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

Abstract

This review delves into the intricate relationship between excess folate (vitamin B9) intake, especially its synthetic form, namely, folic acid, and its implications on health and disease. While folate plays a pivotal role in the one-carbon cycle, which is essential for DNA synthesis, repair, and methylation, concerns arise about its excessive intake. The literature underscores potential deleterious effects, such as an increased risk of carcinogenesis; disruption in DNA methylation; and impacts on embryogenesis, pregnancy outcomes, neurodevelopment, and disease risk. Notably, these consequences stretch beyond the immediate effects, potentially influencing future generations through epigenetic reprogramming. The molecular mechanisms underlying these effects were examined, including altered one-carbon metabolism, the accumulation of unmetabolized folic acid, vitamin-B12-dependent mechanisms, altered methylation patterns, and interactions with critical receptors and signaling pathways. Furthermore, differences in the effects and mechanisms mediated by folic acid compared with natural folate are highlighted. Given the widespread folic acid supplementation, it is imperative to further research its optimal intake levels and the molecular pathways impacted by its excessive intake, ensuring the health and well-being of the global population.

Epigenetic regulation by TET1 in gene-environmental interactions influencing susceptibility to congenital malformations

“…The most recent recommendation by the US Preventive Services Task Force re-affirmed the substantial NTD-protective benefit of FA supplementation, when taken at 0.4 to 0.8 mg daily during the peri-conceptual period (72). However, whether excessive maternal FA intake, as high as 5 mg/day in certain medical conditions such as those linked to low folate levels, may introduce aberrant DNA methylation events or de novo point mutations that pre-dispose the offspring to chronic diseases in adulthood is not resolved (23,73,74) . The influence of excessive maternal dietary folate on DNA methylation has been reported to affect specific loci including imprinted genes (75)(76)(77)(78).…”

Dietary folate intake and serum klotho levels in adults aged 40–79 years: a cross-sectional study from the national health and nutrition examination survey 2007–2016

“…Furthermore, certain research suggests that a long-term, high-dose regimen of folic acid could correlate with an elevated risk of specific cancers ( 57 ). Consequently, it is imperative to regulate folic acid intake meticulously to prevent excessive ingestion ( 58 ).…”

The Significance of Genetically Determined Methylation and Folate Metabolism Disorders in the Pathogenesis of Coronary Artery Disease: A Target for New Therapies?

“…Methylation is crucial for maintaining the proper function of the vascular endothelium, the maturation and development of the central nervous system, and in the regulation of gametogenesis and embryo development [9]. Moreover, recently, the folate cycle and the one-carbon cycle have been identified as regulators of the aging process [10].…”