Excessive Folic Acid Mimics Folate Deficiency in Human Lymphocytes

Abstract

Food fortification with synthetic folic acid (FA), along with supplementation, results in a marked increase in the population total of serum folates and unmetabolized folic acid (UMFA). Despite the success in reducing neural tube defects at birth in the intended target population (women of childbearing age), the potential deleterious effects of chronically high levels of UMFA in susceptible segments of the population require further investigation. In this study, we examine the effects of FA concentrations, ranging from depletion to supraphysiological levels, on markers of proliferation, DNA methylation, and DNA damage and repair in a human lymphoblastoid cell line (LCL). We note that both low and high levels of FA similarly impact global DNA methylation, cytome biomarkers measured through the CBMN assay, DNA damage induced by oxidative stress, and DNA base excision repair gene expression.

High Dietary Folic Acid Intake Is Associated with Genomic Instability in Peripheral Lymphocytes of Healthy Adults

“…Folate’s role in nucleotide synthesis, DNA repair, and genomic stability is well established. Several studies evaluated the impact of folate deficiency and adequacy on MNi, NPB and NBUD formation in human lymphocytes in vitro [ 41 , 56 , 57 , 58 , 59 ]. Based on the current body of evidence, the prevailing paradigm suggests that folate deficiency is deleterious, while a high folate intake is beneficial.…”

“…In fact, many in the field inadvertently use the term folate to describe both natural and synthetic forms, potentially leading to misinterpretation of results. We previously demonstrated that excess folic acid could mimic folate deficiency in a human lymphoblastoid cell line (LCL) [ 41 ]. To date, the effects of excessive folic acid intake on cytome biomarkers in human lymphocytes in vivo has not been investigated.…”

“…Slides were cover-slipped using DPX mountant (Sigma Aldrich, St. Louis, MO, USA). The frequency of MNi, NPB and NBUD was determined in 2000 binucleated (BN) cells following the scoring criteria of the HUMN project guidelines [ 55 ] by two trained scorers in a blinded manner as previously described [ 41 ].…”

“…We recently reported that excess folic acid can mimic folate deficiency in a human lymphoblastoid cell line (LCL) by similarly impacting genomic damage, global methylation, and expression of DNA repair genes [ 41 ]. Others reported complementary findings in C. elegans and mouse models where both FA deficiency and excess supplementation led to deleterious effects [ 42 , 43 , 44 ].…”

High Dietary Folic Acid Intake is Associated with Genomic instability in Peripheral Lymphocytes of Healthy Adults

“…We recently reported that excess folic acid can mimic folate deficiency in a human lymphoblastoid cell line by similarly impacting genomic damage, global methylation, and expression of DNA repair genes [41]. Others reported complementary findings in C. elegans and mouse models where both FA deficiency and excess supplementation led to deleterious effects [42][43][44].…”