Folate and Human Development

373 Pages·2002·3.019 MB·English

by  Edward J. Massaro, John M. Rogers

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Folate and Human Development

Folate and Human
Development
Edited by
Edward J. Massaro
and
John M. Rogers
The National Health and Environmental Effects Research Laboratory,
Research Triangle Park, NC
Humana Press
Totowa, New Jersey
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Folate and human development / edited by Edward J. Massaro and John M. Rogers.
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Includes bibliographical references and index.
ISBN 0-89603-936-6 (alk. paper)
1. Neural tube--Abnormalties--Etiology. 2. Folic acid deficiency. 3. Folic acid in
human nutrition. I. Massaro, Edward J. II. Rogers, John M.
RG629.N48 F65 2002
612.3'99--dc21 2001051863
Preface
Neural tube defects (NTDs) are a complex developmental trait in
which several genes, interacting with environmental factors, create the
phenotype. In the United States, the rate of NTDs has been reported to
range from 4 to 10 per 10,000 live births. Currently, in the United States,
the two most common types of NTDs, anencephaly and spina bifida,
which occurs in varying degrees of severity, affect approximately 4000
pregnanciesper annum, resulting in the birth of 2500 to 3000 children
manifesting one or the other of these conditions. Nevertheless, it has
been proposed that 50–70% of the defects comprising this constellation
of conditions could be prevented with daily intake of 400 µg of folic
acid throughout the periconceptional period. In this regard, The Cen-
ters for Disease Control and Prevention (CDC) recommended, in 1991,
that women who have experienced a pregnancy affected by NTDs who
are planning a new pregnancy consume 400 µg of folic acid daily
beginning at least one month prior to conception and continuing
through the first three months of pregnancy. In addition, in 1992, the
US Public Health Service (USPHS) recommended that all women of
reproductive age consume 400 µg of folic acid per diem. In 1996, the US
Food and Drug Administration authorized and then required (1998)
that enriched grain products be supplemented with folate. Also in
1998, the Institute of Medicine (IOM) recommended that all women of
childbearing potential consume 400 µg of synthetic folic acid per day
from fortified foods and/or a supplement in addition folate obtained
from a varied diet.
These actions resulted in a significant decrease in the incidence of
NTDs despite the 1998 report that only 29% of US women complied
with the USPHS and IOM recommendations. Thus, in women receiv-
ing prenatal care, the rate decreased more than 19% (from 3.78/10,000
live births to 3.05/10,000) while in women receiving prenatal care
only during the third trimester or none at all, the rate decreased
approximately 13% (from 5.34/10,000 live births to 4.65/10,000).
v
vi Preface
The greatest need for folate occurs during pregnancy. During devel-
opment, as the number of rapidly dividing cells increases, the require-
ment for folate increases. The situation is complicated by decreased
absorption and increased clearance of folate during pregnancy. By the
third trimester, the requirement for folate has almost doubled. In
addition to NTDs, periconceptional folic acid supplementation reduces
the occurrence of several human congenital malformations including
craniofacial and heart defects. In the United States, because normal
diets seldom supply the 400 µgper diemof folate required during preg-
nancy, 20–25% of otherwise normal pregnancies are associated with
low-serum folate levels. During July and August 1998, a survey was
conducted to assess knowledge of the benefits of adequate folic acid
consumption among women of childbearing age in the United States.
The results were compared to those obtained from a similar survey
conducted in 1995. The 1998 findings revealed that only 7% of women
knew that folic acid should be taken prior to pregnancy to reduce the
risk of NTDs. It is to be noted that, although recommendations regard-
ing folic acid consumption were issued by health authorities in a num-
ber of countries in the early 1990s, assessment of periconceptional
intake of folic acid revealed a disappointingly low level of compliance.
