Folate, a water-soluble B vitamin, and its synthetic form folic acid (FA) used in fortification and supplements, are critical to human health due to their role in one-carbon transfer reactions required for biological methylation and nucleotide biosynthesis. As such, folate deficiency has been linked to a variety of adverse health outcomes such as megaloblastic anaemia, neural tube defects, coronary heart disease and cancer among others. Corollary to this, FA supplementation has garnered a considerable amount of interest as an ideal functional food component for disease prevention. Although the benefits of FA supplementation in treatment of megaloblastic anaemia and in prevention of neural tube defects are well established, the effects of FA supplementation on other disease outcomes remain largely equivocal. In addition, an emerging body of evidence has raised concern regarding potentially serious adverse health effects of excessive FA intake, which warrant further studies. Key Concepts: Folate, a water-soluble B vitamin, and its synthetic form folic acid used in fortification and supplements, are critical to one-carbon transfer reactions required for DNA synthesis and biological methylation reactions. Dietary folate intake is the main source of folate for humans; inadequate dietary intake, impaired absorption or metabolism of folate, and increased folate demand and utilisation may result in deficiency. Folate deficiency has been associated with various adverse health effects including megaloblastic anaemia, neural tube defects and other congenital disorders, adverse pregnancy outcomes, neuropsychiatric disorders and cognitive decline, coronary heart disease, stroke and development of some cancers. Folic acid supplementation is effective in treatment of folate-deficiency associated megaloblastic anaemia and in prevention of neural tube defects. The primary objective of periconceptional folic acid supplementation and mandatory folic acid fortification of the food supply, typically wheat, implemented in North American in 1998, is to prevent neural tube defects. It appears that folic acid fortification has led to up to 50% reduction in the rates of neural tube defects in North America. Folate requirements are increased throughout pregnancy due to rapid growth of the uterus, placenta and foetus, and during lactation as to maintain an adequate folate supply in breast milk for infants. Folate appears to play a dual modulatory role in colorectal carcinogenesis depending on the dose and the stage of cell transformation at the time of folate exposure. Animal studies conducted in colorectal cancer models have shown that folic acid supplementation prevents the development of cancer in normal tissues but promotes the progression of established (pre)neoplastic lesions. Animal studies have also suggested that supraphysiological supplemental doses of folic acid supplementation may promote, rather than prevent cancer development. However, folic acid intervention trials in humans have produced inconsistent results. Although folate deficiency and raised plasma homocysteine levels have been associated with increased risk of coronary heart disease in observational studies; clinical trials have reported largely null effects of folic acid supplementation on the secondary prevention of coronary heart disease. Folate status may play an important role in regulation of epigenetic determinants of gene expression such as DNA methylation relating to its critical role in the provision of S-adenosylmethionine, the primary methyl donor in most biological methylation reactions. Excessive folic acid intake from fortified foods and supplements has been linked to certain adverse health effects including masking of vitamin B12 deficiency and tumour-progression. Keywords: folate; folic acid; homocysteine; unmetabolised folic acid; folic acid supplementation; megaloblastic anaemia; neural tube defects; pregnancy; carcinogenesis; epigenetics

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