Glyoxalase Centennial: 100 Years of Glyoxalase Research and Emergence of Dicarbonyl Stress
Dicarbonyl stress and glyoxalases in ovarian function Carla Tatone*1 , Ursula Eichenlaub-Ritter† and Fernanda Amicarelli* *Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy †Faculty of Biology, Gene Technology Microbiology, University of Bielefeld, 33501 Bielefeld, Germany
Biochemical Society Transactions
www.biochemsoctrans.org
Abstract The ovary is the main regulator of female fertility. Changes in maternal health and physiology can disrupt intraovarian homoeostasis thereby compromising oocyte competence and fertility. Research has only recently devoted attention to the involvement of dicarbonyl stress in ovarian function. On this basis, the present review focuses on clinical and experimental research supporting the role of dicarbonyl overload and AGEs (advanced glycation end-products) as key contributors to perturbations of the ovarian microenvironment leading to lower fertility. Particular emphasis has been given to oocyte susceptibility to methylglyoxal, a powerful glycating agent, whose levels are known to increase during aging and metabolic disorders. According to the literature, the ovary and the oocyte itself can rely on the glyoxalase system to counteract the possible dicarbonyl overload such as that which may occur in reproductive-age women and patients with PCOS (polycystic ovarian syndrome) or diabetes. Overall, although biochemical methods for proper evaluation of dicarbonyl stress in oocytes and the ovarian microenvironment need to be established, AGEs can be proposed as predictive markers and/or therapeutic targets in new strategies for improving reproductive counselling and infertility therapies.
Introduction Although reproductive success is related to positive outcome of intrauterine fetal growth, it begins in the ovary with the production of a healthy euploid oocyte. The oocyte is a longlived cell marked by an extraordinary biological competence: upon fertilization, it completes DNA haploidization, reprogrammes the sperm chromatin into a functional pronucleus, gives rise to totipotency and activates the embryonic genome supporting basic processes in the early embryo [1]. Normal ovarian function is crucial to the ovulation of a competent oocyte and makes the ovary the main regulator of female fertility. Disruptions of intraovarian homoeostasis through changes in maternal health and physiology can compromise oocyte quality, leading to reduced fertility and epigenetic defects that affect the long-term health of the offspring [2]. Recently, much evidence has suggested that ovarian function and oocyte quality are influenced by toxic by-products of cellular metabolism that could accumulate in the ovary when imbalance of detoxifying activity occurs [3]. Although the implication of ROS (reactive oxygen species) in both ovarian physiology and ovarian dysfunctions is largely known [4], the interest in the possible role of so-called dicarbonyl stress has been growing for less than a decade. Dicarbonyl stress is a condition under which reactive carbonyls, low-molecularKey words: advanced glycation end-product (AGE), female fertility, oocyte aging, ovarian aging, oxidative stress, polycystic ovarian syndrome (PCOS). Abbreviations: AGE, advanced glycation end-product; CML, Nε -carboxymethyl-lysine; COC, cumulus oocyte complex; COL6A2, collagen type VI α2; ECM, extracellular matrix; FF, follicular fluid; Glo, glyoxalase; IVF, in vitro fertilization; MG, methylglyoxal; MII, metaphase II; PCOS, polycystic ovarian syndrome; RAGE, receptor for AGEs; sRAGE, soluble RAGE; TAGE, toxic AGE. 1 To whom correspondence should be addressed (email [email protected]).
