Bekalu seminar ppt 2018

COLLEGE OF HEALTH SCIENCE
DEPARTEMENT OF BIOMEDICAL
SCIENCE (ANATOMY)
Role And Mechanism Of Folic Acid Supplementation On Placenta
Development And Prevention Of Neural Tube Defects
By: Bekalu Getachew
Submitted to:- Anatomy course team
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Outline
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 Objective
 Introduction
 Folate metabolism and transport
 Role and mechanism of folate in placenta development
 Role of folate in decidualization
 Folate and Neural tube defect
 Conclusion
 Reference

Objectives
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 At the end of the session should be able to:-
 Describe the role of folic acid supplementation on placenta
development.
 Mechanism of folic acid supplementation for placenta development.
 Explain mechanism of folic acid supplementation on prevention of
neural tube defect.

Methods and Materials
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 Google scholar, PubMed central were the databases that are used to
search for articles.
 Then those ideas were synthesized, summarized and contextualized.
 Finally, presented as a seminar.

Introduction
Background
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 The gestational period is key for fetal development and for a healthy life.
 Different genetic, environmental and endocrine factors can influence
positively or negatively during this period.
 The nutritional status of the mother is undoubtedly one of the main
environmental factors that influence pregnancy. This includes the selection
of foods, the nutrients contained in them, their metabolism and the transport
of them to the fetus through the placenta.
 Embryogenesis implies a series of programming processes involving
accurate time-controlled gene activation/silencing expressions.

Background…….
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 Folic acid, the synthetic form of folate, is an essential water soluble B-
vitamin B9.
 It involved in a number of important functions within the body
 Synthesis of proteins required for DNA replication
 Essential substrate for a range of enzymatic reactions
 Vitamin metabolism.
 purine and thymidine nucleotides
( Fox JT et al….2013)

Background ……
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 However, folic acid is needed for successful pregnancy, including
angiogenesis and vasculogenesis (Duan J..et al,2003)
 Methylation of the harmful, sulphur-containing homocysteine(Bivona
G et..al,2008) antioxidant protection (Joshi R et..al,2001), and
endothelial-dependent vascular relaxation.(Chaytor AT et..al,2005)

Background …….
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 Folate plays a role in
various one-carbon
transfer reactions and is
important for normal
placental and fetal growth
and development.

Sources of folic acid in food
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 Natural foods like leafy green vegetables, potatoes dried beans,
legumes, fruits (such as citrus fruits and juices), and organ foods such
as liver are rich sources of folate.
 Most dietary folates exist as polyglutamates, which are converted to
the monoglutamate form and absorbed in the proximal small intestine.
 However, the body absorbs only about 50% of food folate. This
problem is compounded by cooking practices such as prolonged
stewing, processing, and storage, which can destroy some of the folate
in natural foods. (Talaulikar & Arulkumaran, 2011)

Dietary Requirements
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 For all women capable of becoming pregnant should consume 400 μg of
folic acid daily.
 For women who have previously had an NTD-affected pregnancy,4000 mg
of folic acid per day starting 1 month before the time they plan to become
pregnant and throughout the first 3 months of pregnancy.

Folate metabolism
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 Folate in the 5-methyl THFA form is a
substrate required by methionine
synthase when it converts
homocysteine to methionine.

Folate metabolism…cont..
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 SAM is the novel methyl donor in many biological reactions.
 SAM then transfers the methyl group to an acceptor molecule, (i.e.,
norepinephrine as an acceptor during epinephrine synthesis, DNA methyl-
transferase as an intermediate acceptor in the process of DNA methylation.
 As a result, in the scenario of folate deficiency, homocystéine accumulates.
(Gentili et al., 2009).
 Hyperhomocysteinemia is a pathological condition characterized by an
increase in plasma concentration of total homocysteine (15 mol/L). (Shai et
al., 2004)

Folate transport
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Three human transports are
responsible for folate:
 The reduced folate carrier
 The folate receptor
 The proton coupled folate
transporter.

