Countries worldwide recommend women planning pregnancy to use daily 400 µg of synthetic folic acid in the periconceptional period to prevent birth defects in children. The underlying mechanisms of this preventive effect are not clear, however, epigenetic modulation of growth processes by folic acid is hypothesized. Here, we investigated whether periconceptional maternal folic acid use and markers of global DNA methylation potential (S-adenosylmethionine and S-adenosylhomocysteine blood levels) in mothers and children affect methylation of the insulin-like growth factor 2 gene differentially methylation region (IGF2 DMR) in the child. Moreover, we tested whether the methylation of the IGF2 DMR was independently associated with birth weight. IGF2 DMR methylation in 120 children aged 17 months (SD 0.3) of whom 86 mothers had used and 34 had not used folic acid periconceptionally were studied. Methylation was measured of 5 CpG dinucleotides covering the DMR using a mass spectrometry-based method. Children of mother who used folic acid had a 4.5% higher methylation of the IGF2 DMR than children who were not exposed to folic acid (49.5% vs. 47.4%; p = 0.014). IGF2 DMR methylation of the children also was associated with the S-adenosylmethionine blood level of the mother but not of the child (+1.7% methylation per SD S-adenosylmethionine; p = 0.037). Finally, we observed an inverse independent association between IGF2 DMR methylation and birth weight (−1.7% methylation per SD birthweight; p = 0.034). Periconceptional folic acid use is associated with epigenetic changes in IGF2 in the child that may affect intrauterine programming of growth and development with consequences for health and disease throughout life. These results indicate plasticity of IGF2 methylation by periconceptional folic acid use.

Current treatments of subfertile couples are usually empiric, as the true cause of subfertility often remains unknown. Therefore, we outline the role of nutritional and biochemical factors in reproduction and subfertility. A literature search was performed using MEDLINE, Science Direct and bibliographies of published work with both positive and negative results. The studies showed that folate has a role in spermatogenesis. In female reproduction, folate is also important for oocyte quality and maturation, implantation, placentation, fetal growth and organ development. Zinc has also been implicated in testicular development, sperm maturation and testosterone synthesis. In females, zinc plays a role in sexual development, ovulation and the menstrual cycle. Both folate and zinc have antioxidant properties that counteract reactive oxygen species (ROS). Thiols, such as glutathione, balance the levels of ROS produced by spermatozoa and influence DNA compaction and the stability and motility of spermatozoa. Oocyte maturation, ovulation, luteolysis and follicle atresia are also affected by ROS. After fertilization, glutathione is important for sperm nucleus decondensation and pronucleus formation. Folate, zinc, ROS and thiols affect apoptosis, which is important for sperm release, regulation of follicle atresia, degeneration of the corpus luteum and endometrial shedding. Therefore, the concentrations of these nutrients may have substantial effects on reproduction. In conclusion, nutritional and biochemical factors affect biological processes in male and female reproduction. Further research should identify pathways that may lead to improvements in care and treatment of subfertility.

Most reproductive failures originate during the periconceptional period and are influenced by the age and the lifestyle of parents-to-be. We advance the hypothesis that these failures can arise as a partial consequence of derangements to one-carbon (1-C) metabolism (i.e. metabolic pathways that utilize substrates/cofactors such as methionine, vitamin B₁₂, folate). 1-C metabolic pathways drive the synthesis of proteins, biogenic amines and lipids required for early growth, together with the synthesis and methylation of DNA and histones essential for the regulation of gene expression. We review how deficiencies in periconceptional 1-C metabolism affect fertility and development together with underlying mechanisms derived from animal studies. A literature search was performed using PubMed and bibliographies of all relevant original research articles and reviews. We define ‘periconception’ as a 5–6-month period in women embracing oocyte growth, fertilization, conceptus formation and development to Week 10 of gestation (coinciding with the closure of the secondary palate in the embryo). During this period significant epigenetic modifications to chromatin occur that correspond with normal development. Subtle variations in 1-C metabolism genes and deficiencies in 1-C substrates/cofactors together with poor lifestyle, such as smoking and alcohol consumption, disturb 1-C metabolism and contribute to subfertility and early miscarriage and compromise offspring health. Procedures used in assisted reproduction can also disturb these metabolic pathways and contribute to poor pregnancy outcomes. Evidence presented indicates that parental nutrition and other lifestyle factors during the periconceptional period can affect reproductive performance via 1-C metabolic pathways. This knowledge provides opportunities for treatment and prevention of reproductive failures and future non-communicable diseases.

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BACKGROUND: Thiols are scavengers of reactive oxygen species (ROS). We aim to investigate associations between thiols in various fluids in (sub)fertile couples and fertility outcome parameters. METHODS: In 156 couples undergoing assisted reproduction techniques (ART), we measured the concentrations of glutathione (GSH), cysteine (Cys), homocysteine (Hcy) and cysteinylglycine (CGS) and fertility outcome parameters in the ejaculate, purified spermatozoa and follicular fluid. RESULTS: All thiols were detectable in most ejaculates, spermatozoa and follicular fluids, of which Cys concentrations were highest. Thiol concentrations in the ejaculate were similar in fertile and subfertile men. However, Hcy in follicular fluid was higher in women with endometriosis compared with women in the idiopathic subfertile group (P = 0.04). The GSH, Cys, Hcy and CGS concentrations in spermatozoa of subfertile men were significantly higher compared with men in the idiopathic subfertile group and fertile men (P < 0.001). Most notably, Hcy concentrations in both the ejaculate and follicular fluid were negatively associated with embryo quality on culture day 3 in the IVF/ICSI procedure. CONCLUSIONS: Spermatozoa of subfertile men contain significantly higher thiol concentrations as compared with those of fertile men. The detrimental effect on embryo quality of a high Hcy concentration in the ejaculate and in follicular fluid is intriguing and may suggest that Hcy is inversely associated with fertility outcome.