The healthy cell cycle at the heart of reproductive health and normal embryonic development
A healthy cell cycle is based on the smooth running of a series of biochemical events allowing the protection, the correct functioning of DNA and the maintenance of its structural integrity. These biochemical pillars include, among others, DNA duplication, methylation and repair. The correct synchronization of these processes ensures rapid and error-free cell division, which can be very important during periods of high cell proliferation such as embryonic development, gametogenesis or follicle growth.
Metabolically active folic acid: its importance for fertility and healthy pregnancy
Folic acid (or folate or vitamin B9): properties known for a long time
The fundamental role of folic acid in the process of cell division has been known for many years. A low folate intake can cause cell cycle arrest, increase the rate of DNA breaks and cause a slowdown in DNA duplication or even cell necrosis (ref 1). Folates are major players in DNA methylation, with methylation being a chemical modification (the transfer of a -CH3 methyl group) that is part of epigenetic regulation. Dysfunction of epigenetic regulation during gamete growth and early development may increase the risk of occurrence of genomic imprinting disorders and associated syndromes (Beckwith-Wiedemann, Angelman, Silver-Russell syndromes) in the child.
Classic folic acid is not operational without enzymatic modification
To provide its full benefits, folic acid must be reduced in the body by a set of folate cycle enzymes; the last transformation is carried out by the enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR). Thanks to this modification, folic acid becomes metabolically active and usable by the body (image 1).
Enzymatic mutations responsible for vitamin B9 deficiency: high associated risks
More than 70% of the population carry at least one mutation of the MTHFR gene; in some cases, this results in an enzyme deficiency which makes the process of converting folic acid into its metabolically active form inefficient. This deficiency leads to a lack of operational vitamin B9 even if folic acid intake is high. Therefore, the risks associated with folate deficiency in people with an MTHFR mutation are higher: male and female fertility disorders, miscarriages, appearance of neural tube defects in the developing fetus, heart disease congenital, cleft lip and palate, etc.
A supply of metabolically active folic acid to cover the risks even in the event of mutations folate cycle enzymes
Being absolutely essential for normal fertility and reproduction, this vitamin must accompany all pregnancy plans. The use of folic acid in its metabolically active form would cover the risks associated with its insufficient intake in everyone, including people carrying enzymatic mutations of the folate cycle.
Additional support of folate and methionine cycles to stabilize methylation and enhance homocysteine recycling.
Homocysteine is the result of the chemical transformations of the methionine cycle
Homocysteine is a non-proteinogenic amino acid made in the methionine cycle during transfer of methyl groups for methylation. Once made, homocysteine must either be transformed into methionine to re-enter the methionine cycle or recycled to produce cysteine. The catalytic activity of the enzymes responsible for this transformation requires vitamins B9, B12 or B6 as well as zinc. An insufficient intake of these elements or an enzyme deficiency can be the cause of a high homocysteine level (homocysteinemia).
Link to health and health risks
The level of homocysteine in the blood is positively correlated with cardiovascular risks as well as with the risks of miscarriage and congenital malformations. This amino acid is both the indicator of these risks and their cause. In fact, homocysteinemia reflects a dysfunction at the level of the associated biochemical cycles (folates and methionine) which may be linked to a nutritional deficiency (group B vitamin, zinc) or enzymatic deficiency. Accumulation of homocysteine introduces an imbalance in the methionine cycle by reducing the amount of donor methyl groups, which affects methylation and can lead to a state of general hypomethylation.
Moreover, homocysteine itself is harmful: it associates with proteins, modifying their function, reduces the activity of glutathione peroxidase – one of the main defense enzymes against oxidative stress – and generates free radicals. The enzymatic apparatus that ensures stable methylation and DNA integrity leading to normal cell division depends on a sufficient supply of B vitamins and zinc. Supplementation with B vitamins and zinc therefore improves fertility and reduces the risk of malformations in the fetus.
Oxidative stress has a detrimental effect on the quality of gametes
Oxidative stress is a chemical attack on cellular macromolecules – DNA, fatty acids and proteins – by free radicals and peroxides. This modification disrupts the function of cellular components and can cause DNA mutations. Natural defense mechanisms against oxidative stress include enzymes that neutralize free radicals using molecules with strong reducing properties, glutathione being the main endogenous element of this defense.
A decline in the effectiveness of defense systems against oxidative stress may be related to age and/or to a lifestyle that has a significant negative impact on gamete quality and fertility. A supply of exogenous antioxidants helps protect cells by improving fertility. More importantly, a supply of cysteine, the amino acid at the base of glutathione synthesis, and vitamin B6, essential for the recycling of homocysteine into cysteine, makes it possible to boost the synthesis of glutathione by reinforcing the endogenous defense against oxidative stress.