Folate transport……
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 Monoglutamylated folates are subsequently absorbed in the duodenum and
upper part of the jejunum by the high-affinity proton-coupled folate
receptor PCFT1 (Qiu et al. 2006).
 5-MethylTHF is the main form of folate circulating in the plasma and can
be transported into the cell by means of carrier- or receptor mediated
transport.

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 The enzyme folylpoly-γ-glutamate carboxypeptidase (FGCP), that is
anchored to the intestinal apical brush border and is encoded by the
glutamate carboxypeptidase II (GCPII) gene, is responsible for this
hydrolysis in the gut (Chandler et al. 1991).

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 Folate receptor α (FR-α) is a glycoprotein with a high affinity for the
monoglutamate 5-methylTHF and is expressed in a limited number of
epithelial cells, predominantly in the proximal tubules of the kidney, the
choroid plexus and the placenta.(Kamen and Smith 2004).
 How polyglutamates leave mitochondria remains unclear.(suh JR
et..al,2008)

Folate transport……cont.
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 Syncytiotrophoblasts involves co-localization of FRα and PCFT on
the microvillus plasma membrane, which bind and internalize 5-
MTHF.
 Transport across the basal plasma membrane (BM) into
cytotrophoblasts involves and the RFC and may include other
mechanisms localized to the BM.
(Glazier J..et..al,2010)

Folate transport……cont.
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 Placental folate transporters play a critical role in mediating placental
transport of maternal folate to the fetus.
 They act by transferring 5-methyltetrahydrofolate against a concentration
gradient, achieving about a 3-fold higher folate concentration in the fetal
circulation than in the maternal plasma.
(Murohara T et..al,2003)

Development of placenta
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 Placenta has two
parts
 Fetal-Chorion
frondosum
 Maternal- decidua
basalis
 Function- endocrine,
respiratory, metabolic

Role and mechanism of folic acid in placenta
Development
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 The placenta, a tissue of fetal origin, plays distinct roles in the maternal-
fetal transfer of oxygen and nutrients as well as the synthesis of hormones
and various proteins.
 The placenta has recently received a great deal of attention due to its
importance in imprinting and epigenetic regulation during the development
of offspring.
 Restrictions of nutrient intake during the critical period of rapid placental
growth may restrict the degree of growth and development of the placenta.
(Sibley CP et…al,2010)

Role and Mechanism….
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 Placental folate receptor α (FRα) is responsible for the initial step in
placental folate transfer by mediating apical folate uptake at physiological
pH as well as the entry of folate from maternal blood into the
syncytiotrophoblast (Pijnenborg R..et..al,2011)
 Maternal folate deficiency causes changes in placental folate content,
expression of folate transporters, and global DNA methylation and is
known to result in placental complications such as placental abruption,
vascular thrombosis.(Meisser A et…al,2014)

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 Paternal folate deficiency alone, despite the maternal folate sufficiency, caused a
decrease in placental folate contents along with FRα upregulation and a decrease in
placental weight. These results clearly suggest that paternal folate status was critical
for placental folate metabolism and development, and this effect was independent
from the effect of maternal folate status.
 Changes in paternal folate status could affect sperm DNA methylation, which would
disrupt gene expression.
(Burton GJ et..al,2011)

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 Placentation requires the invasion of fetally derived extravillous trophoblast
(EVT) cells into maternal uterine spiral arteries, converting these arteries
from highly resistant low-capacity vessels into a high-capacity system
capable of transporting large volumes of blood to the intervillous
space.(Vercruysse L et..al,2012)
 This process of EVT invasion requires the degradation and remodeling of
the extracellular matrix, which is performed mainly by matrix
metalloproteinases (MMPs).(Bischof P et..al,2014)

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 Between 8 and 12 wk of pregnancy, trophoblast plugs that have
accumulated in the spiral arteries are released, allowing the complete
perfusion of the syncytiotrophoblast with maternal blood and the
establishment of hemotrophic nutrition.(Alouini S et..al,2013)
 The sudden perfusion of placental villi at the onset of maternal placental
circulation has been associated with the generation of oxidative stress,
although the placenta is protected from undue harm by a number of
antioxidant enzymes.(Symonds ME et..al,2015)

