Expression of folate transporters in human placenta and implications for homocysteine metabolism.
Poor folate status during pregnancy can lead to elevated maternal plasma levels of homocysteine (Hcy) with associated pregnancy complications and adverse neonatal outcomes, suggesting placental metabolism of Hcy might be an important determinant in influencing fetal development. The metabolic pathways for Hcy in placenta are not well defined. In this study we examined the gene expression of key enzymes involved in Hcy metabolism in first trimester and term human placenta to determine which metabolic pathways prevail. Expression of mRNA for methionine synthase and 5,10-methylene tetrahydrofolate reductase, enzymes involved in the methionine cycle and responsible for the re-methylation of Hcy to methionine, were expressed at similar levels between first trimester and term and in comparison to human liver as positive control. In contrast, cystathionine beta-synthase mRNA expression was markedly lower than that in liver at both gestational periods. Betaine-homocysteine methyltransferase mRNA was undetectable at either gestational age. These data suggest that re-methylation of Hcy using methyl donation from 5-methyltetrahydrofolate is the prevalent pathway, indicating a marked reliance on folate availability. This led to further investigations examining the expression and localisation of folate transporters in first trimester and term placenta. Folate receptor alpha (FRalpha) was highly polarised to the microvillous plasma membrane (MVM) of the syncytiotrophoblast at both gestational periods, a distribution shared by the proton-coupled folate transporter which co-localised with FRalpha. Reduced folate carrier was distributed to both MVM and basal syncytiotrophoblast plasma membranes at term suggesting a role at both loci, and in first trimester was localised to MVM as well as cytotrophoblast plasma membranes. These data support the concept that placental folate transport is established early in pregnancy, providing folate for utilisation in placental Hcy metabolism.
Solanky
N
N
School of Clinical and Laboratory Sciences, University of Manchester, Manchester Academic Health Science Centre, St Mary's Hospital, Manchester, UK. nita.solanky@manchester.ac.uk
Requena Jimenez
A
A
D'Souza
S W
SW
Sibley
C P
CP
Glazier
J D
JD
D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002462:Cell Membrane / Q000201:enzymology / Q000378:metabolism; D016764:Cell Polarity; D003541:Cystathionine beta-Synthase / Q000235:genetics / Q000378:metabolism; D005260:Female; D019084:Fluorescent Antibody Technique, Indirect; D058973:Folate Receptors, GPI-Anchored; D005492:Folic Acid / Q000378:metabolism*; D006710:Homocysteine / Q000378:metabolism*; D006801:Humans; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics / Q000378:metabolism; D010920:Placenta / Q000201:enzymology / Q000378:metabolism* / Q000648:ultrastructure; D011247:Pregnancy; D011257:Pregnancy Proteins / Q000235:genetics / Q000378:metabolism*; D011261:Pregnancy Trimester, First; D021381:Protein Transport; D058979:Proton-Coupled Folate Transporter; D012333:RNA, Messenger / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D058978:Reduced Folate Carrier Protein; D020133:Reverse Transcriptase Polymerase Chain Reaction; D047929:Term Birth; D014327:Trophoblasts / Q000201:enzymology / Q000378:metabolism* / Q000648:ultrastructure
D002352:Carrier Proteins; D058973:Folate Receptors, GPI-Anchored; D026901:Membrane Transport Proteins; D011257:Pregnancy Proteins; D058979:Proton-Coupled Folate Transporter; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D058978:Reduced Folate Carrier Protein; C548699:SLC19A1 protein, human; C505058:SLC46A1 protein, human; D006710:Homocysteine; D005492:Folic Acid; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase; D003541:Cystathionine beta-Synthase