Epigenetic analysis of sperm DNA methylation from a randomized placebo controled study of zinc and folic acid suplementation
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PROVIDER: PRJNA771400 | ENA |
REPOSITORIES: ENA
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Project description:Sperm DNA methylation was assessed in pateints who were randomly assigned to a folic acid suplementation group or a palcebo group. Basic differential methylation analysis was performed to identify sites of differential methylation.
2021-11-01 | GSE185920 | GEO
Project description:Study question: Do short-term and long-term exposures to low dose folic acid supplementation alter DNA methylation in sperm? Summary answer: No alterations in sperm DNA methylation patterns were found following the administration of low dose folic acid supplements of 400 μg/day for 90 days (short-term exposure) or when pre-fortification of food with folic acid and post-fortification sperm samples (long-term exposure) were compared. What is known already: Excess dietary folate may be detrimental to health and DNA methylation profiles due to folate’s role in one carbon metabolism and the formation of S-adenosyl methionine, the universal methyl donor. DNA methylation patterns are established in developing male germ cells and have been suggested to be affected by high dose (5 mg/day) folic acid supplementation. Participants/materials, setting, methods: Blood and seminal plasma folate levels were measured in participants before and following the 90-day treatment with placebo or supplement. Sperm DNA methylation was assessed using the whole genome and genome-wide techniques, MassArray epityper, restriction landmark genomic scanning, methyl-CpG immunoprecipitation and Illumina HumanMethylation450 Bead Array. Main results and the role of chance: Following treatment, supplemented individuals had significantly higher levels of blood and seminal plasma folates compared to placebo. Initial first generation genome-wide analyses of sperm DNA methylation showed little evidence of changes when comparing pre- and post-treatment samples. With Illumina HumanMethylation450 BeadChip arrays, no significant changes were observed in individual probes following low-level supplementation; when compared with those of the post-fortification cohort, there were also few differences in methylation despite exposure to years of fortified foods. Limitations, reasons for caution: This study was limited to the number of participants available in each cohort, in particular those who were not exposed to early (pre-1998) fortification of food with folic acid. While genome-wide DNA methylation was assessed with several techniques that targeted genic and CpG rich regions, intergenic regions were less well interrogated. Wider implications of the findings: Overall, our findings provide evidence that short term exposure to low dose folic acid supplements of 400 μg/day, over a period of 3 months, a duration of time that might occur during infertility treatments, has no major impact on the sperm DNA methylome.
2016-11-12 | GSE89781 | GEO
Project description:Supplementation with high doses of folic acid, an important mediator of one-carbon transfers for DNA methylation, is used clinically to improve sperm parameters in infertile men. We recently detected an unexpected loss of DNA methylation in the sperm of idiopathic infertile men after 6 months of daily supplementation with 5mg folic acid (>10× the daily recommended intake-DRI), exacerbated in men homozygous for a common variant in the gene encoding an important enzyme in folate metabolism, methylenetetrahydrofolate reductase (MTHFR 677C>T). To investigate the epigenomic impact and mechanism underlying effects of folic acid on male germ cells, wildtype and heterozygote mice for a targeted inactivation of the Mthfr gene were fed high-dose folic acid (10× the DRI) or control diets for six months. No changes were detected in general health, sperm counts or methylation of imprinted genes. Reduced representation bisulfite sequencing revealed sperm DNA hypomethylation in Mthfr+/- mice on the 10× diets. Wildtype mice demonstrated sperm hypomethylation only with a very high dose (20×) of folic acid for 12 months. Testicular MTHFR protein levels decreased significantly in wildtype mice on the 20× diet but not in those on the 10× diet, suggesting a possible role for MTHFR deficiency in sperm DNA hypomethylation. In-depth analysis of the folic acid-exposed sperm DNA methylome suggested mouse/human susceptibility of sequences with potential importance to germ cell and embryo development. Our data provide evidence for a similar cross-species response to high dose folic acid supplementation, of sperm DNA hypomethylation, and implicate MTHFR downregulation as a possible mechanism.
