Long-Term Moderate Oxidative Stress Decreased Ovarian Reproductive Function by Reducing Follicle Quality and Progesterone Production

Abstract

Ovarian aging is a long-term and complex process associated with a decrease in follicular quantity and quality. The damaging effects of reactive oxygen species (ROS) in ovarian aging and ovarian aging-associated disorders have received relatively little attention. Thus, we assessed if the oxidative stress induced by long-term (defined by the Environmental Protection Agency as at least 30 days in duration) moderate ozone inhalation reduced ovarian reserves, decreased ovarian function and induced ovarian aging-associated disorders. The expression of oxidative stress markers and antioxidant enzymes was used to determine the degree of oxidative stress. Ultrastructural changes in ovarian cells were examined via electron microscopy. The ovarian reserve was assessed by measuring multiple parameters, such as the size of the primordial follicle pool and anti-Müllerian hormone (AMH) expression. The estrous cycle, hormone levels and fertility status were investigated to assess ovarian function. To investigate ovarian aging-associated disorders, we utilized bone density and cardiovascular ultrasonography in mice. The levels of oxidized metabolites, such as 8-hydroxy-2´-deoxyguanosine (8-OHdG), 4-hydroxynonenal (4-HNE) and nitrotyrosine (NTY), significantly increased in ovarian cells in response to increased oxidative stress. The ultrastructural analysis indicated that lipid droplet formation and the proportion of mitochondria with damaged membranes in granulosa cells were markedly increased in ozone-exposed mice when compared with the control group. Ozone exposure did not change the size of the primordial follicle pool or anti-Müllerian hormone (AMH) expression. The estrogen concentration remained normal; however, progesterone and testosterone levels decreased. The mice exposed to ozone inhalation exhibited a substantial decrease in fertility and fecundity. No differences were revealed by the bone density or cardiovascular ultrasounds. These findings suggest that the decreased female reproductive function caused by long-term moderate oxidative damage may be due to a decrease in follicle quality and progesterone production.

The role of mitochondrial activity in female fertility and assisted reproductive technologies: overview and current insights

“…Conversely, granulosa cells and follicular fluid provide a favourable microenvironment with distinct antioxidants (Eichenlaub-Ritter et al, 2011). Despite increased levels of antioxidant enzymes within ovarian tissue, mice exposed to long-term OS present with not only a substantially higher percentage of defective mitochondria in follicular granulosa cells, but also lower fertility and fecundity rates (Shi et al, 2016). Babayev et al (2016) reported increased expression of mitochondrial stress-related genes in older mouse oocytes, along with accumulated ROS content and insufficient antioxidant capacity.…”

Association of GRIA1 polymorphisms with ovarian response to human menopausal gonadotropin in Iranian women

“…Many factors, including ge- Table 3. Comparison of the mean number of follicles on day 9 of the menstrual cycle in subjects with different genotypes of GRIA1 (rs548294 C > T and rs2195450 G > A) in the study group [27]. In this study, comparison of the mean number of follicles at day 9 of the menstrual cycle showed that, similarly to the mean LH and FSH levels, the number of follicles in subjects with the CT and GG genotypes was higher than in subjects with the other genotypes in the GRIA1 rs548294 C > T and rs2195450 G > A SNPs, respectively.…”

Crosstalk between PTEN/PI3K/Akt Signalling and DNA Damage in the Oocyte: Implications for Primordial Follicle Activation, Oocyte Quality and Ageing

“…This may be related to the finding that oocytes from young mice have a greater DNA repair capacity [48]. Qualitative analysis of recent findings of studies in DNA damage and ovarian ageing are summarised in Table 2. ROS accumulation in mitochondria can be an underlying factor in ageing, by increasing oxidative damage leading to a gradual decrease in follicle quality [150]. Increased ROS activity due to senescence parallels diminished activity of the oxidative defence system and may lead to increased lipid peroxidation, oxidative stress and damage to macromolecules including DNA with either single-strand breaks (SSBs) or DSBs [151].…”