The effects of a possible dicarbonyl overload with PCOS
The effects of a possible dicarbonyl overload with PCOS, aging or diabetes have been explored in mouse oocytes by means of MG cytotoxicity assays [, , ]. In vivo and in vitro experiments have shown that MG induced a significant reduction in the rate of oocyte maturation, fertilization, and embryonic development. MG was found to cause disturbances in redox regulation and distribution of mitochondria, aberrant and delayed spindle formation, epigenetic alterations and DNA damage which probably explain resorption of post-implantation embryos and decreased foetal weight observed after embryo transfer [, , ]. Nevertheless, the expression of glyoxalases in mouse oocytes and cumulus Talaporfin sodium (ME2906) suggests that female germ cells are competent to deal with reactive carbonyl compounds .
Overall, the effects of dicarbonyl stress in the female reproductive system have been well characterized [19,20]. Nevertheless, the adaptive response orchestrated at molecular level to cope with glycation injury in female reproductive cells and ovaries has been poorly investigated. Glycation-related oxidative challenge may result in altered activity of sirtuins, NAD+-dependent enzymes with deacetylase and/or mono-ADP-ribosyltransferase activity [21,22]. SIRT1, one of the seven members of the mammalian sirtuin family, plays a key role during different stages of folliculogenesis by regulating energy homoeostasis, mitochondrial biogenesis, chromatin remodelling and protection against oxidative stress [23,24]. The SIRT1 network includes transcription factors, which control genes encoding for antioxidant enzymes such as catalase (CAT) and mitochondrial superoxide dismutase (SOD2), and genes required to meet energetic demands during cellular stresses . Indeed a key SIRT1 substrate is PGC1α (peroxisome proliferator-activated receptor gamma co-activator 1 alpha), which is known to act as a master regulator of mitochondrial biogenesis and functions [26,27]. A downstream effector of SIRT1/PGC1α is the mitochondrial transcription factor A (mtTFA), which plays a central role in transcription, replication and maintenance of mtDNA [28,29]. The SIRT1 functional network also includes the mitochondrial sirtuin, SIRT3 . This sirtuin deacetylates a range of mitochondrial target enzymes, including SOD2 and components of oxidative phosphorylation system thus improving the efficacy of reactive oxygen species (ROS) removal from the mitochondrial compartment and energy production . Evidence of beneficial effects of resveratrol, a SIRT1 activator, have suggested that this sirtuin may be involved in defence against in vitro oocyte MG toxicity as well as in attenuating PCOS development and progression [18,32].
In the present study, we investigated the adaptive response to glycation insult in female reproductive cells and ovaries by focusing on SIRT1 network. In the first part we investigated whether modulation of SIRT1 activity influences the effects MG on glyoxalases expression and in vitro maturation (IVM) of mouse oocytes (Fig. 1a). In the second part, we aimed to study the in vivo effects of supraphysiological MG on the ovary and ovarian SIRT1 network as well as on the production of competent gametes (Fig. 1b). To this end we selected the regimen of MG oral administration in mice previously established by Ghosh et al. . According to this model, blood MG concentrations rapidly increased to reach a five-fold increase to remain stable during the 28 day-MG-administration so ensuring a MG overload during the overall follicle growth time of about 17–19 days in the ovary of mature mice .
Materials and methods
Discussion Recently, it has emerged that overload of reactive dicarbonyl compounds and AGEs are key factors in ovarian dysfunctions and reduced fertility associated with aging, PCOS and oxidative stress [10,, , , ]. Consumption of glycotoxins contained in thermally processed foods and various beverages and foodstuffs typical of a Western diet contribute to increase AGE-related dysfunctions [, , ]. In search for mechanisms underlying an efficient scavenging of MG and AGEs at ovarian level, the present study provides evidence for the involvement of SIRT1 in the antiglycation response orchestrated by female germ cells and ovary.