5-methyltetrahydrofolate and Fetal-Growth-Retardation

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.

Topics: Animals; Disease Models, Animal; DNA Methylation; Female; Fetal Growth Retardation; Fetus; Folic Acid; Folic Acid Deficiency; Long Interspersed Nucleotide Elements; Male; Maternal-Fetal Exchange; Mice; Mice, Inbred C57BL; Placenta; Pregnancy; S-Adenosylhomocysteine; S-Adenosylmethionine; Tetrahydrofolates

Folate deficiency in pregnancy is associated with neural tube defects, restricted fetal growth and fetal programming of diseases later in life. Fetal folate availability is dependent on maternal folate levels and placental folate transport capacity, mediated by two key transporters, Folate Receptor-α and Reduced Folate Carrier (RFC). We tested the hypothesis that intrauterine growth restriction (IUGR) is associated with decreased folate transporter expression and activity in isolated syncytiotrophoblast microvillous plasma membranes (MVM). Women with pregnancies complicated by IUGR (birth weight <3rd percentile, mean birth weight 1804±110 g, gestational age 35.7±0.61 weeks, n=25) and women delivering an appropriately-for gestational age infant (control group, birth weight 25th-75th centile, mean birth weight 2493±216 g, gestational age 33.9±0.95 weeks, n=19) were recruited and placentas were collected at delivery. MVM was isolated and folate transporter protein expression was measured using Western blot and transporter activity was determined using radiolabelled methyltetrahydrofolic acid and rapid filtration. Whereas the expression of FR-α was unaffected, MVM RFC protein expression was significantly decreased in the IUGR group (-34%, P<.05). IUGR MVM had a significantly lower folate uptake compared to the control group (-38%, P<.05). In conclusion, placental folate transport capacity is decreased in IUGR, which may contribute to the restricted fetal growth and intrauterine programming of childhood and adult disease. These findings suggest that continuation of folate supplementation in the second and third trimester is of particular importance in pregnancies complicated by IUGR.

Topics: Adult; Birth Weight; Case-Control Studies; Cell Membrane; Down-Regulation; Female; Fetal Growth Retardation; Folate Receptor 1; Humans; Infant, Newborn; Microvilli; Placenta; Pregnancy; Reduced Folate Carrier Protein; Tetrahydrofolates; Trophoblasts

Maternal folate deficiency is associated with fetal growth restriction, however, transfer of folate across placentae of pregnancies complicated by fetal growth restriction has never been investigated. We studied whether maternal to fetal 5-methyltetrahydrofolate (5MTF) transport in the ex vivo dually perfused isolated cotyledon, binding of [(3)H] folate (PteGlu) to the syncytial microvillous membrane, and protein expression of folate receptor alpha (FR-alpha) and reduced folate carrier (RFC) in these placentae are disturbed. Placental clearance of 5MTF from the maternal perfusate appeared to be non-saturable over a range of 50 to 500 nm, independent of albumin and flow-independent. No statistically significant differences between placentae complicated with fetal growth restriction and uncomplicated pregnancies were observed. Binding characteristics of [(3)H-]PteGlu to microvillous membranes of fetal growth restriction versus control placentae were similar: B(max)of 3.9+/-2.0 (mean+/-s.d.) versus 4.0+/-1.6 pmol/mg protein and a K(d)of 0.037+/-0.010 versus 0.040+/-0.018 nm. Expression of FR-alpha and RFC were not different in placentae of both groups studied. In conclusion, fetal growth restriction appears not to be associated with impaired maternal to fetal placental folate transport, placental receptor binding, or expression of FR-alpha and RFC.

Topics: Adult; Biological Transport; Carrier Proteins; Female; Fetal Growth Retardation; Folate Receptors, GPI-Anchored; Folic Acid; Humans; Immunoblotting; Kinetics; Membrane Transport Proteins; Microvilli; Placenta; Pregnancy; Receptors, Cell Surface; Reduced Folate Carrier Protein; Tetrahydrofolates; Tritium; Trophoblasts