Folate Deficiency And Cancer

The biochemical manifestations of a folate deficiency can be seen in a decreased supply of S-adenosylmethionine and then in loss of methylation of CpG islands as well as a decrease in dTMP and a rise in the dUMP pool, which has been shown to result in misincorporation of deoxyuridine (du) into DNA. Recently, Ames and colleagues showed the significant extent of misincorporation of dU into DNA in folate-deficient patients (9) and, like others (10), speculated on the consequences. The protective...

Homocysteine And The Child

Disturbance of the Folate-Dependent Homocysteine Metabolism in Children with NTD Is the Cause of the Disease In children with spina bifida, folate and homocysteine metabolism is disturbed (70). A strong correlation was found between plasma homocysteine and B vitamins with age in 70 spina bifida children and 185 controls. Adjustment for age was performed. Homocysteine levels above the 95th percentile showed an odds ratio of 6.4 (95 CI 2.7-15.2) and for the 5th percentile of plasma folate, an...

References

A. (1991) Neural tube defects in 18th century. Lancet 337, 504 2. Stein, Z., Susser, M., Saenper, G., Marolla, F., eds. (1975) Famine and Human Development The Dutch Hunger Winter of1944-1945. Oxford University Press New York. 3. Hibbard, B. M. (1964) The role of folic acid in pregnancy with particular reference to anaemia, abruption, and abortion. J. Obstet. Gynaecol. Br. Commonwlth. 71, 529-542. 4. Hibbard, B. M. and Smithells, R. W. (1965) Folic acid metabolism and human...

Absorption Transport And Metabolism Of Dietary Folates

Because man is unable to manufacture folate, he depends on a variety of exogenous sources for the vitamin. In addition to the rich sources mentioned earlier, moderate sources such as bread, potatoes, and dairy products are consumed in large amounts and thus contribute a significant proportion to our total folate requirement. If one takes into account all folyl oligo-y-glutamyl forms of the various one-carbon and unsubstituted oxidation states of the vitamin, folate metabolism becomes complex....

Developmental Toxicants Which May Act Via Folate Perturbation

A number of compounds alter normal development either in humans or in animal models and may act via alterations in folate levels or metabolism. Several of these will be discussed below. The antimetabolites, aminopterin and methotrexate, were reviewed previously (36) and will not be included here. Anticonvulsant drugs, particularly phenytoin, were first reported to possibly produce birth defects in the mid-1960s. The defects observed included cleft lip with without cleft palate, heart defects,...

Choline And Brain Development

Choline availability during embryogenesis and perinatal development are especially important for brain development. There are two sensitive periods in rat brain development during which treatment with choline (about 1 mmol d administered to the mother during a critical period during pregnancy, or 300 mg kg administered subcutaneously 2 wk after after birth) produces long-lasting enhancement of spatial memory that is lifelong (28-36). The first critical period occurs during embryonic d 12-17...

Info

Note A Mann-Whitney test on this combined data shows that TT Hcy is significantly higher than combined CT and CC Hcy (p 0.026). Note A Mann-Whitney test on this combined data shows that TT Hcy is significantly higher than combined CT and CC Hcy (p 0.026). proportion of all NTD (79), with subsequent studies not always being able to confirm it as a risk factor at all (24,80,81). The lower blood folate and, particularly, the moderately elevated plasma Hcy levels associated with the C677T MTHFR SNP...

Evidence From In Vivo Studies With Humans

The early evidence of chromosome damage in human cells in vivo from folate and vitamin B12 deficiency was first obtained from studies linking the expression of Howell-Jolly bodies in erythrocytes with megaloblastic anemias (20-22). Howell-Jolly bodies are whole chromosomes or chromosome fragments that lag behind at anaphase during production and maturation of Fig. 2. Relationship between folic acid concentration and four different biomarkers of DNA damage MNed micronucleated cells, a biomarker...

Cart1 Knockout

Gene targeting has been used to generate mice with a null mutation in Cartl, a homeobox-containing gene that encodes the transcription factor, cartilage homeoprotein 1 (16,17). Homozygous Cartl mutant mice develop cranial NTD and die shortly after birth. The penetrance is influenced by genetic background with a maximum NTD incidence of 100 on a 129 SvEv strain background (17). Cranial NTD result from failure of closure at the prospective forebrain midbrain boundary, so called Closure 2. Failure...

