Is folic acid good for everyone?

Abstract

Fortification of food with folic acid to reduce the number of neural tube defects was introduced 10 y ago in North America. Many countries are considering whether to adopt this policy. When fortification is introduced, several hundred thousand people are exposed to an increased intake of folic acid for each neural tube defect pregnancy that is prevented. Are the benefits to the few outweighed by possible harm to some of the many exposed? In animals, a folic acid-rich diet can influence DNA and histone methylation, which leads to phenotypic changes in subsequent generations. In humans, increased folic acid intake leads to elevated blood concentrations of naturally occurring folates and of unmetabolized folic acid. High blood concentrations of folic acid may be related to decreased natural killer cell cytotoxicity, and high folate status may reduce the response to antifolate drugs used against malaria, rheumatoid arthritis, psoriasis, and cancer. In the elderly, a combination of high folate levels and low vitamin B-12 status may be associated with an increased risk of cognitive impairment and anemia and, in pregnant women, with an increased risk of insulin resistance and obesity in their children. Folate has a dual effect on cancer, protecting against cancer initiation but facilitating progression and growth of preneoplastic cells and subclinical cancers, which are common in the population. Thus, a high folic acid intake may be harmful for some people. Nations considering fortification should be cautious and stimulate further research to identify the effects, good and bad, caused by a high intake of folic acid from fortified food or dietary supplements. Only then can authorities develop the right strategies for the population as a whole.

Gestational intake of methyl donors and global LINE-1 DNA methylation in maternal and cord blood: Prospective results from a folate-replete population

“…This is reassuring considering the concern about potential adverse effects, possibly through epigenetic changes, of folic acid fortification of the food supply in the US and elsewhere. 27,28 were deficient in methyl donor nutrients, especially by the second trimester of pregnancy. For example, only 96 (9%) of women had second trimester folate intake <600 μg/d.…”

Erythrocyte folate concentrations, CpG methylation at genomically imprinted domains, and birth weight in a multiethnic newborn cohort

“…A commensurate increase in erythrocyte folate concentrations was reported in women of reproductive age within two years. 7 What is described as "supra-physiological" levels of circulating folate [8][9][10] has been reported in a quarter of the US population since FA fortification began. 7 Approximately 10% of pregnant women report taking supplements containing FA in doses exceeding 1000 µg per day, the maximum tolerable limit recommended by the Institute of Medicine.…”

Endogenous folates and single-carbon metabolism in the ovarian follicle, oocyte and pre-implantation embryo

“…Indeed, the nature and extent of single-carbon metabolism within these cells are not understood . Given the importance attached to folic acid in the diet of intending mothers aimed, primarily, at reducing the incidence of neural tube defects (Lucock 2000, Smith et al 2008, Osterhues et al 2009, it seems surprising that so little attention has been directed towards understanding its metabolism and that of related B-vitamins by the follicle-enclosed oocyte and pre-implantation embryo. We have previously shown that human embryonic stem cells express transcripts for most of the methyl cycle enzymes illustrated in Fig.…”