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 Folic acid also has antioxidant activity and is directly able to scavenge free
radicals and also increase the bioavailability of nitric oxide.(Villar J
et..al,2010)
 Endothelial cells differentiate from mesenchymal cells, forming the first
capillaries of the fetal placental vasculature. This coincides with maternal
vascular remodeling and the onset of maternal blood flow into the placental
intervillous space.(Kreienberg R et..al,2016)

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 Development of the placental circulation requires both vasculogenesis, the
development of new blood vessels from primitive precursor cells, and
angiogenesis, which is the development of new vessels from a preexisting
vasculature.(Seval Y et..al,2017)
 Placental angiogenesis is critical for development of a normal placental
circulation and, consequently, normal development of the baby. (Nardozza
LM et..al,2015)

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 Folic acid may have a key role in regulation of EVT invasion, which is a
crucial part of placental development.
 Invasion of EVT into the maternal decidua and inner third of the
myometrium is crucial for the remodeling/transformation/ conversion of the
maternal spiral arteries, allowing the establishment of uteroplacental
circulation.
(Adamson SL et..al,2016)

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 Maternal folic acid deficiency has been associated with miscarriage
(Olander B et..al,2002) placental abruption, and intrauterine growth
restriction (Yang Q et..al,2008). Low folate levels have also been found in
plasma samples from women with preeclampsia.(Symonds M et..al,2009)

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 Inadequate EVT invasion is associated with defective placental
development, with a reduction in both the number of remodeled spiral
arteries in decidua and in the depth of remodeling, this is suggested to be
the primary defect that occurs in preeclampsia and intrauterine growth
restriction.
(Robertson WB et..al,2012)

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 Endothelial dysfunction is demonstrable within the myometrial arteries of
women with placental abruption and pre eclampsia.(Ashworth et al., 2010)
 Furthermore, among women with recurrent early pregnancy loss, chorionic
vessel wall diameter is inversely related to fasting maternal plasma Hcy
(Nelen et al., 2009).

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 The increase in EVT invasion
associated with folic acid
supplementation may be explained
by the increased production of
MMP2, MMP3, and MMP9.
(Meisser A et..al,2011)

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 Increased production of the gelatinases (MMP2 and MMP9) may be
associated with increased EVT invasion due to increased degradation of
type IV collagen in the basement membrane, allowing increased numbers of
EVT cells to invade through the maternal decidua.
 MMP3, also known as stromelysin-1, may also be involved in the increased
invasion of EVT via degradation of a variety of extracellular matrix
components, including proteoglycans, fibronectin, laminin, and type IV
collagen, and has been shown to be present throughout pregnancy.
(Prast J et..al,2010)

Role and mechanism……
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 Decidual angiogenesis forms a new vascular network that serves as the first
exchange apparatus between the maternal circulation and the developing
embryo and thus is a crucial and fundamental process for embryonic
survival and a successful pregnancy.(Winterhager E et..al,2013)

Steps in Human placental vasculogenesis and
angiogenesis
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 Step-1: Vasculogenesis starts with haemangiogenic stem-cell-
induced cytotrophoblast differentiation that is regulated by VEGF in
a paracrine manner.
 Step-2: Angiogenesis I (activation) is a prevascular network
formation process. Growth factors produced by cytotrophoblast cells
and Hofbauer cells play a major role.
 Step-3: Angiogenesis II (remodeling) is a process of differentiation
of perivascular cells (pericytes and myofibroblast-like cells) to form
contractile vessels. (Efeyan, A et..al,2011)

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 Vascular endothelial growth factor A (VEGFA), placental growth factor
(PLGF), and vascular endothelial growth factor (VEGF) receptor 2
(VEGFR2) are key molecules regulating decidual angiogenesis and
maternal spiral artery remodeling.
 They are expressed in the endometrium, decidua, and placenta and play an
important role in ensuring a successful pregnancy.
(Kaufmann P et..al,2014)

