Low Maternal Dietary Folate Alters Retrotranspose by Methylation Regulation in Intrauterine Growth Retardation (IUGR) Fetuses in a Mouse Model
Baiyi Li, Shaoyan Chang, Chi Liu, Min Zhang, Lianfeng Zhang, Liang Liang, Rui Li, Xiuwei Wang, Chuan Qin, Ting Zhang, Bo Niu, Li Wang
(Department of Biochemistry and Molecular Biology, Shanxi Medical University, Taiyuan, Shanxi, China (mainland))
Med Sci Monit 2019; 25:3354-3365
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