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Both high FA and low FA intake increases de novo mutation rate and disrupt genome DNA methylation in the offspring. a Violin Plot of DNSNV/DNM (de novo mutation) counts among the three different FA dietary groups (sample size for each group was as follows; combined panel: 0.3 ppm group n = 26; 3 ppm group n = 26; 30 ppm group n = 25. Male panel: 0.3 ppm group n = 17; 3 ppm group n = 26; 30 ppm group n = 17. Female panel: 0.3 ppm group n = 9; 3 ppm group n = 26; 30 ppm group n = 8). Mann-Whitney U test was performed to test the differences among different groups. b Nucleotide substitution, Ts/Tv transition versus transversion ratio and CpG island DNM enrichment. Asterisks indicate significant enrichments (P < 0.05, one-sided binomial test). c DNSNV counts and enrichment analysis of promoter, promoter flanking, CTCF, TF binding site, enhancer, and open chromatin DNA region. Plots showed log2 ratio of the number of observed and expected DNSNVs indicates the effect size of the enrichment or depletion in each region. Asterisks indicate significant enrichments or depletion (*P < 0.05, one-sided binomial test). d DNSNV counts and enrichment analysis in histone methylation genomic DNA recognition regions, including H3K4me1, H3K4me2, H3K4me3, H3K36me3, H3K27ac and H3K27me3. Asterisks indicate significant enrichments or depletion (P < 0.05, one-sided binomial test). e Metagene plot showing the methylation level (percent methylated) of 2 kb upstream, TSS (Transcription Start Site), gene body, TES (Transcription End Site) 2-kb downstream region of all RefSeq annotated genes. The red, green, and blue lines represent FA-deficient, FA-control and FA-high groups, respectively. The mean methylation level of the gene regions for FA-deficient, normal, and FA-high group are shown by boxplot. The horizontal line of the box refers to the 25th percentiles, median and 75th percentiles, respectively. f Number of hypermethylated and hypomethylated DMRs identified between two FA treatment groups. g Annotation of DMR genomic location in different FA treated groups. TTS Transcription Terminate Site. h Comparison of methylation levels of 2 kb regions centered on the identified mutations (left: from FA-deficient group; right: from FA-high group) in FA-deficient and FA-control group (left) or in FA-high and FA-control group (right). i Heatmaps showing the methylation level of 790 canyons (identified from FA-control group) in FA-deficient, FA-control and FA-high. j Track figure of hypermethylation DMRs in the promoters of five DNA repair genes: Lig4, Ubr5, and Atm. k Hypermethylated DMRs in FA-high group are enriched to DNA repair genes. Permutation test was performed with the P value: 2 × 10–5. l Hypermethylated DMRs in FA-high group are enriched to autism genes. Permutation (10-6) P value is less than 1 × 10–6. Autism gene list is downloaded from SAFRI database (Simons Foundation Autism Research Initiative, 11-13-2019-updated-version, total counts = 832). Fisher’s Exact test P-value = 6.9 × 10–8. *P-value is represented on each plot. *P < 0.05, ns not significant. Credit: Cell Discovery (2023). DOI: 10.1038/s41421-022-00512-0
It is well established that folic acid supplementation can significantly reduce the risk of birth defects, including neural tube defects like spina bifida, the most common birth defect of the central nervous system and the second most common of all structural birth defects. More than 80 nations, including the U.S. 25 years ago, have established mandated folic acid food fortification programs, which have been successful.
"However, there is a lack of research on whether excessive folic acid intake has the potential to harm human beings," said co-corresponding author, Dr. Richard H. Finnell, William T. Butler, M.D., Distinguished Chair Professor in the Center for Precision Environmental Health and the departments of molecular and cellular biology, molecular and human genetics and medicine at Baylor College of Medicine.
There are reports of adverse effects associated with high folate intake in humans. In this study published in the journal Cell Discovery, Finnell and his colleagues investigated in an animal model the potential effect of folic acid supplementation on DNA mutation rates and other genetic modifications such as whole genome methylation, which can change how much of any given gene product gets expressed in cells.
The animals received one of three folic-acid-supplemented diets: folic acid low, folic acid control and folic acid high. "Compared to the mutation frequency of the folic acid-control diet group, that of the folic acid-low diet group increased two-fold and the folic acid-high diet group increased 1.8 fold," Finnell said.
The researchers found that DNA repair genes were significantly hypermethylated in the folic acid-high diet, suggesting that excess folic acid supplementation may affect the mutation rate by reducing the expression of DNA repair genes and consequently impairing DNA repair activity. Understanding these mechanisms requires further investigation.
"The effects of high- or low-folic acid diets should be confirmed in human population in future studies," Finnell said. "Our data supports that folic acid supplementation should be restricted to an ideal benefit range. What we have here is a 'Goldilocks Effect': Too little or too much of a good thing (folic acid) may not be such a good thing."
More information:
Xuanye Cao et al, Excess folic acid intake increases DNA de novo point mutations, Cell Discovery (2023). DOI: 10.1038/s41421-022-00512-0
Citation:
Assessing the risk of excess folic acid intake (2023, March 6)
retrieved 20 June 2024
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