The periconceptional period, reproduction and long-term health of offspring: the importance of one-carbon metabolism
TL;DR: Evidence presented indicates that parental nutrition and other lifestyle factors during the periconceptional period can affect reproductive performance via 1-C metabolic pathways and provides opportunities for treatment and prevention of reproductive failures and future non-communicable diseases.
Abstract: BACKGROUND 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. METHODS A literature search was performed using PubMed and bibliographies of all relevant original research articles and reviews. RESULTS 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. CONCLUSIONS 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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University of Southampton1, University of Nottingham2, Newcastle University3, University of London4, University College London5, University Hospital Southampton NHS Foundation Trust6, University of Melbourne7, University of the West Indies8, University of Auckland9, Agency for Science, Technology and Research10
TL;DR: It is proposed that the evidence for periconceptional effects on lifetime health is now so compelling that it calls for new guidance on parental preparation for pregnancy, beginning before conception, to protect the health of offspring.
651 citations
TL;DR: It is proposed that an 'undernourished' microbiome is intergenerational, thereby perpetuating growth impairments into successive generations and identifying and discussing the intertwining host-microbe-environment interactions occurring prenatally and during early infancy.
409 citations
TL;DR: A role for population context is suggested in determining health responses and filling extensive gaps in knowledge on micronutrient intake recommendations, risks and consequences of deficiencies, and the effects of interventions with a particular emphasis on offspring.
Abstract: Micronutrients, vitamins and minerals accessible from the diet, are essential for biologic activity. Micronutrient status varies widely throughout pregnancy and across populations. Women in low-income countries often enter pregnancy malnourished, and the demands of gestation can exacerbate micronutrient deficiencies with health consequences for the fetus. Examples of efficacious single micronutrient interventions include folic acid to prevent neural tube defects, iodine to prevent cretinism, zinc to reduce risk of preterm birth, and iron to reduce the risk of low birth weight. Folic acid and vitamin D might also increase birth weight. While extensive mechanistic and association research links multiple antenatal micronutrients with plausible materno-fetal health advantages, hypothesized benefits have often been absent, minimal or unexpected in trials. These findings suggest a role for population context in determining health responses and filling extensive gaps in knowledge. Multiple micronutrient supplements reduce the risks of being born with low birth weight, small for gestational age or stillborn in undernourished settings, and justify micronutrient interventions with antenatal care. Measurable health effects of gestational micronutrient exposure might persist into childhood but few data exists on potential long-term benefits. In this Review, we discuss micronutrient intake recommendations, risks and consequences of deficiencies, and the effects of interventions with a particular emphasis on offspring.
392 citations
TL;DR: The epigenotype could be used not only to predict susceptibility to certain cancers but also to assess the effectiveness of dietary modifications to reduce such risk.
Abstract: Unlike the genome, the epigenome can be modified and hence some epigenetic risk markers have the potential to be reversed. Such modifications take place by means of drugs, diet or environmental exposures. It is widely accepted that epigenetic modifications take place during early embryonic and primordial cell development, but it is also important that we gain an understanding of the potential for such changes later in life. These “later life” epigenetic modifications in response to dietary intervention are the focus of this paper. The epigenetic modifications investigated include DNA methylation, histone modifications and the influence of microRNAs. The epigenotype could be used not only to predict susceptibility to certain cancers but also to assess the effectiveness of dietary modifications to reduce such risk. The influence of diet or dietary components on epigenetic modifications and the impact on cancer initiation or progression has been assessed herein.
153 citations
Cites background from "The periconceptional period, reprod..."
...Folate is an important one-carbon donor, and one-carbon metabolism is essential for the synthesis of DNA, proteins and phospholipids [101]....
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TL;DR: The CE marking of IVF culture media is a significant development in the field, however, the quality and efficiency of culture media should be monitored closely.
Abstract: Background The advances in the world of IVF during the last decades have been rapid and impressive and culture media play a major role in this success. Until the 1980s fertility centers made their media in house. Nowadays, there are numerous commercially available culture media that contain various components including nutrients, vitamins and growth factors. This review goes through the past, present and future of IVF culture media and explores their composition and quality assessment. Methods A computerized search was performed in PubMed regarding IVF culture media including results from 1929 until March 2014. Information was gathered from the websites of companies who market culture media, advertising material, instructions for use and certificates of analysis. The regulation regarding IVF media mainly in the European Union (EU) but also in non-European countries was explored. Results The keyword 'IVF culture media' gave 923 results in PubMed and 'embryo culture media' 12 068 results dating from 1912 until March 2014, depicting the increased scientific activity in this field. The commercialization of IVF culture media has increased the standards bringing a great variety of options into clinical practice. However, it has led to reduced transparency and comparisons of brand names that do not facilitate the scientific dialogue. Furthermore, there is some evidence suggesting that suboptimal culture conditions could cause long-term reprogramming in the embryo as the periconception period is particularly susceptible to epigenetic alterations. IVF media are now classified as class III medical devices and only CE (Conformite Europeene)-marked media should be used in the EU. Conclusion The CE marking of IVF culture media is a significant development in the field. However, the quality and efficiency of culture media should be monitored closely. Well-designed randomized controlled trials, large epidemiological studies and full transparency should be the next steps. Reliable, standardized models assessing multiple end-points and post-implantation development should replace the mouse embryo assay. Structured long-term follow-up of children conceived by assisted reproduction technologies and traceability are of paramount importance.
144 citations
Cites background from "The periconceptional period, reprod..."
