Periconceptional folic acid supplementation and DNA methylation patterns in adolescents
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PROVIDER: PRJNA891273 | ENA |
REPOSITORIES: ENA
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Project description:DNA methylation profiles from saliva collected from 89 mothers and 179 adolescent children who received or did not receive perinatal folic acid supplementation Periconceptional folic acid supplementation and DNA methylation patterns in adolescents
2023-01-18 | GSE212564 | GEO
Project description:STUDY QUESTION: Could clinically-relevant moderate and/or high dose maternal folic acid supplementation prevent aberrant developmental and epigenetic outcomes associated with assisted reproductive technologies (ART)? SUMMARY ANSWER: Our results demonstrate dose-dependent and sex-specific effects of folic acid supplementation in ART and provide evidence that moderate dose supplements may be optimal for both sexes. WHAT IS KNOWN ALREADY: Children conceived using ART are at an increased risk for growth and genomic imprinting disorders, often associated with DNA methylation defects. Folic acid supplementation is recommended during pregnancy to prevent adverse offspring outcomes; however, the effects of folic acid supplementation in ART remain unclear. STUDY DESIGN, SIZE, DURATION: Outbred female mice were fed 3 folic-acid supplemented diets, control (rodent daily recommended intake or DRI; CD), moderate (4-fold DRI; 4FASD) or high (10-fold DRI; 10FASD) dose, for six weeks prior to ART and throughout gestation. Mouse ART involved a combination of superovulation, in vitro fertilization, embryo culture and embryo transfer. PARTICIPANTS/MATERIALS, SETTING, METHODS: Upon collection of midgestation embryos and placentas (n=74-99 embryos/group), all embryos were assessed for developmental delay and gross morphological abnormalities. Embryos and placentas were also examined at the epigenetic level. We assessed methylation at four imprinted genes (Snrpn, Kcnq1ot1, Peg1, and H19) in matched midgestation embryos and placentas (n=31-32/group) using bisulfite pyrosequencing. In addition, we examined genome-wide DNA methylation patterns in midgestation placentas (n=6 normal placentas per sex/group) and embryos (n=6 normal female embryos/group; n=3 delayed female embryos/group) using reduced representation bisulfite sequencing. MAIN RESULTS AND THE ROLE OF CHANCE: Moderate, but not high dose supplementation, was associated with a decrease in the proportion of developmentally delayed embryos. Although moderate dose folic acid supplementation reduced DNA methylation variance at certain imprinted genes in embryonic and placental tissues, high dose supplementation exacerbated the negative effects of ART at imprinted loci. Furthermore, folic acid supplements resolved female-biased aberrant imprinted gene methylation. Supplementation was more effective at correcting ART-induced genome-wide methylation defects in male versus female placentas; however, folic acid supplementation also led to additional methylation perturbations which were far more pronounced in males. LIMITATIONS, REASONS FOR CAUTION: Although the combination of mouse ARTs utilized in this study consisted of techniques commonly used in human fertility clinics, there may be species differences. Therefore, human studies, designed to determine the optimal levels of folic acid supplementation for ART pregnancies, and taking into account fetal sex, are warranted. WIDER IMPLICATIONS OF THE FINDINGS: Taken together, our findings support moderation in the dose of folic acid supplements taken during ART.
2019-05-15 | GSE123143 | GEO
Project description:Folic acid supplements prior to and during gestation are recommended and necessary to prevent neural tube defects in developing embryos. But there are also studies suggesting possible adverse effects of high-dose folic acid supplementation. Here, we address whether maternal dietary folic acid supplementation at 40 mg/kg chow (FD), restricted to a period prior to conception, affects gene expression in the offspring generation.
2017-06-08 | GSE80587 | GEO
Project description:UGA Folic acid supplementation in pregnant women
| PRJNA473156 | ENA
Project description:To prove our hypothesis that excess folic acid supplementation is responsible for widespread gene expression changes during gestational development that may be responsible for abnormal behaviors later on in the life, we have used whole genome microarray expression profiling in lymphoblstoid cells as a proof of concept. Human lymphoblastoid cells in culture were supplemented with folic acid, and four days later gene expression changes were measured. Expression of three genes (FMR1, GPR37L1 and TSSK3) from this data was confirmed by Western blot analyses. Dysregulation of other genes (ARHGAP6, EF1A1, MEST, SMAD3) was confirmed by qRT-PCR. Lymphoid cells at confluence were grown with or without folic acid for four days. Total mRNA was prepared and labeled with cyanine-3 (Cy3), followed by hybridization. RNA samples from three independent experiments were pooled.
2011-08-23 | E-GEOD-29141 | biostudies-arrayexpress
Project description:To prove our hypothesis that excess folic acid supplementation is responsible for widespread gene expression changes during gestational development that may be responsible for abnormal behaviors later on in the life, we have used whole genome microarray expression profiling in lymphoblstoid cells as a proof of concept. Human lymphoblastoid cells in culture were supplemented with folic acid, and four days later gene expression changes were measured. Expression of three genes (FMR1, GPR37L1 and TSSK3) from this data was confirmed by Western blot analyses. Dysregulation of other genes (ARHGAP6, EF1A1, MEST, SMAD3) was confirmed by qRT-PCR.
2011-08-24 | GSE29141 | 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:Adverse effect of folic acid supplementation on cilia
| PRJNA564746 | ENA
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:We determined the effects of excess folic acid supplementation (5x recommendation) on maternal and fetal offspring metabolic health. Using a mouse (female C57BL/6J) model of gestational dibetes (GDM; 45% kcal fat diet) and control mice (10% kcal diet) we show that folic acid supplementation increased weight gain and fat mass in both GDM and control mice but improved insulin sensitivity in GDM mice and worsened insulin sensitivity in control mice. We found no unmetabolized folic acid in liver from supplemented mice suggesting the metabolic effects of folic acid supplementation may not be due to unmetabolized folic acid. Male fetal (gestational day 18.5) offspring from folic acid supplemented dams (GDM and control) had greater beta cell mass and density than those from unsupplemented dams; this was not observed in female offspring. Differential sex-specific hepatic gene expression profiles were observed in the offspring from supplemented dams but this differed between GDM and controls. Our findings suggest that folic acid supplementation affects insulin sensitivity in female mice, but is dependent on their metabolic phenotype, and has sex-specific effects on offspring pancreas and liver.
2023-09-29 | GSE237149 | GEO