Roles of Reactive Oxygen Species and Antioxidants in Ovarian Toxicity1

Abstract

Proper functioning of the ovary is critical to maintain fertility and overall health, and ovarian function depends on the maintenance and normal development of ovarian follicles. This review presents evidence about the potential impact of oxidative stress on the well-being of primordial, growing and preovulatory follicles, as well as oocytes and early embryos, examining cell types and molecular targets. Limited data from genetically modified mouse models suggest that several antioxidant enzymes that protect cells from reactive oxygen species (ROS) may play important roles in follicular development and/or survival. Exposures to agents known to cause oxidative stress, such as gamma irradiation, chemotherapeutic drugs, or polycyclic aromatic hydrocarbons, induce rapid primordial follicle loss; however, the mechanistic role of ROS has received limited attention. In contrast, ROS may play an important role in the initiation of apoptosis in antral follicles. Depletion of glutathione leads to atresia of antral follicles in vivo and apoptosis of granulosa cells in cultured antral follicles. Chemicals, such as cyclophosphamide, dimethylbenzanthracene, and methoxychlor, increase proapoptotic signals, preceded by increased ROS and signs of oxidative stress, and cotreatment with antioxidants is protective. In oocytes, glutathione levels change rapidly during progression of meiosis and early embryonic development, and high oocyte glutathione at the time of fertilization is required for male pronucleus formation and for embryonic development to the blastocyst stage. Because current evidence suggests that oxidative stress can have significant negative impacts on female fertility and gamete health, dietary or pharmacological intervention may prove to be effective strategies to protect female fertility.

Histone acetyltransferase KAT8 is essential for mouse oocyte development by regulating ROS levels

“…In most cells, including oocytes, ROS are removed by a series of antioxidant enzymes (Devine et al, 2012). RNA-seq and real-time PCR showed that in Kat8…”

“…S5C). Continuous scavenging of ROS by antioxidant enzymes represents one cellular mechanism of defense against oxidative damage, which may compromise DNA integrity and cause oocyte apoptosis (Devine et al, 2012). Among the differently expressed genes after Kat8 deletion, the antioxidant genes peroxiredoxin 1 and 2 (Prdx1, Prdx2) and glutathione peroxidase 1 and 4 (Gpx1, Gpx4) were significantly downregulated in Kat8…”

Chemotherapy-induced ovarian toxicity in patients affected by endocrine-responsive early breast cancer

“…Oocytes/PMF In human fetal ovary exposed to CTX, apoptosis was shown before in oocytes (PMF), than GCs [121] CTX metabolites induce H2AX, a marker of double strand DNA breaks predominantly in mouse oocytes (but also in GCs) cultured in vitro [122] GCs In the GCs of rat ovaries CTX damage to mitochondria induce the release of the cytocrome C into cytoplasm leading to cell apoptosis mediated by caspase family proteins. Damage in human GCs nuclei and follicular basement membranes [32,33,[122][123][124][125][126][127][128][129] Oxidative stress has been associated with CTX toxicity in GCs of mature follicles. CTX induces depletion in glutathione and rise in reactive oxygen species mediating apoptosis in GCs Stromal cells/vessels…”

What lies behind chemotherapy-induced ovarian toxicity?

“…Treatment with cyclophosphamide results in a depletion of glutathione, a crucial cellular antioxidant, and a rise in reactive oxygen species that mediates apoptosis in granulosa cells (Tsai-Turton et al 2007, Devine et al 2012.…”