Therefore, it appears that, regardless of food fortification policies, con-
tinued promotion of the benefits of folic acid supplementation to
optimize the folate status of women of child-bearing age will be required
in most countries. Indeed, although periconceptional folate supple-
mentation has been encouraged in the United Kingdom since the early
1990s, no concurrent decline in NTD pregnancies has been observed by
regional congenital anomaly registries. Conceivably, additional nutri-
tional inadequacies also may be involved. However, these have not
been extensively researched. In this regard, it is of interest to note that,
in California between 1989 and 1991, the interaction between maternal
preconceptional dietary and supplemental zinc intake and the risk of
NTDs was investigated in a population-based case-control study. Four
hundred and thirty (430) NTD-affected fetuses/infants and 429 ran-
domly selected, non-malformed infants comprised the case and con-
trol populations. The preconceptional use of vitamins, minerals, and
food supplements was reported by the mothers who completed a
98-item food frequency questionnaire. Phytate intake, a dietary con-
stituent known to interfere with zinc absorption, appeared to nega-
tively impact the zinc/NTD association. It was observed that increased
servings of animal products, which are the most bioavailable food
source of zinc, were associated with a reduced risk for NTDs. Risk
estimates for zinc intake changed little after controlling for multiple
Preface vii
sociodemographic factors and total folate intake, but were attenuated
after controlling for nutrients highly correlated with dietary sources of
zinc. The analyses indicated that risk of NTDs in fetuses and infants
decreased with increasing maternal preconceptional zinc intake. How-
ever, it remains unclear whether increased zinc intake or other nutri-
ents or combinations of nutrients that may be highly correlated with
dietary zinc intake are causally associated with reduced NTD risk.
Homocysteine status also appears to play a role in NTDs. Homocys-
teine, a sulfur-containing amino acid is generated through the
demethylation of methionine. It is metabolized via three principal
routes. The predominant pathway is selected by physiological need.
Thus, homocysteine can be metabolized to cysteine by transsulfuration
or remethylated to methionine or hydrolyzed to (cid:95)-ketobutyrate,
ammonia, and H S. Regulation of the plasma level of homocysteine is
2
dependent on nutrient uptake, especially uptake of folate and vita-
mins B (pyridoxine) and B (cobalamin). In addition, its metabolism
6 12
is affected by genetic individuality. Excess levels of homocysteine are
thrombophilic and damage the vascular endothelium. In adult popu-
lations, total plasma homocysteine (tHcy) is an established clinical risk
factor for coronary artery disease as well as other arterial and vaso-
occlusive diseases. These vascular effects appear to be related to its role
as a teratogen in the pathogenesis of NTDs and other developmental
defects since genetic variants resulting in hyperhomocysteinemia are
associated with NTDs. Thus, genetic variation in folate metabolic genes
is expected to contribute to the risk of NTDs.
The observation that homocysteine and vitamin B levels are inde-
12
pendent predictors of NTD risk suggested that the gene encoding
methionine synthase might play a role in the induction of NTDs.
