The periconceptional period, reproduction and long-term health of offspring: the importance of one-carbon metabolism
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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The periconception period, defined as the 14 weeks before and 10 weeks after conception, is a critical window with a substantial impact on fetal growth and development.
“The periconception period, defined as the 14 weeks before and 10 weeks after conception, is a critical window with a substantial impact on fetal growth and development [8].”
From Associations between periconceptional lifestyle behaviours and adverse pregnancy outcomes (2021) · cites this paper as [8]
Cites
Transposable elements: targets for early nutritional effects on epigenetic gene regulation
Waterland, R. A., & Jirtle, R. L. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.15.5293-5300.2003 · Cited by 2,019 · cited 1× · see citing works
“Working with the viable yellow agouti ( A vy ) 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…”
BackgroundEpigenetics and aging: the targets and the marks
Fraga, M. F., & Esteller, M. (2007) · Trends in Genetics · doi:10.1016/j.tig.2007.05.008 · Cited by 690 · cited 1× · see citing works
“These observations are consistent with the association of ageing and global DNA hypomethylation (Fraga and Esteller, 2007).”
BackgroundHoman, G. F., Davies, M., & Norman, R. (2007) · Human Reproduction Update · doi:10.1093/humupd/dml056 · Cited by 546 · see citing works
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Origins of lifetime health around the time of conception: causes and consequences
Fleming, T. P., Watkins, A. J., Velazquez, M. A., Mathers, J. C., Prentice, A. M., Stephenson, J., Barker, M., Saffery, R., Yajnik, C. S., Eckert, J. J., et al. (2018) · The Lancet · doi:10.1016/s0140-6736(18)30312-x · Cited by 1,147 · see citing works
The Human Microbiome and Child Growth – First 1000 Days and Beyond
Robertson, R. C., Manges, A. R., Finlay, B. B., & Prendergast, A. J. (2019) · Trends in Microbiology · doi:10.1016/j.tim.2018.09.008 · Cited by 793 · see citing works
van Dijk, M. R., Koster, M. P. H., Oostingh, E. C., Willemsen, S. P., Steegers, E. A. P., & Steegers-Theunissen, R. P. M. (2020) · Journal of Medical Internet Research · doi:10.2196/15773 · Cited by 80 · see citing works
Self-citationAssociations between periconceptional lifestyle behaviours and adverse pregnancy outcomes
Maas, V. Y. F., Poels, M., Lamain-de Ruiter, M., Kwee, A., Bekker, M. N., Franx, A., & Koster, M. P. H. (2021) · BMC Pregnancy and Childbirth · doi:10.1186/s12884-021-03935-x · Cited by 43 · see citing works
Rubini, E., Baijens, I. M. M., Horánszky, A., Schoenmakers, S., Sinclair, K. D., Zana, M., Dinnyés, A., Steegers-Theunissen, R. P. M., & Rousian, M. (2021) · Genes · doi:10.3390/genes12101634 · Cited by 35 · see citing works
Self-citation
- Authors
- Steegers-Theunissen, R. P. M., Twigt, J., Pestinger, V., & Sinclair, K. D.
- Affiliations
- Erasmus MC (NL)
- University of Nottingham (GB)
- Corresponding author
- Sinclair, K. D.
- Venue
- Human Reproduction Update
- Publisher
- Oxford University Press (OUP)
- Published
- 2013-08-19
- Volume
- 19
- Issue
- 6
- Pages
- 640-655
- ISSN
- 1355-4786 (ISSN-L)
- 1460-2369
- OpenAlex
- W2127382802
- Cited by
- 378
- References
- 3
- Citations by year
- 2026: 22 · 2025: 18 · 2024: 35 · 2023: 18 · 2022: 50 · 2021: 43 · 2020: 21 · 2019: 30 · 2018: 35 · 2017: 28 · 2016: 26 · 2015: 25 · 2014: 21 · 2013: 6
- FWCI
- 4.22
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Human Reproduction Update (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- Funders
- Biotechnology and Biological Sciences Research Council
- Topics
- Health Sciences › Medicine › Rheumatology › Folate and B Vitamins Research
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Birth, Development, and Health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- periconceptional period, one-carbon metabolism, folic acid, methionine, vitamin B12, epigenetic methylation, DNA methylation, histone methylation, chromatin regulation, subfertility, miscarriage, parental nutrition, parental lifestyle, smoking, alcohol consumption, assisted reproduction, pregnancy outcomes, offspring health, non-communicable diseases, reproductive failure
- MeSH terms
- Alcohol Drinking, Animals, Carbon, Female, Fertilization, Folic Acid, Humans, Pregnancy, Pregnancy Outcome, Smoking, Vitamin B 12, Reproductive Techniques, Assisted, Metabolic Networks and Pathways
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