Role and mechanism……..
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 PLGF and VEGFA have synergistic effects in the induction of angiogenesis,
but PLGF-induced vessels are more mature and stable than VEGF-induced
vessels.
(Liao F et..al,2013)

Role and mechanism…..
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 A reduction of these three factors (VEGFA, VEGFR2, and PLGF) was
accompanied by the damage of decidual angiogenesis in pregnant mice
during the post-implantation period.
 It revealed that the abnormal expression and distribution of VEGFA,
VEGFR2, and PLGF resulted in abnormal decidual angiogenesis in folate-
deficient pregnant mice.
(Siow Y.L et..al,2014)

Role and mechanism….
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 Studies have found that Homocysteine has vasculotoxic properties, causing
endothelial cell damage and dysfunction is also known to induce oxidative
stress responses and to decrease the cellular antioxidant potential which can
damage all components of the endothelial cell.
 It is known that dietary or genetically determined folate deficiency leads to
Homocysteine accumulation because both the re methylation and trans
sulfuration pathways are inhibited in folate deficiency.
(Rich S et..al,2013)

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 Accumulation of misfolded proteins in the endoplasmic reticulum due to
Hcy can trigger an unfolded protein response which may cause cellular
growth arrest and apoptosis.
 Hcy exposure causes impaired early extra-embryonic vascular
development, as evidenced by the altered composition of the vascular beds
as well as the reduced expression of VEGFA and VEGFR2.
(Steegers E.A et..al,2012)

Role and mechanism…..
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 Genes expression of endometrium decidualization including bone
morphogenetic protein 2 (BMP2), homeobox A 10 (Hoxa10), matrix
metalloproteinase 2 (MMP2), and matrix metalloproteinase 9 (MMP9)
proteins was markedly reduced in folate-deficient.
 Deficiency of folate impairs nucleotide and DNA synthesis that support cell
division, leading to megaloblasts and cell death, especially of highly
prolific somatic cells.
(Critchley H.O et..al,2009)

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 It is reported that both mTORC1 and mTORC2 signaling pathways in
primary human trophoblast cells are influenced by folate availability with
folate deficiency causing a profound inhibition of mTOR signaling activity.
(Powell, T et..al,2015)
 The mechanistic target of rapamycin (mTOR) is master regulator of cell
growth, aging, ribosome biogenesis, protein synthesis, actin-cytoskeletal
organization, autophagy and metabolism.(Efeyan, A et..al,2011)

Neural Tube defects
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 The human nervous system originates from the primitive ectoderm that also
develops into the epidermis.
 The ectoderm, endoderm, and mesoderm form the three primary germ
layers that are developed by the 3rd wk.
 The endoderm, particularly the notochordal plate and the intraembryonic
mesoderm, induces the overlying ectoderm to develop the neural plate in
the 3rd wk of development
 Failure of normal induction is responsible for most of the NTDs, as well as
disorders of prosencephalic development.

Neurulation
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Role of folate in Neural induction
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 Folic acid supplementation modulates intracellular signaling pathways that
regulate mitosis and apoptosis.
 The Notch signaling pathway is necessary for cell-cell communication,
which involves gene regulation mechanisms that control multiple cell
differentiation processes during embryonic life.
 It is likely that folic acid stimulated the transcription and translation of
Notch1, because folic acid supplementation increased Notch1 mRNA and
protein levels in NSC neurospheres.
(Ortiz D et..al,2011)

Role of folate in Neural induction
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 It has been reported that folate deficiency and DNA hypomethylation can
lead to misexpression of miRNAs which in turn may substantially affect
neural development.(Shookhoff JM et…al,2010)
 MicroRNAs (miRNAs) are small noncoding RNAs that regulate
posttranscriptional gene expression. The presence of specific miRNAs is
enriched in the central nervous system where they influence cell cycling,
cell differentiation, and apoptosis during development.(Fineberg SK
et..al,2009)