2018-01-23 | GSE100849 | GEO
Project description:Flavonoids and fish oils have anti-inflammatory and immune-modulating influences. The purpose of the study was to determine if a mixed flavonoid-fish oil supplement (Q-Mix; 1000 mg quercetin, 400 mg isoquercetin, 120 mg EGCG from green tea extract, 220 mg EPA and 180 mg DHA from fish oil, 1000 mg vitamin C, 40 mg niacinamide, and 800 ug folic acid) would reduce inflammatory and oxidative stress markers and alter genomic profiles in overweight women. Women were assigned using a randomized double-blinded placebo-controlled trial to Q-Mix or placebo groups. Overnight fasted blood samples were collected and subjected to RNA expression analysis on Affymetrix Hugene ST1_1 arrays. Randomized, double-blinded, placebo controlled study.Subjects were randomized to either mixed flavonoid-fish oil supplement group (Q-Mix; 1000 mg quercetin, 400 mg isoquercetin, 120 mg EGCG from green tea extract, 400 mg n3-PUFAs (220 mg EPA and 180 mg DHA) from fish oil, 1000 mg vitamin C, 40 mg niacinamide, and 800 µg folic acid) or placebo (n=29 samples, including pre- and post-treatment samples in the Q-Mix and placebo arms).The placebo did not contain quercetin, vitamin C, and niacin. Subjects were instructed to ingest two soft chew supplements twice daily (upon awakening, and between 6:00-7:00 pm) for 70 days. A three-day food record was used to assess typical energy and nutrient intake. No restrictions were placed on diet, supplement usage or medications with the exception that subjects agreed to avoid any non-steroidal anti-inflammatory drugs and dietary supplements that influence inflammation or oxidative stress.
2015-11-02 | E-GEOD-74560 | biostudies-arrayexpress
Project description:Dietary folate is a major source of methyl groups required for DNA methylation, an epigenetic modification that is actively maintained and remodelled during spermatogenesis. While high dose folic acid supplementation (up to ten times the daily recommended dose) has been shown to improve sperm parameters in infertile men, the effects of supplementation on the sperm epigenome are unknown. To assess the impact of six months of high dose folic acid supplementation on the sperm epigenome, we studied 30 men with idiopathic infertility. Blood folate concentrations increased significantly after supplementation with no significant improvements in sperm parameters. Methylation levels of the differentially methylated regions of several imprinted loci (H19, DLK1/GTL2, MEST, SNRPN, PLAGL1, KCNQ1OT1) were normal both before and after supplementation. Reduced representation bisulfite sequencing (RRBS) revealed a significant global loss of methylation across different regions of the sperm genome. The most marked loss of DNA methylation was found in sperm from patients homozygous for the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism, a common polymorphism in a key enzyme required for folate metabolism. RRBS analysis also showed that most of the differentially methylated tiles were located in DNA repeats, low CpG density and intergenic regions. Ingenuity Pathway Analysis revealed that methylation of promoter regions was altered in several genes involved in cancer and neurobehavioral disorders including CBFA2T3, PTPN6, COL18A1, ALDH2, UBE4B, ERBB2, GABRB3, CNTNAP4 and NIPA1. Our data reveal alterations of the human sperm epigenome associated with high dose folic acid supplementation, effects that were exacerbated by a common polymorphism in MTHFR. Reduced representation bisulfite sequencing of 28 human sperm samples before and after 6 month of high dose folic acid supplementation.
2015-09-10 | E-GEOD-72606 | biostudies-arrayexpress
Project description:Flavonoids and fish oils have anti-inflammatory and immune-modulating influences. The purpose of the study was to determine if a mixed flavonoid-fish oil supplement (Q-Mix; 1000 mg quercetin, 400 mg isoquercetin, 120 mg EGCG from green tea extract, 220 mg EPA and 180 mg DHA from fish oil, 1000 mg vitamin C, 40 mg niacinamide, and 800 ug folic acid) would reduce inflammatory and oxidative stress markers and alter genomic profiles in overweight women. Women were assigned using a randomized double-blinded placebo-controlled trial to Q-Mix or placebo groups. Overnight fasted blood samples were collected and subjected to RNA expression analysis on Affymetrix Hugene ST1_1 arrays.
2015-11-02 | GSE74560 | GEO
Project description:Folate, and its synthetic form folic acid, function as donor of one-carbon units and have been, together with other B-vitamins, implicated in programming of epigenetic processes such as DNA methylation during early development. To what extent regulation of DNA methylation can be altered via B-vitamins later in life, and how this relates to health and disease, is not exactly known. The aim of this study was to identify effects of long-term supplementation with folic acid and vitamin B12 on genome-wide DNA methylation in elderly subjects. This project was part of a randomized, placebo-controlled trial on effects of supplemental intake of folic acid and vitamin B12 on bone fracture incidence (B-PROOF study). Participants with mildly elevated homocysteine levels, aged 65-75 years, were randomly assigned to take 400 µg folic acid and 500 µg vitamin B12 per day or a placebo during an intervention period of two years. DNA was isolated from buffy coats, collected before and after intervention, and genome-wide DNA methylation was determined in 87 participants (n=44 folic acid/vitamin B12, n=43 placebo) using the Infinium HumanMethylation450 BeadChip. After intervention with folic acid and vitamin B12, 162 (versus 14 in the placebo group) of the 431,312 positions were differentially methylated as compared to baseline. Comparisons of the DNA methylation changes in the participants receiving folic acid and vitamin B12 versus placebo, revealed one single differentially methylated position (cg19380919) with a borderline statistical significance. However, based on the analyses of differentially methylated regions (DMRs) consisting of multiple positions, we identified 6 regions that differed statistically significantly between the intervention and placebo group. Pronounced changes were found for regions in the DIRAS3, ARMC8 and NODAL genes, implicated in carcinogenesis and early embryonic development. Furthermore, serum levels of folate and vitamin B12 or plasma homocysteine were related to DNA methylation of 173, 425 and 11 regions, respectively. Interestingly, for several members of the developmental HOX genes, DNA methylation was related to serum levels of folate. Long-term supplementation with folic acid and vitamin B12 in elderly subjects resulted in effects on DNA methylation of several genes, among which genes implicated in developmental processes.
