Physiological levels of reactive oxygen species (ROS) play an important regulatory role through various signaling transduction pathways in folliculogenesis, oocyte maturation, endometrial cycle, luteolysis, implantation, embryogenesis, and pregnancy. Persistent and elevated generation of ROS leads to a disturbance of redox potential that in turn causes oxidative stress (OS). Our literature review captures the role of ROS in modulating a range of physiological functions and pathological processes affecting the female reproductive life span and even thereafter (i.e., menopause). The role of OS in female reproduction is becoming increasingly important, as recent evidence suggest that it plays a part in conditions such as polycystic ovarian disease, endometriosis, spontaneous abortions, preeclampsia, hydatidiform mole, embryopathies, preterm labor, and intrauterine growth retardation. OS has been implicated in different reproductive scenarios and is detrimental to both natural and assisted fertility. Many ext...

Redox Considerations in Female Reproductive Function and Assisted Reproduction: From Molecular Mechanisms to Health Implications

Novel signaling mechanisms in the ovary during oocyte maturation and ovulation

In the efforts aimed at improving the quality of in-vitro-matured human oocytes, the dynamic balance and roles of pro-/antioxidants merit further consideration. In-vitro maturation (IVM) is emerging as a popular technology at the forefront of fertility treatment and preservation. However, standard in-vitro culture conditions exert oxidative stress or an imbalance between oxidants and antioxidants. Reactive oxygen species (ROS) are oxygen-derived molecules formed as intermediary products of cellular metabolism. By acting as powerful oxidants, ROS can oxidatively modify any molecule, resulting in structural and functional alterations. ROS are neutralized by an elaborate defence system consisting of enzymatic and nonenzymatic antioxidants. This review captures the inherent and external factors that may modulate the oxidative stress status of oocytes. It discusses the suspected impacts of oxidative stress on the gamut of events associated with IVM, including prematuration arrest, meiotic progression, chromosomal segregation, cytoskeletal architecture and gene expression. In-vivo and in-vitro strategies that may overcome the potential influences of oxidative stress on oocyte IVM are presented. Future studies profiling the oxidative stress status of the oocyte may permit not only the formulation of a superior IVM medium that maintains an adequate pro-/antioxidant balance, but also the identification of predictors of oocyte quality.

https://www.rbmojournal.com/article/S1472-6483(10)60038-7/pdf

Could oxidative stress influence the in-vitro maturation of oocytes?

It has been generally accepted for more than half a century that, in most mammalian species, oocytes cannot renew themselves in postnatal or adult life, and that the number of oocytes is already fixed in fetal or neonatal ovaries. This assumption, however, has been challenged over the past decade. In this study, we have taken an endogenous genetic approach to this question and generated a multiple fluorescent Rosa26rbw/+;Ddx4-Cre germline reporter mouse model for in vivo and in vitro tracing of the development of female germline cell lineage. Through live cell imaging and de novo folliculogenesis experiments, we show that the Ddx4-expressing cells from postnatal mouse ovaries did not enter mitosis, nor did they contribute to oocytes during de novo folliculogenesis. Our results provide evidence that supports the traditional view that no postnatal follicular renewal occurs in mammals, and no mitotically active Ddx4-expressing female germline progenitors exist in postnatal mouse ovaries.

https://www.pnas.org/content/pnas/109/31/12580.full.pdf

Experimental evidence showing that no mitotically active female germline progenitors exist in postnatal mouse ovaries

Recent advances have uncovered a previously unknown function of vitamin C in epigenetic regulation. Vitamin C exists predominantly as an ascorbate anion under physiological pH conditions. Ascorbate was discovered as a cofactor for methylcytosine dioxygenases that are responsible for DNA demethylation, and also as a likely cofactor for some JmjC domain-containing histone demethylases that catalyze histone demethylation. Variation in ascorbate bioavailability thus can influence the demethylation of both DNA and histone, further leading to different phenotypic presentations. Ascorbate deficiency can be presented systematically, spatially and temporally in different tissues at the different stages of development and aging. Here, we review how ascorbate deficiency could potentially be involved in embryonic and postnatal development, and plays a role in various diseases such as neurodegeneration and cancer through epigenetic dysregulation.