...Time is the only true counselor regarding the safety of any intervention during the periconception period as it is characterized by increased epigenetic plasticity that creates a window for long-term reprogramming (El Hajj and Haaf, 2013; Steegers-Theunissen et al., 2013)....
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TL;DR: It is shown that individuals who were prenatally exposed to famine during the Dutch Hunger Winter in 1944–45 had, 6 decades later, less DNA methylation of the imprinted IGF2 gene compared with their unexposed, same-sex siblings.
Abstract: Extensive epidemiologic studies have suggested that adult disease risk is associated with adverse environmental conditions early in development. Although the mechanisms behind these relationships are unclear, an involvement of epigenetic dysregulation has been hypothesized. Here we show that individuals who were prenatally exposed to famine during the Dutch Hunger Winter in 1944-45 had, 6 decades later, less DNA methylation of the imprinted IGF2 gene compared with their unexposed, same-sex siblings. The association was specific for periconceptional exposure, reinforcing that very early mammalian development is a crucial period for establishing and maintaining epigenetic marks. These data are the first to contribute empirical support for the hypothesis that early-life environmental conditions can cause epigenetic changes in humans that persist throughout life.
2,723 citations
"The periconceptional period, reprod..." refers result in this paper
...In contrast to the periconceptional rat studies cited above, Heijmans et al. (2008) reported reduced IGF2 DMR methylation in genomic DNA from whole blood of human subjects who were prenatally exposed to famine during the Dutch Hunger Winter of 1944–1945 relative to their unexposed, same-sex…...
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TL;DR: Although the rise in ischaemic heart disease in England and Wales has been associated with increasing prosperity, mortality rates are highest in the least affluent areas.
2,548 citations
"The periconceptional period, reprod..." refers background in this paper
...Theconcept thatmaternal nutritionduring pregnancy can impingeon the long-term well-being of offspring arose from retrospective cohort studies of Barker and Osmond (1986) in adult humans....
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...Epigenetic programming and long-term development The concept that maternal nutrition during pregnancy can impinge on the long-term well-being of offspring arose from retrospective cohort studies of Barker and Osmond (1986) in adult humans....
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TL;DR: In 1969, McCully reported autopsy evidence of extensive arterial thrombosis and atherosclerosis in two children with elevated plasma homocyst(e)ine concentrations and homocysteine thiolactone, and it has recently become clear that hyperhomocyst (e)inemia is an independent risk factor.
Abstract: In 1969, McCully made the clinical observation linking elevated plasma homocyst(e)ine concentrations with vascular disease.1 He reported autopsy evidence of extensive arterial thrombosis and atherosclerosis in two children with elevated plasma homocyst(e)ine concentrations and homocystinuria. On the basis of this observation, he proposed that elevated plasma homocyst(e)ine (hyperhomocyst(e)inemia) can cause atherosclerotic vascular disease. The term “homocyst(e)ine” is used to define the combined pool of homocysteine, homocystine, mixed disulfides involving homocysteine, and homocysteine thiolactone found in the plasma of patients with hyperhomocyst(e)inemia. Subsequent investigations have confirmed McCully's hypothesis, and it has recently become clear that hyperhomocyst(e)inemia is an independent risk factor . . .
1,981 citations
TL;DR: The results show that dietary methyl supplementation of a/a dams with extra folic acid, vitamin B12, choline, and betaine alter the phenotype of their Avy/a offspring via increased CpG methylation at the AvY locus and that the epigenetic metastability which confers this lability is due to the Avy transposable element.
Abstract: Early nutrition affects adult metabolism in humans and other mammals, potentially via persistent alterations in DNA methylation. With viable yellow agouti (Avy) mice, which harbor a transposable element in the agouti gene, we tested the hypothesis that the metastable methylation status of specific transposable element insertion sites renders them epigenetically labile to early methyl donor nutrition. Our results show that dietary methyl supplementation of a/a dams with extra folic acid, vitamin B12, choline, and betaine alter the phenotype of their Avy/a offspring via increased CpG methylation at the Avy locus and that the epigenetic metastability which confers this lability is due to the Avy transposable element. These findings suggest that dietary supplementation, long presumed to be purely beneficial, may have unintended deleterious influences on the establishment of epigenetic gene regulation in humans.
1,914 citations
"The periconceptional period, reprod..." refers background in this paper
...Working with the viable yellow agouti (Avy) mouse, Waterland and Jirtle (2003) demonstrated that dietary supplementation with methionine, folate, B12, choline and betaine throughout gestation and lactation increased CpG methylation at the agouti locus, thereby recapitulating the mottled and healthy…...
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TL;DR: Article de synthese sur le metabolisme de la methionine, acide amine essentiel, chez les mammiferes, de la regulation du metabolisme (mise en evidence and importance relative of chaque facteur).
Abstract: Article de synthese sur le metabolisme de la methionine, acide amine essentiel, chez les mammiferes. Etude du schema metabolique, de la regulation du metabolisme (mise en evidence et importance relative de chaque facteur). Etude de la transamination de la methionine, du role de la S-adenosyl-methionine, de l'oxydation de l'homocysteine et de la cystathionine. Etude du disfonctionnement du metabolisme et des consequences chez les hommes
1,456 citations
"The periconceptional period, reprod..." refers background in this paper
...…developmental events occurring in germ cells within the ovary, and in the preimplantation embryo, one cannot lose sight of the fact that, in mammals, as much as 50% of methionine metabolism and up to 85% of all transmethylation reactions occur in the liver (Mudd and Poole, 1975; Finkelstein, 1990)....
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