2015-11-16 | GSE74548 | GEO
Project description:Dietary folate is a major source of methyl groups required for DNA methylation, an epigenetic modification that is actively maintained and remodelled during spermatogenesis. While high dose folic acid supplementation (up to ten times the daily recommended dose) has been shown to improve sperm parameters in infertile men, the effects of supplementation on the sperm epigenome are unknown. To assess the impact of six months of high dose folic acid supplementation on the sperm epigenome, we studied 30 men with idiopathic infertility. Blood folate concentrations increased significantly after supplementation with no significant improvements in sperm parameters. Methylation levels of the differentially methylated regions of several imprinted loci (H19, DLK1/GTL2, MEST, SNRPN, PLAGL1, KCNQ1OT1) were normal both before and after supplementation. Reduced representation bisulfite sequencing (RRBS) revealed a significant global loss of methylation across different regions of the sperm genome. The most marked loss of DNA methylation was found in sperm from patients homozygous for the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism, a common polymorphism in a key enzyme required for folate metabolism. RRBS analysis also showed that most of the differentially methylated tiles were located in DNA repeats, low CpG density and intergenic regions. Ingenuity Pathway Analysis revealed that methylation of promoter regions was altered in several genes involved in cancer and neurobehavioral disorders including CBFA2T3, PTPN6, COL18A1, ALDH2, UBE4B, ERBB2, GABRB3, CNTNAP4 and NIPA1. Our data reveal alterations of the human sperm epigenome associated with high dose folic acid supplementation, effects that were exacerbated by a common polymorphism in MTHFR.
2015-09-10 | GSE72606 | GEO
Project description:In this proof-of-concept study, we tested whether placebo effects can be monitored and predicted by plasma proteins. In a randomized controlled design, 90 participants were exposed to a nauseating stimulus on two separate days and were randomly allocated to placebo treatment or no treatment on the second day. Significant placebo effects on nausea, motion sickness, and gastric activity could be verified. Using state-of-the-art proteomics, 74 differentially regulated proteins were identified as correlates of the placebo effect. Gene ontology (GO) enrichment analyses identified acute-phase proteins and microinflammatory proteins to be involved, and the identified GO signatures predicted day-adjusted scores of nausea indices in the placebo group. We also performed GO enrichment analyses of specific plasma proteins predictable by the experimental factors or their interactions and identified ‘grooming behavior’ as a prominent hit. Finally, Receiver Operator Characteristics allowed to identify plasma proteins differentiating placebo responders from non-responders, comprising immunoglobulins and proteins involved in oxidation reduction processes and complement activation. Plasma proteomics are a promising tool to identify molecular correlates and predictors of the placebo effect in humans.
2020-11-13 | PXD020563 | Pride
Project description:5,10-Methylenetetrahydrofolate reductase (MTHFR) is an enzyme that plays a key role in providing methyl groups for DNA methylation, including during spermatogenesis. A common genetic variant in humans (MTHFR 677C>T), results in reduced enzyme activity and has been linked to various disorders, including male infertility. A new animal model has been created by reproducing the human equivalent of the polymorphism in mice using CRISPR/Cas9. Biochemical parameters in the Mthfr 677TT mice recapitulate alterations found in MTHFR 677TT men. Our aims were to: 1) characterize the sperm DNA methylome of the Mthfr 677CC and TT mice on a control diet (2mg folic acid/kg diet) and 2) assess the effects of folic acid deficiency (0.3mg/kg diet) and supplementation (10 mg/kg diet) on the sperm DNA methylome. Body and reproductive organ weights, testicular sperm counts, and histology were examined. DNA methylation in sperm was assessed using bisulfite pyrosequencing, Illumina Mouse Methylation Array and whole genome bisulfite sequencing. Reproductive parameters and imprinted gene methylation were unaffected by genotype or diets. The largest effect was due to genotype, with sperm from 677TT mice showing more hypo- than hypermethylation. Folate-deficient diets resulted in sperm hyper- and hypomethylation in CC and TT mice. Folic acid supplementation caused mostly hypermethylation in sperm of males of both genotypes and was found to partially correct the DNA methylation alterations in sperm associated with the TT genotype. The new mouse model will be useful in understanding the role of MTHFR deficiency in male fertility and in designing folate supplementation regimens for the clinic.
2024-04-17 | GSE240712 | GEO