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Journal of Assisted Reproduction and Genetics
Published in: Journal of Assisted Reproduction and Genetics 12/2016

Open Access 01-12-2016 | Review

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

Authors: Maurizio Dattilo, D’Amato Giuseppe, Caroppo Ettore, Yves Ménézo

Published in: Journal of Assisted Reproduction and Genetics | Issue 12/2016

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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.
Glossary
1 Carbon Cycle (1CC)
Also called transmethylation pathway, is a main pathway for non-photosynthetic organisms to add the carbon unit to molecules, it is essential for cell growth and differentiation, including DNA methylation. Upregulates transsulfurations.
Betaine Homocysteine Methyl Transferase (BHMT)
Zinc metallo-enzyme that catalyzes the transfer of a methyl group from betaine (trimethylglycine) to homocysteine to form dimethylglycine and methionine. Provides folate-independent Hcy re-methylation.
Choline Dehydrogenase (CHDH)
Oxidoreductases oxidising choline to betaine aldehyde, which is ultimately transformed to betaine by aldehyde dehydrogenase. Feeds the endogenous betaine availability for the BHMT reaction.
Cystathionine Beta Synthase (CBS)
Redox-regulated enzyme having vit. B6 as essential co-factor and allosterically up-regulated by SAMe. It forms cystathionine from Hcy and serine thereby opening the transsulphuration pathway leading to GSH synthesis.
Glutathione (GSH)
It is a tripeptide formed by cysteine, glycine and glutamate. Thanks to the -SH group from cysteine it is able to act as electron donor forming glutathione disulfide (GSSG). GSH de-novo biosynthesis occurs within the transsulfuration pathway.
Homocysteine (Hcy)
It is a non-proteogenic aminoacid similar to cysteine and formed by de-methylation of methionine. Within the 1CC it is re-methylated to methionine by methyl groups donated by folates or betaine. It is also the substrate of CBS for the start of the transsulfuratuion pathway. Hcy accumulation is toxic to cells.
Methionine synthase (MTR)
It is responsible for the remethylation of homocysteine from folates and uses vit. B12 as essential co-factor. After a reductive activation of the enzyme-bound cobalamin to methylcobalamin by MTRR, MTR passes the methyl group from methylfolate to Hcy forming methionine.
Methionine synthase reductase (MTRR)
It is the enzyme responsible for the activation of MTR. It operates a reductive methylation of the oxidised form of the MTR-cobalamin complex using SAMe as methyl donor and NADPH as the electron donor.
Methyl-Tetra-Hydro-Folate-Reductase (MTHFR)
Reductase containing a bound flavin cofactor (from riboflavine) and using NAD(P)H as the electron donor. MTHFR irreversibly reduces 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate to feed the MTR-dependent re-methylation of Hcy (rate-limiting enzyme).
Nicotinamide adenine dinucleotide (NAD)
Di-nucleotide acting as electron donor in oxy-redox reactions. Also occurring in its phosphate form (NADP) to serve specific enzymes. The equilibrium between its reduced (NADH/NADPH) and oxydised (NAD+/NADP+) form influences the direction of oxy-redox reactions.
S-Adenosyl-Methionine (SAMe)
Ubiquitous substrate involved in in anabolic methyl group transfers and transsulfurations. It is formed within the 1CC by activating adenylation of methionine and, after releasing the methyl group to acceptors, forms S-adenosyl-homocysteine and thereafter Hcy. It occurs in any cells with a massive production and consumption in the liver.
Transsulfuration pathway (reverse)
Pathway responsible for the passage of the -SH group from Hcy to cysteine. The opposite passage (forward) occurs only in bacteria. It is a relevant source of -SH groups for GSH synthesis and also contributes to the de-toxication of high Hcy. It upregulates the 1CC.
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Metadata
Title
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
Authors
Maurizio Dattilo
D’Amato Giuseppe
Caroppo Ettore
Yves Ménézo
Publication date
01-12-2016
Publisher
Springer US
Published in
Journal of Assisted Reproduction and Genetics / Issue 12/2016
Print ISSN: 1058-0468
Electronic ISSN: 1573-7330
DOI
https://doi.org/10.1007/s10815-016-0767-4

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