Role of folate……
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 let-7 (lethal 7) and miR-34 genes are believed to exert a requisite role at
various steps of cerebral development, while they would influence the
occurrence of NTDs.(.(Shookhoff JM et…al,2010)
 Folate also influence Wnt signaling.(Gray et al., 2010)
 Folate helps to express canonical complement 5a receptor(C5aR)which is
found in the neuroepithelium of early human embryos.(Theveneau, A
et..al,2011)

NTDs…..
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 Although the precise cause of NTDs remains unknown.
 Risk factors- Family history of NTDs,Certain syndromes and chromosomal
disorders, Low dietary low folic acid Administration of sodium valproate
and folic acid, chemical exposure, radiation.
 Methylene tetrahydrofolate reductase (MTHFR) gene defects
 Methionine synthase gene defects
 Cystathionine beta synthase (CBS) gene defects

Epidemiology of NTDs
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 Globally, it is estimated that approximately 300,000 babies are born each
year with NTDs resulting in approximately 88,000 deaths and 8.6 million
disability-adjusted life years (DALYs).(WHO,2015)
 In low income countries, NTDs may account for 29% of neonatal deaths
due to observable birth defects.(Cousens S et..al,2010)
 According to a study in Ethiopia showed that the birth prevalence of NTDs
was 63.4 per 10,000 births (LBs and SBs)(Abel Gedefaw et al..,2018)

Folate and NTDs
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 DNA methylation, which is reprogrammed during early embryogenesis
(Reik et al. 2001), is part of the epigenetic code and is a chief regulator of
gene expression (Dean et al. 2005), has been hypothesized to be associated
with NTDs (Blom et al. 2006).
 Inhibition of MAT in cultured mouse embryos also decreased the
AdoMet/AdoHcy ratio, and these embryos also presented with cranial
closure defects (Dunlevy et al. 2006).

Folate and NTDs
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 Studies in mice demonstrate that the de novo DNA methyltransferase,
Dnmt3b, is expressed in the elevating neural folds during neural tube
formation, and that Dnmt3b null mutants develop NTDs.(Wang L.
et..al,2010)
 Folr1 is expressed in the neural folds during neurulation (Saitsu et al.,
2003). Knockout of the Folr1 gene in the mouse leads to NTDs ( Spiegel-
stein et al., 2004), demonstrating the importance of folate uptake to proper
neural tube development.

Folate and NTDs
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 The autoantibodies were shown to block the binding of folic acid to the
folate receptors.
 Suggested mechanism for Autoantibody against folic acid receptor
 Could be a decreased T cell DNA methylation.

Folate and NTDs
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 Folates may be related to NTD risk through their roles in nucleotide
synthesis. In fact, in embryos, the rapidly dividing cells of the developing
neural tube require the synthesis of large amounts of nucleotides in order to
facilitate DNA replication.
 Neuroepithelial cells do not have an adequate internal supply of
nucleotides, cellular replication will slow down and the development of the
neural folds will be retarded(Shaw et..al,2010)

Folate and NTDs
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 An extra amount of folic acid could theoretically overcome this blockage,
and the presence of folate receptor autoantibodies may thus explain part of
the preventive effect of periconceptional folic acid supplementation
(Rothenberg et al., 2004).
 At the cellular level, the supplementation with FA has an effect on the
differentiation, proliferation, and junction formation in neuropore could
explain the FA effect on NTD in this model.(Nakazaki, H et..al,2012)

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 Subsequent small trials in women who had a NTD-affected pregnancy
indicated that periconceptional supplementation with 0.4–5 mg of folic acid
per day decreased the recurrence risk of NTDs about fourfold (Blom 2009).

Conclusion
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 Folic acid supplementation plays a crucial role fetal and maternal outcome.
 Folate deficiency significantly impairs the expression of VEGE,PGF that
play a role in placental vasculogenesis and angiogenesis.
 Folate facilities extracellular matrix degradation for the invasion of
trophoblast.
 DNA methylation plays a key role in epigenetics mechanism.
 Folic acid plays a vital role in Notch 1 signaling, miRNA during embryonic
development.

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THANK YOU!!!

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