Methionine synthase catalyzes the vitamin B -dependent conversion
12
of homocysteine and 5-methyltetrahydrofolate to methionine and
tetrahydrofolate. However, tests of an association between specific
methionine synthase alleles and NTDs indicated that inherited varia-
tions in the gene do not contribute to NTD risk, at least not in the
population studied. However, impairment of folate and vitamin B
12
metabolism has been observed in families with NTDs. Therefore, it is
conceivable that genetic variants/mutants of enzymes in the homocys-
teine remethylation pathway might act as predisposing factors con-
tributing to NTD risk. The first polymorphism discovered that was
associated with increased NTD risk was the 677C–>T mutation
(A222V) in methylenetetrahydrofolate reductase (MTHFR). It is to be
noted that this variant also has been associated with increased risk of
nonsyndromic orofacial clefts. A polymorphism, 66A–>G (I22M), in
viii Preface
the gene that encodes the enzyme, methionine synthase reductase
(MTRR), that activates vitamin B -dependent methionine synthase,
12
also has been reported. This mutation has an allelic frequency of 0.51
and increases the risk of NTDs when vitamin B status is low. In
12
addition, in the presence of the 677C–>T mutant MTHFR genotype, the
66A–>G (I22M) MTRR mutant increases the risk of NTDs under con-
ditions of adequate vitamin B . When the genotype and B status of 56
12 12
children with spina bifida and 58 mothers of spina bifida children were
compared to control groups consisting of 97 children and 89 mothers,
the spina bifida cases and associated mothers were approximately twice
as likely to possess the homozygous 66A–>G (I22M) MTRR mutant
genotype than the control groups. But, the difference was not statisti-
cally significant. However, the risk for homozygous 66A–>G (I22M)
MTRR mutant genotype mothers with low B status to deliver a child
12
with spina bifida increased approximately fivefold [odds ratio (OR)
= 4.8, 95%; CI = 1.5–15.8], while the OR for spina bifida in children with
this combination was 2.5 (95%; CI = 0.63–9.7). On a background of
combined MTHFR and MTRR homozygous mutant genotypes, chil-
dren had a fourfold increase in risk (OR = 4.1, 95%; CI = 1.0–16.4) of
manifesting spina bifida while mothers had a threefold increase in risk
(OR = 2.9, 95%; CI = 0.58–14.8) in delivering a child with this condition.
Clearly, the interaction between vitamin B deficiency and the mutant
12
MTHFR and MTRR genotypes indicates a multifactorial induction of
NTDs. However, the mechanism is complex and unresolved. Further-
more, the MTHFR 677C–>T and MTRR 66A–>G mutations are each
associated with increased risk of Down syndrome. In the presence of
both mutations, the risk is even greater.
It is well known that drugs and other chemicals can induce birth
defects in humans. For example, pharmaceuticals such as valproic acid
and other antiepileptic drugs that interfere with folate metabolism can
induce NTDs. Therefore, a question worth considering is: Is low folate
status during pregnancy a factor that increases or contributes to an
increase in the risk of induction of NTDs and other birth defects from
exposure to ambient levels of environmental xenobiotics? Unfortu-
nately, this is a public health issue for which we have little information.
Therefore, to gain further insight into the etiology of NTDs as well as
all other birth defects that affect so many for their lifetime, continued
research on the role of folate and other nutrients is imperative. The
editors believe that the research data gathered by the contributors to
this work are a step in the right direction.
Edward J. Massaro
John M. Rogers
Contents
Preface......................................................................................................... v
Contributors..............................................................................................xi
1 • Animal Models of Folate-Related Neural Tube Defects........... 1
Nicholas D. E. Greene and Andrew J. Copp
2 • Genetic Variation in Folate Metabolism: Impact
on Development............................................................................ 27
Rima Rozen
3 • Folate Deficiency and the Molecular Determinants
of Chromosome Instability: Possible Link to Meiotic
Nondisjunction and Down Syndrome......................................... 43
S. Jill James and Charlotte A. Hobbs
4 • Folic Acid, Vitamin B , and Genomic Stability of Human
12
Cells.............................................................................................. 71
Michael Fenech
5 • Molecular Genetics of Folate Metabolism................................. 91
Manuela Födinger, Sonja Skoupy, and Gere Sunder-Plassmann
6 • Folate Receptor-(cid:95): An Update.....................................................117
Barton A. Kamen
7 • Folate, Homocysteine, and Neural Tube Defects...................137
Tom K. A. B. Eskes
8 • Folic Acid and Homocysteine as Risk Factors for Neural
Tube Defects .............................................................................165
Robert C. Barber, Janée van Waes, Edward J. Lammer,
Gary M. Shaw, Thomas H. Rosenquist,
and Richard H. Finnell
9 • Developmental Toxicants Potentially Acting via Folate
Perturbation..............................................................................183
Deborah K. Hansen
ix