Meiotic Nondisjunction And Down Syndrome

Prevalence and Consequence of Down Syndrome Down syndrome or trisomy 21 is a complex metabolic and genetic disorder that stems from the failure of chromosome 21 to segregate normally during meiosis (84,85). It is the first clinically defined syndrome shown to be chromosomal in origin and, as a result, has been the prototype for intense clinical, cytogenetic, epidemiologic, and molecular investigation into mechanisms of human aneuploidy. The origin of the extra chromosome 21 has been shown to be...

Folate Deficiency And Chromosome Instability

Chromosomal Aberrations and Micronuclei Folate and or B12 deficiency in humans has been long associated with chromosomal instability and multiple chromosomal aberrations. Early cytogenetic studies of folate- or B12-deficient human lymphocytes or marrow cells revealed multiple chromosomal breaks and gaps, decondensed chromosomes, premature centromeric division, and centromeric spreading (31,32). Chronic folate deficiency is manifested in a futile cycle of uracil misincorporation during DNA...

Clinical And Animal Studies Reinterpretation In Light Of Molecular Data

Studies of clinical populations and animals have indicated that iron deficiency alters folate-dependent one-carbon metabolism. Specifically, iron deficiency can influence all of the biochemical indicators listed in Fig. 2. However, marked discrepancies exist within the literature, primarily resulting from different patient populations, indicators of folate status or metabolism, experimental protocols, as well as insufficient measurements and lack of experimental controls (70). These...

Choline And Apoptosis

Choline deficiency also resulted in an increase in apoptosis in a specific region of the hippocampus, namely the dentate gyrus. We observed an inverse correlation between apoptosis rates in the brains of rat fetuses and dietary intake of choline by their mothers (65). Others have reported apoptosis in the hippocampus and cortex of rats during the perinatal period (66,67) we were the first to report an effect of maternal nutrition. Apoptosis is usually inducible when cells are dividing and then...

Environmental And Genetic Factors That Determine The Bioavailability Of Folic Acid And Vitamin B12

Alcoholism is associated with significantly reduced levels of tissue folate, vitamin B12, and vitamin B6 in humans at intakes greater than 3.0 g kg d, there was a doubling in the level of DNA hypomethylation of lymphocytes (57). The reduced folate level in alcoholics may be the result of reduced absorption or suboptimal dietary intake. However, if results in the rat model reflect the situation in humans, then there is a good probability that the microbial metabolism of alcohol can result in...

Choline And Cell Cycling

The brain is not the only organ in which choline increases mitosis. The availability of choline alters cell proliferation in the adult rat liver (58), and in cultured liver cells choline availability influences cell cycling by affecting the availability of phosphatidylcholine in membranes (53,59). Choline deficiency alters the expression of growth factors and cell cycle regulatory factors (e.g., TGF 1, p27Kip1) known to alter mitotic activity (60,61). During fetal brain development, correct...

H

Heat exposure, maternal, NTD, 16-17 HIV integrase, 79 Homocysteine, 299-301, child, 150-153 C677T gene mutation, 334-336 DNA damage, 77-78 early miscarriage, 308-309 elevated serum concentrations, 244 embryo, 148-149 estrogen, 305-307 fetus, 150 folate, 332-334 folic acid, 166 genetic factors, 334-336 menopausal transition, 305-308 menstrual cycle, 303-304 metabolism, 300-301, 331-332, metabolic pathways, 72 pathway, 5 NTD, 14-15, 144-149 OVD, 279-282 preeclampsia, 310-312 endothelial...

Homocysteine And Early Miscarriage

Clinical Background of Early Miscarriage The term miscarriage is used to emphasize the spontaneous interruption of pregnancy. For clinical and scientific reasons, it is important to avoid the international confusion on the duration of pregnancy when the term abortion is used because the range of pregnancy duration can be as wide as from 0 to 28 wk. Another reason for this distinction is that the causes for embryonic loss are quite different from those of fetal loss. We therefore tried to...

