In/Fertility: The Role of DNA Methylation

Infertility affects more couples than we might think. 1 in 7 couples - or 15% of couples - have difficulty conceiving a child (1). A diagnosis of infertility means you haven’t been able to get pregnant after a year of trying. If you’re a woman over 35, it means you haven’t been able to get pregnant after 6 months of trying. Women who are able to conceive but not carry a pregnancy to term may also be diagnosed with infertility. A woman who’s never been able to get pregnant will be diagnosed with primary infertility, and a woman who’s had at least one successful pregnancy in the past will be diagnosed with secondary infertility (2).

But infertility isn’t just a woman’s problem. Men can be infertile too. In fact, men and women are equally likely to have fertility problems.We often think that the problem comes from women but actually, half of couples infertility cases arise from male factor infertility. As the reproductive system is complex, there are many possible causes of infertility, and fertility problems can affect either partner. It’s also worth noting that for a quarter of infertility cases, it is not possible to identify the cause (3).

What are the different causes of infertility?

There are various reasons for a men or a women’s infertility. Infertility in men can be caused by poor quality of semen and sperm, testicles issues, ejaculation disorders, hypogonadism (a failure of the testes to produce the male sex hormone testosterone, sperm, or both) or a consequence of medication. Infertility in women can be due to ovulation issues, scarring from surgery, cervical mucus issues, fibroids, endometriosis, pelvic inflammatory disease or again, a consequence of medicines and drugs (3). There are many risk factors involved in infertility issues but the main ones are the following: age – fertility declines with age, weight – being overweight or underweight, sexually transmitted infections (STIs), smoking, alcohol, environmental factors, stress and genetics. All of these can affect ovulation, sperm quality and production, or sex drive and libido (3). 

Today, we’re talking about genetics. To be more precise, we’ll be talking about nutrigenomics and in/fertility. Nutrigenomics is an area of genomics which focuses on genes that relate and respond to nutrition and lifestyle interventions. The takeaway from this area is that it is possible to modify gene expression with nutrition. Genes are not destiny (4). So the good news is if your fertility issues have a genetic component, then it’s possible to do something about it! Indeed, DNA Methylation can be a factor in explaining certain causes of infertility, for example due to endometriosis or poor sperm quality - such as low sperm count or low sperm motility (5,6).

What is Methylation?

Methylation, also referred to as one carbon metabolism, is a process by which methyl groups are added to molecules. It is involved in almost every biochemical reaction in the body, occurring billions of times every second in our cells and contributing to numerous crucial bodily functions, including: detoxification, DNA integrity, energy production, inflammation control, immune function, gene expression & suppression, neurotransmitter balance and telomere protection (ageing) (7).

Basically, methylation is essential. 

When methylation is impaired, it can contribute to major chronic conditions, including cardiovascular diseases, unexplained miscarriages, problems during pregnancy, mood and psychiatric disorders, cancer, free radical damage (premature ageing), diabetes, infertility, neural tube defects, adult neurological conditions and chronic fatigue syndrome (7). To sum up, methylation can affect your fertility abilities. And we’re going to tell you what you can do about it to overcome (or at least try to overcome) your infertility methylation-related issues.

Nutrigenomics involves talking about ... genes. So this is where we'll start. There are many (hundreds) of genes involved in DNA methylation but we won't bore you with all the details, and today we are going to mention only five genes. Why these five genes specifically? Because they are part of the methylation cycles and because research has shown that they have impactful and significant roles in fertility issues.

Nutrigenomics

Let’s start with MTHFD1. This gene codes for a protein called Methylenetetrahydrofolate Dehydrogenase 1. MTHFD1 possesses three distinct activities which catalyse the sequential reactions in the interconversion of the carbon-1 derivatives of THF, which are substrates for methionine, thymidylate, and de novo purine synthesis. These are reversible reactions that can be directed towards 5-MTHF - and homocysteine re-methylation - or away from it and can impact the methionine cycle. If that didn’t mean anything to you, that’s fine. That’s why we’re here! What we can tell you is that mutations called SNPs (Single Nucleotide Polymorphisms) alter this gene and down-regulate its activity. This has been linked to increased risk of folate sensitive neural tube defects and endometriosis related infertility due to choline depletion (8,9,10,11).

The second gene - MTHFR - is quite famous, and has also been linked to infertility issues. The MTHFR gene is responsible for making the protein methylenetetrahydrofolate reductase (MTHFR), the rate-limiting enzyme in the methylation cycle which catalyses the conversion of folate to 'active' folate (5-MTHF) needed to support the re-methylation of homocysteine to methionine, DNA synthesis and repair (vital for healthy cell division), and the metabolism of neurotransmitters, phospholipids and proteins such as myelin. SNPs on the MTHFR gene usually result in lower enzyme activity. The C677T variant, which occurs in about 30% of people, can result in significantly reduced 5-MTHF levels, between 40% and 70% reduction for the carriers of the SNP. This SNP can cause vulnerability to folate sensitive neural tube defects but just as with the MTHFD1 mutation, you can support them with nutrition (12,13,14). Supplementing folate during pregnancy reduces the prevalence of neural tube defects by not exposing this mutation to aggravating conditions. MTHFR activity can be supported by increasing the intake of folate (B9) and the cofactors riboflavin (vitamin B2), niacin (vitamin B3), cobalamin (vitamin B12) and zinc.