/pdf/the-epigenetic-role-of-vitamin-c-in-health-and-disease-85pfmc7uxv.pdf

The epigenetic role of vitamin C in health and disease.

It is known that alpha-tocopherol (vitamin E) and L-ascorbic acid (vitamin C) can modulate many biochemical processes intracellularly or extracellularly as antioxidants. The objective of the present study was to investigate the effects of alpha-tocopherol and L-ascorbic acid on porcine oocyte meiotic maturation, viability and the functions of cumulus cells. In two independent experiments, porcine oocytes with or free from cumulus cells were exposed to different levels of alpha-tocopherol (0, 10, 100 and 200 microM) or L-ascorbic acid (0, 50, 250 and 750 microM). Cumulus expansion, cumulus cell DNA fragmentation, meiotic maturation and degeneration of oocytes were assessed 48 h after in vitro culture. The results showed that: (1) neither alpha-tocopherol nor L-ascorbic acid influenced cumulus expansion but both prevented cumulus cell DNA fragmentation. (2) Alpha-tocopherol lowered the percentage of denuded oocytes (DOs) arrested at germinal vesicle stage (GV). Among the oocytes undergoing germinal vesicle breakdown (GVBD) proportion, fewer DOs treated by alpha-tocopherol were at metaphase I (MI) and more at metaphase II (MII). L-ascorbic acid caused lower percentage of DOs arrested at GV stage and higher percentage of DOs undergoing GVBD, especially at MII. The influences of alpha-tocopherol and L-ascorbic acid were not obvious in cumulus-enclosed oocytes (CEOs). (3) Both vitamins compromised the viability of CEOs and DOs. These results indicate that exposure to alpha-tocopherol or L-ascorbic acid promotes the development of porcine DOs from MI to MII and prevents cumulus cell DNA fragmentation at certain levels, especially 10 microM alpha-tocopherol or 250 microM L-ascorbic acid.

Exposure to L-ascorbic acid or alpha-tocopherol facilitates the development of porcine denuded oocytes from metaphase I to metaphase II and prevents cumulus cells from fragmentation.

The mechanism regulating primordial follicle formation remains largely unexplored because of the developmental particularity of female germ cells and their ultimate functional structure as follicles. Using an in vitro follicle reconstitution culture model, we explored, in the present study, the possibility of producing transgenetic follicles in vitro. We found that mouse fetal ovarian germ cells progressively lose the flexibility for gene manipulation with their oogonia-oocyte transformation upon entering meiosis, the borderline of which was at around embryonic age of 13.5 days post coitus (dpc). Interestingly, we further observed that fetal ovarian cells, only at this age or beyond achieve the capacity to reform the follicles in culture. Screening of well-known marker gene (Zp1-3, Figalpha, and Cx43) expression in cultured fetal ovarian cells of various developmental ages revealed that Figalpha is one of the determining factors for normal primordial follicle formation. By conducting reciprocal follicle reconstitution experiments, we provided further evidence that a synchronized germ-somatic cell interaction determines the normal duration of primordial folliculogenesis. Besides uncovering a potentially important regulatory mechanism for normal oocyte differentiation and follicle formation, this observation offers an alternative approach to produce transgenic oocytes/follicles, and thus animal models.

Stage-specific germ-somatic cell interaction directs the primordial folliculogenesis in mouse fetal ovaries.

Atrial natriuretic peptide negatively regulates follicle-stimulating hormone-induced porcine oocyte maturation and cumulus expansion via cGMP-dependent protein kinase pathway.

Fengchao Wang

Papers

Exposure to L-ascorbic acid or alpha-tocopherol facilitates the development of porcine denuded oocytes from metaphase I to metaphase II and prevents cumulus cells from fragmentation.

Stage-specific germ-somatic cell interaction directs the primordial folliculogenesis in mouse fetal ovaries.

Atrial natriuretic peptide negatively regulates follicle-stimulating hormone-induced porcine oocyte maturation and cumulus expansion via cGMP-dependent protein kinase pathway.