
Abstract
BACKGROUND: Maternal folate deficiency-mediated metabolic disruption is considered to be associated with the risk of intrauterine growth retardation (IUGR), but the exact mechanism remains unclear. The retrotransposon long interspersed nucleotide element-1 (LINE-1), which can induce birth defects via RNA intermediates, plays crucial roles during embryonic development. We investigated potential relationships between maternal folate and DNA methylation, and possible roles of LINE-1 in IUGR.
MATERIAL AND METHODS: The IUGR model was established by feeding female mice 1 of 3 diets – control diet (CD), folate-deficient diet for 2 weeks (FD2w), and folate-deficient diet for 4 weeks (FD4w) – prior to mating. Maternal serum folate, 5-methyltetrahydrofolate (5-MeTHF), S-adenosylmethionine (SAM), and S-adenosylhomocysteine (SAH) concentrations and global DNA methylation were assessed by LC/MS/MS method. LINE-1 methylation levels in fetuses were examined by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. LINE-1 expression levels were validated by real-time PCR.
RESULTS: Maternal folate deficiency caused plasma folate and 5-MeTHF levels to decrease and SAH level to increase in the FD4w group. Compared with the CD group, methylation levels of genomic DNA and LINE-1 decreased significantly in placenta and fetal tissues from the FD4w group. Expression of LINE-1 open reading frame 1 (ORF1) protein was elevated in fetal liver tissues. Furthermore, a strong correlation was found between methylation and disrupted one-carbon metabolism, implying that dietary folate plays important roles during embryogenesis.
CONCLUSIONS: Maternal dietary folate deficiency impaired one-carbon metabolism, leading to global DNA and LINE-1 hypomethylation, and then increased retrotransposition in fetuses, which can lead to IUGR.
Keywords: DNA Methylation, Fetal Growth Retardation, Folic Acid, Long Interspersed Nucleotide Elements, Fetus, Folic Acid Deficiency, Maternal-Fetal Exchange, Placenta, Pregnancy, S-Adenosylhomocysteine, S-Adenosylmethionine, Tetrahydrofolates
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