Exploring the potential impact of nutritionally actionable genetic polymorphisms on idiopathic male infertility: a review of current evidence

Abstract

Infertility affects about 15% of the world's population. In 40%-50% of infertile couples, a male factor underlies the problem, but in about 50% of these cases, the etiology of male infertility remains unexplained. Some clinical data show that lifestyle interventions may contribute to male reproductive health. Cessation of unhealthy habits is suggested for preserving male fertility; there is growing evidence that most preexisting comorbidities, such as obesity and metabolic syndrome, are highly likely to have an impact on male fertility. The analysis of genetic polymorphisms implicated in metabolic activity represents one of the most exciting areas in the study of genetic causes of male infertility. Although these polymorphisms are not directly connected with male infertility, they may have a role in specific conditions associated with it, that is, metabolic disorders and oxidative stress pathway genes that are potentially associated with an increased risk of male infertility due to DNA and cell membrane damage. Some studies have examined the impact of individual genetic differences and gene-diet interactions on male infertility, but their results have not been synthesized. We review the current research to identify genetic variants that could be tested to improve the chances of conceiving spontaneously through personalized diet and/or oral vitamin and mineral supplementation, by examining the science of genetic modifiers of dietary factors that affect nutritional status and male fertility.

Keywords: energy metabolism; genetic polymorphisms; idiopathic male infertility; lifestyle factors; nutrition; oxidative stress; semen quality.

Figure 1

Choline metabolism and its links to methionine and folate metabolism. The pathways described are all present in the liver, with other tissues having one or more of these pathways. B12: cobalamin; BHMT: betaine-homocysteine S-methyltransferase; CHDH: choline dehydrogenase; DMG: dimethylglycine; MTHFD: methylene-tetrahydrofolate dehydrogenase; MTHFR: methylene-tetrahydrofolate reductase; PEMT: phosphatidylethanolamine N-methyltransferase; THF: tetrahydrofolate.

Figure 2

Effects of MTHFR polymorphisms on male fertility. The MTHFR gene, located on the short arm of chromosome 1 (1p36.3), is composed of 11 exons. It possesses 14 common or rare single-nucleotide polymorphisms that are associated with enzymatic deficiency. Among them, rs1801133 (C677T) and rs1801131 (A1298C) are the most reported to possibly reduce MTHFR activity to various degrees. Reduced enzymatic activity due to MTHFR polymorphisms is considered a risk factor for many diseases, including infertility. B2: riboflavin; B6: pyridoxine; B12: cobalamin; BHMT: betaine-homocysteine methyltransferase; CBS: cystathionine-β-synthase; CL: cystathionine-γ-lyase; DMG: dimethylglycine; MS: methionine synthase; MTHFR: methylenetetrahydrofolate reductase; SAM: S-adenosyl methionine; SAH: A-adenosyl homocysteine; THF: tetrahydrofolate.