Biochemical Mechanisms For Ironfolate Interactions

Iron Metabolism Influences Folate Status Regulation of intracellular folate concentrations is complex and is influenced by dietary folate intake, intestinal and cellular transport systems, polyglutamylation of the cofactor, and folate turnover, including folate catabolism (19,24,38). Folate catabolism is defined as the oxidative and irreversible scission of the p-aminobenzoyl(poly)glutamate moiety of the cofactor from the quinazoline ring system, a reaction that destroys folate as a metabolic...

Placental Abruption

Placental Abruption Great Risk for Mother and Child In obstetrics, various clinical syndromes are accompanied with disturbances of blood coagulation. Placental abruption is a classic example for such disease. Placental abruption is an obstetric syndrome with great risks for mother and child (82,83). The placenta separates from the uterine wall during pregnancy by retroplacental bleeding and blood clotting. Histology points to a rupture of the spiral artery or arteries. When the placenta is...

The Folate Hydrolase Gene

The human folate hydrolase gene (FOLH1, identical with human prostate-specific membrane antigen, gene symbols PSM, PSMA alternative title and symbol glutamate carboxypeptidase II, GCP2) is located on chromosome 11p11 - p12 (70). The FOLH1 gene encompasses approximately 60 kb and consists of 19 exons (GenBank accession number AF007544) (70,71). The entire coding region has a length of 2.653 bp (GenBank accession number M99487) (72), with a predicted molecular mass of 84 kDa excluding...

Mechanisms Of Vascular Toxicity

A wealth of mechanisms have been proposed to contribute to the vascular toxicity of homocysteine, including platelet aggregation, increased coagulation or reduced thrombolysis, endothelial dysfunction, and effects on the blood vessel wall (50). Modest elevations of tHcy have been associated with endothelial dysfunction (51). Endothelial function is impaired after a methionine-loading test or even as a result of a high-protein meal (52). Administration of either folate or ascorbate or a...

Cardiovascular Disease

Gender Difference in Cardiovascular Disease Within the preventive aspects of health care in women, cardiovascular disease should have more attention. The main argument for this statement is the fact that about 40 of women will die from cardiovascular disease and around 20 from malignant disease. In other words, risk factors for cardiovascular disease and blood pressure are more important than a Pap smear. In ischemic heart disease, there is a very marked gender difference Women die 10-15 yr,...

The Mthfr Gene Product MTHFR

The MTHFR gene product consists of 656 amino acid residues with a predicted molecular mass of 74.6 kDa 3-6 and is termed 5,10-methylenetetrahydrofolate reductase MTHFR, EC 1.5.1.20 . The amino acid sequence is highly conserved, showing 90 homology with the mouse polypeptide 4 . MTHFR consists of two identical subunits of approx 70 kDa 7 and represents a key enzyme in the folate cycle. It reduces 5,10- methylenetetrahydrofolate to 5-methyltetrahydrofolate, thus catalyzing the only reaction in...

Folate Receptor

Potocytosis

Receptor-Mediated Folate Transport An Example of Potocytosis Studying cells grown in low levels of folate lt 1 nM , several laboratories identified a folate receptor FR on the membrane of KB human nasopharyngeal carcinoma cells, CACO2 colon carcinoma cells, IGROV-1 ovarian carcinoma , MA104 monkey kidney epithelial cells, and, more recently, in both murine and human leukemia cells 35-39 reviewed in refs. 19 and 40 . A soluble form of the protein was initially found in milk 30 yr ago and in some...

Recommended Dietary Allowances For Folate And Vitamin B12 Based On Genomic Stability

There is now increasing interest to redefine recommended dietary allowances RDAs of minerals and vitamins not only to prevent diseases of extreme deficiency but also to prevent developmental abnormalities and degenerative diseases of old age as well as optimizing cognition 75 . Prevention of chromosome breakage and aneuploidy is an important parameter for the definition of new RDAs for micronutrients 9 such as folic acid and vitamin B12 because increased rates of DNA damage have been shown to...

Nd

Methionine Homocysteine Cycle

Embryos die prior to completion of neural tube closure see text for references. cRad. radiation induced. Embryos die prior to completion of neural tube closure see text for references. cRad. radiation induced. deficiency caused by a defect in methionine synthase appears unlikely, as plasma methionine levels are normal in Axd heterozygous females. A defect in homozygous embryos cannot be excluded, although this does not appear to have been tested 14 . Although methionine treatment has a...