Improvement of gamete quality by stimulating and feeding the endogenous antioxidant system: mechanisms, clinical results, insights on gene-environment interactions and the role of diet

Abstract

Oxidative damage triggers extensive repair in gametes and thereafter in the zygote but it results in clinically relevant damage when affecting the maturation of the gametes chromatin, i.e. padlocking and epigenetic marking. It associates with defective DNA methylation and/or with oxidation of the methyl marks leading to derangement of gamete epigenetics, defects of chromatin condensation and aneuploidy. A proper feed to the one carbon cycle has the potential to stimulate the endogenous antioxidant defences, i.e. gluthatione synthesis, and to activate compensative homeostatic mechanisms restoring both the oxy-redox balance and DNA methylation, which are indeed strictly cross-regulated. This has been shown to produce measurable clinical improvements of male reproductive potential in pilot studies herein summarised. However, the effects of dietary habits and of supplementations are variable according to the individual genetic substrate, as genetic variants of several of the concerned enzymes occur with high frequency. Individual risk assessments and personalised interventions are still difficult to implement, in the meantime, a very varied diet may facilitate metabolic compensation in the majority of the cases. This review aims to report on the mechanisms of damage, on the opportunities to modulate the physiologic oxy-redox homeostasis by means of a varied diet or dietary supplements and on the open issues related to the genetic variability of the population.

Keywords: DNA methylation; Epigenesis; Oocyte; Oxidative stress; Sperm.

Conflict of interest statement

MD is R&D Director and shareholder at Parthenogen SAGL, a private company engaged in the development of dietary supplements. The other authors declare that they have no conflict of interest.

Figures

Fig. 1

Epigenetic instability from oxidative damage. a The methylation of cytosine (filled circles) within CpG repeats to form methyl cytosine causes loss of affinity of the transcription factors for the promoter and silencing of the gene. b If the cytosines are not methylated (empty circles) due to lack of SAMe or if the methylation mark is lost due to de-methylation triggered by methyl cytosine oxidation, the gene is not anymore silenced and may undergo inappropriate expression. c If either the methyl cytosine or the guanosine of the CpG repeat are oxidised (small filled circles), the domain reverts from hydrophobic back to hydrophilic and the transcription factors recover the ability to bind and to express the gene in spite of the methylation of the CpG island. Both cases b and c lead to epigenetic instability

Fig. 2

Connection between the one carbon cycle and the transsulfuration pathway (GSH synthesis). Upper panel The methyl group of methionine is activated by adenylation to form S-Adenosyl-Methionine (SAMe) that acts as the universal methyl donor for any acceptor including DNA: a molecule of homocysteine is formed. Homocysteine can be either re-methylated from folates or betaine or enter the transsulfuration pathway for the synthesis of glutathione (GSH). Lower panel Homocysteine is complexed with serine to form cystathionine and to feed the de-novo synthesis of GSH

Fig. 3

Regulation of cystathionine-beta-synthase (CBS) activity. The enzyme is formed by a tetramer of CBS domains complexed with a heme functioning as a redox sensor. The oxidation of the heme group activates the enzyme. However, a significant activity funneling homocysteine into the trannssulfuration pathway will only occur if SAMe is available and binding to the carboxy-terminal end of the CBS domains. Thus, full efficiency of the transsulfuration pathways for GSH synthesis will only occur after the requirement for activated methyl groups (SAMe) for the one carbon cycle is satisfied

Fig. 4

Schematic map of the possible genetic blockades to the 1CC and the GSH synthesis. All of the enzyme variants of concern have a high prevalence in the population and the chances for multiple defects are accordingly high. The final phenotype, i.e. the function of the carbon metabolism and of the antioxidant defenses, will depend on the variable combination of these genetic substrates with environmental factors including the diet and intercurrent diseases. MTHFR Methyl-Tetra-Hydro-Folate-Reductase, MTR Methionine Synthase, MTRR Methionine Synthase Reductase, BHMT Betaine Homocysteine Methyl Transferase, CBS Cistathionine Beta Synthase, CHDH Choline Dehydrogenase

Fig. 5

Food folates compared to supplement folates. The folates found in food consist of a mixture of reduced folates, mainly 5-Methyl-Tetrahydrofolate as shown in the figure. They also come with a polyglutamate tail (not shown), further increasing the solubility, whose length varies according to the type of food. Dietary supplements and fortified foods usually contain the synthetic form folic acid that is better stable, cheaper and easier to manufacture. Folic acid requires enzymatic reduction by the enzyme MTHFR (see red circles) to become soluble and bioavailable to cell metabolism. Subjects with a deficient MTHFR activity may not be able to process loads of the synthetic form. It is also to be noted that the reduction of folic acid from supplements consumes proportional amounts of NADPH and may be further hampered by any oxidative stress causing imbalance of NADP toward the oxidised form NADP+