Effects of dietary AGE (Advanced Glycation End product) on ovarian microenvironment and oocyte quality

Study question:Does the ovary activate an effective adaptive response to counteract the toxicity derived from dietary AGEs?Summary answer:The ovary activates an adaptive response, which counter- acts AGE accumulation but does not prevent toxic effects of dietary AGE on growing follicles and mature gamete.What is known already: The levels of advanced glycation end products (AGEs) are increased during aging and under conditions of impaired glucose meta- bolism and/or oxidative stress (OS), promoting insulin resistance and other endo- crine abnormalities. AGE deposition may be also ascribed to exogenous factors, such as tobacco smoking and diet. In the ovary, AGE formation has been associated to reproductive aging and polycystic ovarian syndrome (PCOS). In vitro exposure to methylglyoxal (MG), the main precursor of AGE, severely affects oocyte matur- ation, whereas in vivo ovarian and oocyte toxicity of MG is still unknown. Study design, size, duration:To study the effects of dietary AGE (dAGE), 4-week-aged female CD1 mice received water (n = 9) or 100 mg/kg MG (n = 9) by gastric administration for 28 days. This treatment induces increased serum MG levels (Ghosh et al., 2006). Six mice per group were sacrificed 48-h after the last administration and ovaries were collected for further analysis. Three mice were sacrificed 15-h after induction of superovulation by PMSG-hCG protocol and MII oocytes were isolated from ampullae. Main results and the role of chance: Analysis of follicle population revealed a reduced number of primary and secondary follicles in dAGE group. Biochemical investigation demonstrated similar levels of ovarian MG-AGEs in the two groups. Nevertheless dAGE ovaries displayed an increase of SIRT1, an OS sensor, together with up-expression of CAT and SOD2. Expression of the mitochondrial sirtuin SIRT3 and PGC1α, the main regulator of mitochondrial biogenesis, was also increased. Finally, enhanced protein expression of GLO1, the main ovarian AGE detoxifying enzyme, was observed in dAGE group. Although similar ovulation rate were recorded in control and dAGE mice, spin- dle analysis showed that dAGE oocytes exhibited abnormal spindle size resem- bling those previously found in low quality oocytes (Sanfins et al, 2003).Wider implications of the findings: Present results suggest that AGE intake induces ovarian oxidative stress and triggers an adaptive response, which pre- vents ovarian AGE accumulation. Nevertheless, dAGE leads to loss of growing follicles and production of low quality oocytes. These results contribute to the knowledge of mechanisms underlying the reduced fertility in PCOS and diabetes.