We’ll now introduce PEMT, our third gene of the day. PEMT - or Phosphatidylethanolamine N-methyltransferase - encodes an enzyme which converts phosphatidylethanolamine to phosphatidylcholine by sequential methylation in the liver, a significant source of choline relative to dietary intake. Choline is a major source of methyl groups via its metabolite betaine - which catalyses the methylation of homocysteine to form methionine, which is an essential process. A SNP on PEMT can lead to a lower activity of the enzyme, and a potential for reduced choline synthesis, which can impact betaine levels needed to support the conversion of homocysteine to methionine. Dependency on PEMT activity can be reduced by ensuring adequate dietary intake of choline (found in eggs, beef, chicken and fish). This gene is related to fertility because choline is an important vitamin for men and women who are trying to conceive and get pregnant (15,16). 

Another interesting SNP, which is found on the CHDH gene, has been associated with reduced sperm motility. Indeed, this SNP involves a reduction in the activity of the protein which is transferred from choline to betaine, which is essential for fertility. We now report evidence that this SNP is associated with altered sperm motility patterns and dysmorphic mitochondrial structure in sperm. Sperm produced by men who have a GT or TT genotype at G233T have 40% and 73% lower ATP concentrations, respectively, in their sperm. G233T is associated with decreased CHDH protein in sperm and hepatocytes. In a study carried out by Johnson et al. (2012), carriers of this SNP were supplemented with betaine-water and the result was an improvement in the motility of their sperm which implies a potential improvement in fertility (17,18,19,20,21).

Finally, our last gene is BHMT, which catalyses the transfer of a methyl group from betaine to homocysteine to form methionine. It uses a ‘short cut’ mechanism rather than the B12-dependent 'long route'. The BHMT pathway is zinc-dependent and requires adequate levels of TMG - trimethylglycine (betaine) to function properly. This reaction is also required for the irreversible oxidation of choline. It is also reported to increase the risk of neural tube defects (22,23,24). BHMT can be supported by increasing intake of co-factors including foods containing zinc - such as beef, lamb, chicken, chickpeas, pumpkin seeds, cashews, betaine - from quinoa, spinach and beetroot, and choline (substrate of betaine) - found in eggs. 

Voila, we have thus seen five genes of methylation related to fertility. What do we remember from all this? Number one: infertility affects both men and women equally, and is complex. Number two: genetics may be a factor related to infertility. Number three: it is possible to do something and not to sit idly by. Genes are not destiny.

Lifecode Gx

If you want to learn more about methylation and fertility, we recommend that you order our Methylation report (25). Thousands of people have ordered their personalised genetic methylation report and it has changed many of their lives.

If you are a health practitioner and want to use nutrigenomics in your practice, you can register with us as a Lifecode Gx practitioner (26). Practitioners who fully integrate nutrigenomics into their practice find that client engagement improves along with clinical outcomes. We offer a range of nutrigenomics training opportunities presented live online and recorded, from short 'snapshots' (which are free of charge) to practitioner 'masterclass' events which are priced according to the number of CPD approved hours. Access to live and recorded events is via our Crowdcast channel (27) or Vimeo (28).

If you are not a health practitioner, know that our tests are available from registered health professionals who are experienced in using nutrigenomics testing. If you are not working with a practitioner, we offer packages which include testing and support including our Core Package. You can find practitioners experienced in the use of Lifecode Gx DNA tests and reports having completed nutrigenomics in practice core training plus at least two specialist modules here (29).

That's all from us today! If you have any questions, you can contact us at team@lifecodegx.com or on any of our social media channels! 

Sources

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  11. Zeisel SH. (2008). Genetic polymorphisms in methyl-group metabolism and epigenetics: lessons from humans and mouse models. Brain Res. Oct 27;1237:5-11. (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2587491/) 
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  15. Ivanov A, Nash-Barboza S, Hinkis S, Caudill MA. (2009). Genetic variants in phosphatidylethanolamine N-methyltransferase and methylenetetrahydrofolate dehydrogenase influence biomarkers of choline metabolism when folate intake is restricted. J Am Diet Assoc. Feb;109(2):313-8. (http://www.ncbi.nlm.nih.gov/pubmed/19167960) 
  16. Zeisel SH. A Conceptual Framework for Studying and Investing in Precision Nutrition. Front Genet. 2019 Mar 18;10:200. doi: 10.3389/fgene.2019.00200. PMID: 30936893; PMCID: PMC6431609. (https://pubmed.ncbi.nlm.nih.gov/30936893/)
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  18. Corbin KD, Zeisel SH. The nutrigenetics and nutrigenomics of the dietary requirement for choline. Prog Mol Biol Transl Sci. 2012;108:159-177. doi:10.1016/B978-0-12-398397-8.00007-1. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7008405/) 
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  21. Zeisel SH. Choline: clinical nutrigenetic/nutrigenomic approaches for identification of functions and dietary requirements. World Rev Nutr Diet. 2010;101:73-83. doi:10.1159/000314512. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3601485/) 
  22. Boyles AL, Billups AV, Deak KL, Siegel DG, Mehltretter L, Slifer SH, Bassuk AG, Kessler JA, Reed MC, Nijhout HF, George TM, Enterline DS, Gilbert JR, Speer MC, NTD Collaborative Group. Neural tube defects and folate pathway genes: family-based association tests of gene-gene and gene-environment interactions. Environ Health Perspect. 2006 Oct;114(10) 1547-1552. doi:10.1289/ehp.9166. PMID: 17035141; PMCID: PMC1626421. (http://europepmc.org/abstract/MED/17035141)
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  26. Lifecode Gx. 2021. Registration — Lifecode Gx. [online] Available at: <https://www.lifecodegx.com/registration> 
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