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

Abstract

Mandatory fortification of food with synthetic folic acid (FA) was instituted in 1998 to reduce the incidence of neural tube defects. Adequate folate status is correlated with numerous health benefits. However, elevated consumption of FA is controversially associated with deleterious effects on health. We previously reported that excess FA mimicked folate depletion in a lymphoblastoid cell line. To explore the impact of FA intake from fortified food, we conducted an observational human study on 33 healthy participants aged 18–40 not taking any supplements. Food intake, anthropomorphic measurements, and blood samples were collected and analyzed. Our results show that individuals belonging to the highest tertile of folic acid intake, as well as ones with the highest folic acid to total folate intake ratio (FAR), display a significantly greater incidence of lymphocyte genomic damage. A decrease in global DNA methylation is observed in the highest tertile of FAR compared to the lowest (p = 0.055). A downward trend in the overall gene expression of select DNA repair and one carbon cycle genes (MGMT, MLH1, UNG, MTHFR, MTR) is noted with increased folate status and FA intake. These results provide supporting evidence that high consumption of FA from fortified foods can precipitate genomic instability in peripheral lymphocyte in vivo.

Uncovering the Hidden Dangers and Molecular Mechanisms of Excess Folate: A Narrative Review

“…In rodent studies, excess folate can be defined as exceeding the accepted standard baseline supplementation of 2 mg/kg diet. However, the optimal folate requirements for animals may be lower, and the activity of rate-limiting one-carbon metabolism enzymes is typically much higher in rodents compared with humans [20][21][22][23]. Chow diets fed to laboratory rodents can contain a variable amount of FA ranging from 2 to 15 mg/kg diet and averaging about 8 mg/kg diet [22].…”

“…Similarly, excess FA supplementation in rat dams (20 mg/kg diet) exacerbated weight gain and inflammation [123]. High folic acid exposure negatively impacted human lymphocyte stress response, genomic stability, and DNA methylation in both in vitro and in vivo conditions [21,124]. Others found that folic acid supplementation could promote a proinflammatory transcriptomic milieu in the colon [125,126] and that excess FA increased inflammation in response to a high-fat diet in rats [127].…”

“…Work with multiple models suggests that both folate deficiency and excess FA can disrupt the folate cycle and the connected methionine cycle, leading to dysregulated methylation [93,218,225,226]. In human lymphocytes, high folic acid intake relative to natural folate can influence DNA methylation, disrupt genomic stability, and diminish the capacity to withstand oxidative stress [21,124]. Excess folic acid supplemented to cancer cell organoids can counteract methionine dependency, thus promoting cancer stem cell formation [227].…”

Advances in Folic Acid Biosensors and Their Significance in Maternal, Perinatal, and Paediatric Preventive Medicine

“…As summarised above, low FA intake results in adverse pregnancy outcomes. On the other hand, excess FA supplement consumption could induce genomic and epigenomic instability [63,64]. Although further studies on the human population is essential to estimate the true impact of high and low FA intake, it is highly likely that excess FA intake could also result in unfavourable outcomes.…”