Neural tube closure takes place during early embryogenesis and requires interactions between genetic and environmental factors. Failure of neural tube closure is a common congenital malformation that results in morbidity and mortality. A major clinical achievement has been the use of periconceptional folic acid supplements, which prevents approximately 50-75% of cases of neural tube defects. However, the mechanism underlying the beneficial effects of folic acid is far from clear. Biochemical, genetic and epidemiological observations have led to the development of the methylation hypothesis, which suggests that folic acid prevents neural tube defects by stimulating cellular methylation reactions. Exploring the methylation hypothesis could direct us towards additional strategies to prevent neural tube defects.

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Neural tube defects and folate: case far from closed

Folate and human reproduction

Folate receptor alpha (FRalpha) is a membrane-bound protein with high affinity for binding and transporting physiologic levels of folate into cells. Folate is a basic component of cell metabolism and DNA synthesis and repair, and rapidly dividing cancer cells have an increased requirement for folate to maintain DNA synthesis, an observation supported by the widespread use of antifolates in cancer chemotherapy. FRalpha levels are high in specific malignant tumors of epithelial origin compared to normal cells, and are positively associated with tumor stage and grade, raising questions of its role in tumor etiology and progression. It has been suggested that FRalpha might confer a growth advantage to the tumor by modulating folate uptake from serum or by generating regulatory signals. Indeed, cell culture studies show that expression of the FRalpha gene, FOLR1, is regulated by extracellular folate depletion, increased homocysteine accumulation, steroid hormone concentrations, interaction with specific transcription factors and cytosolic proteins, and possibly genetic mutations. Whether FRalpha in tumors decreases in vivo among individuals who are folate sufficient, or whether the tumor's machinery sustains FRalpha levels to meet the increased folate demands of the tumor, has not been studied. Consequently, the significance of carrying a FRalpha-positive tumor in the era of folic acid fortification and widespread vitamin supplement use in countries such as Canada and the United States is unknown. Epidemiologic and clinical studies using human tumor specimens are lacking and increasingly needed to understand the role of environmental and genetic influences on FOLR1 expression in tumor etiology and progression. This review summarizes the literature on the complex nature of FOLR1 gene regulation and expression, and suggests future research directions.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/ijc.21712

The role of folate receptor α in cancer development, progression and treatment: Cause, consequence or innocent bystander?

http://www.columbia.edu/itc/hs/medical/humandev/2005/NTDreivew.pdf

Human neural tube defects: Developmental biology, epidemiology, and genetics

Over three years have passed since an increase in the intake of folic acid among women planning a pregnancy was shown to prevent most neural tube defects.1 The evidence is conclusive; prevention is effective for women who have not had a pregnancy in which the fetus had a neural tube defect as well as for those who have.2 National authorities have recommended that women planning a pregnancy should increase their intake of folic acid.3 4 5 The extra folic acid needed for a reasonable protective effect is 0.4 mg a day, twice the current average dietary intake of 0.2 mg. If no screening was carried out for neural tube defects (with subsequent abortions) about 1500 affected children would be born each year in Britain. Over 1000 of these defects could be prevented by women consuming extra folic acid. Sadly, most people are still not aware of the importance of folic acid in the prevention of neural tube defects.6 7 A public health initiative is urgently needed; the tragedy of a pregnancy in which the fetus has a neural tube defect is even greater when it can be so easily prevented.

Some people argue that preventive strategies should be selectively targeted at women planning a pregnancy—on the grounds that only pregnant women and their children stand to benefit and only a few of these are affected. From a public health perspective, however, most disorders affect only a minority of people at risk …

Folic acid and the prevention of neural tube defects

Background In the absence of clinical folate deficiency, periconceptional supplementation with folic acid reduces a woman's risk of having an infant with a neural-tube defect. Since antiserum to folate receptors induces embryo resorption and malformations in rats, we hypothesized that autoantibodies against folate receptors in women may be associated with pregnancy complicated by a neural-tube defect. Methods Serum from 12 women who were or had been pregnant with a fetus with a neural-tube defect and from 24 control women (20 with current or prior normal pregnancies and 4 who were nulligravid) was analyzed for autoantibodies by incubation with human placental folate receptors radiolabeled with [3H]folic acid. The properties of these autoantibodies were characterized by incubating serum and the autoantibodies isolated from serum with placental membranes, ED27 cells, and KB cells, which express the folate receptors. Results Serum from 9 of 12 women with a current or previous affected pregnancy (index subjec...

https://www.nejm.org/doi/pdf/10.1056/NEJMoa031145

Autoantibodies against Folate Receptors in Women with a Pregnancy Complicated by a Neural-Tube Defect

Even if in the absence of clinical folate deficiency, providing supplemental folic acid in the periconceptional period lowers the risk that the infant will have a neural tube defect (NTD). Findings that antifolate receptor antiserum leads to resorption of embryos as well as malformations in rats suggested that autoantibodies against these receptors could dispose to defects. The study group included 12 women who were, or had been, pregnant with an affected fetus and 24 control women (20 with a normal current or prior pregnancy and 4 nulligravidas). Serum specimens were analyzed for antifolate receptor autoantibodies by incubating samples with purified human placental folate receptors radiolabeled with 3 H-folic acid. Serum and autoantibodies isolated from serum were incubated with placental membranes, ED27 human placental cells, and KB cells, a human epidermoid carcinoma cell line, which express folate receptors. No significant demographic or clinical differences were found between the index subjects and control subjects. Serum antibodies against folate receptors were identified in 9 of the 12 index women (75%). Two of them were currently pregnant with a fetus exhibiting a NTD, whereas 7 had a history of such a pregnancy. Two of 20 control women (10%) had a current or previous infant with a NTD. The mean value for folate receptors bound by antiantibody was significantly greater in the index subjects. Only sera testing positive for autoantibody-blocked folic acid binding to placental membrane receptors, ED27 cells, and KB cells incubated at 4°C. Autoantibodies also blocked the uptake of 3 H-folic acid by KB cells incubated at 37°C. No anticardiolipin, antisingle-stranded DNA, or antithyroid autoantibodies were identified in sera from index subjects. Autoantibodies against folate receptors are present in sera from women whose pregnancies are complicated by a NTD. It remains to be determined whether these autoantibodies are pathogenic.

Jaclyn L. Roberts

Papers

Autoantibodies against Folate Receptors in Women with a Pregnancy Complicated by a Neural-Tube Defect

Autoantibodies Against Folate Receptors in Women With a Pregnancy Complicated by a Neural Tube Defect