Biochem. Soc. Trans. (2014) 42, 433–438; doi:10.1042/BST20140023
mass toxic by-products of cellular metabolism, in particular glycolysis, increase to levels perturbing molecular functions and cell metabolism [5]. By interacting with proteins, DNA and lipids, dicarbonyls generate AGEs (advanced glycation end-products), that with their prolonged half-life gradually accumulate contributing to the pathogenesis of diseases across different organ systems. The AGEs can be considered as both triggers and results of oxidative stress. By promoting the last step of advanced glycation, oxidative stress is a key factor in the production of AGEs which in turn activate signalling pathways potentiating spatiotemporal widespread oxidative stress [3]. Dicarbonyls include MG (methylglyoxal), a highly reactive α-oxoaldehyde deriving from spontaneous degradation of glycolytic intermediates and from other non-enzymatic and enzymatic pathways [6,7]. MG acts as a powerful glycating agent and exerts deleterious effects on mitochondrial respiration, proliferation, survival and redox balance [8]. Most endogenous MG is metabolized to innocuous products by Glo1 (glyoxalase I) that, working in tandem with Glo2 (glyoxalase II), ensures an enzymatic defence crucial to proteome protection against MG-mediated glycation [9]. Only recently have studies in humans and animal models provided evidence for correlation of dicarbonyl stress with ovarian dysfunction, i.e. ovarian aging and PCOS (polycystic ovarian syndrome) [10]. In this context, our purpose in the present review is to provide an overview of current literature that may be helpful to understand possible critical aspects and issues that would deserve attention in order to establish the relevance of dicarbonyl stress to female fertility. C The
C 2014 Biochemical Society Authors Journal compilation
433
434
Biochemical Society Transactions (2014) Volume 42, part 2
Ovarian function: a brief overview The mammalian ovary is endowed with a finite pool of follicles, highly specialized structures formed during fetal life or soon after birth in a few species. The single follicle is the fundamental unit of the ovary and is composed of an oocyte arrested at the diplotene stage of meiosis I surrounded by granulosa cells. During reproductive life, primordial follicles are periodically recruited into the growth phase under the influence of intraovarian factors. The majority of growing follicles are lost in atresia, and a small cohort of antral follicles is recruited for further growth, dominance and ovulation under the cyclic stimulation of gonadotropins. As a result, the oocyte/follicle pool declines exponentially with age, with a marked increase in the rate of disappearance from 37–38 years of age onwards. When the follicle pool reaches a critical size, cycles become irregular, ovulation arrests and menopause occurs [11]. These quantitative changes are associated with a reduced quality of oocytes reaching ovulation, a factor that represents an early marker of reproductive aging [12,13]. Behaving as post-mitotic cells that can be required to start growing after 10–50 years, primordial ovarian follicles are likely to be exposed to environmental factors related to aging of the ovarian somatic compartment. Primordial and primary follicles within the avascular ovarian cortex rely on passive diffusion of nutrients and growth factors from the surrounding stroma. In the secondary stage, theca cells are recruited from the surrounding stroma and participate in providing a vascular network to the growing follicle [14]. During the final stages of growth, the oocyte is surrounded by cumulus cells and is bathed by FF (follicular fluid) present in the pre-ovulatory follicle antrum delimitated by mural granulosa cells. Being both an exudate of plasma and a product of granulosa cells, FF composition may well reflect the metabolic status of a single follicle, the oocyte quality and the whole ovarian function [15]. Thus FF samples recovered from IVF (in vitro fertilization) patients represent an important source of molecules and follicle cells useful for the study of dicarbonyl stress in the human ovary.
Oocyte sensitivity to dicarbonyl stress Direct and indirect evidence support the hypothesis that the mammalian ovary experiences dicarbonyl stress during aging, diabetes and PCOS [3,16,17,18]. As a result, increased intraovarian levels of dicarbonyls might negatively affect oocyte competence during its prolonged stay in the ovary and especially during the final stage of oogenesis when the fully grown oocyte has to establish the molecular and energetic reserve to sustain resumption of meiosis, a process critical for the ovulation of an euploid oocyte [19,20]. Relevant to pre-ovulation events is the metabolic activity of the COC (cumulus oocyte complex), an intrafollicular niche where oocyte and cumulus cells act as a single metabolic unit [21]. Although glycolysis is active in the COC, the oocyte itself is unable to metabolize glucose and requires glycolysis in cumulus cells that then send pyruvate to the oocyte for C The
C 2014 Biochemical Society Authors Journal compilation
oxidative phosphorylation. On the other hand, glycolysis in cumulus cells is stimulated by the oocyte in the prematuration phase [22]. Since oocyte competence is highly influenced by glucose concentration inside the COC and FF [23], it is reasonable to speculate that glycolysis-derived MG passing from cumulus cells to the oocyte through gap junctions may pose a risk of dicarbonyl stress during prematuration events. In vivo and in vitro studies have shown that supraphysiological MG concentrations affect mouse oocyte maturation, fertilization and embryonic development [19,20]. The finding that Glo1 and Glo2 genes are expressed in both mouse cumulus cells and oocytes reveals the importance of anti-glycation defence in the production of a competent oocyte. The relevance of the glyoxalase system seems to decrease following maturation when reduced mRNA levels were observed. However, since Glo1 protein has been detected in mouse MII (metaphase II) oocytes by means of proteomic analysis [24], further investigation is needed to clarify changes in anti-glycation defence during oogenesis. MG is also found to cause oocyte apoptosis and DNA damage in the form of double-strand breaks that represent a high risk to genome integrity during oogenesis [20,25]. Moreover, the presence of abnormal chromatin condensation in maturing oocytes exposed to MG has suggested possible epigenetic effects. The influence of MG on meiotic maturation in vitro has been investigated in two different studies. According to these investigations, meiotic arrest and delay at meiosis I observed in MG-exposed oocytes result from anomalies in spindle formation and chromosome congression (Figure 1). Although there is no induction of aneuploidy, it can be proposed that the increased oocyte susceptibility to MG observed in aged oocytes may contribute to meiotic disturbances by acting synergistically with other aberrations [12,23]. Since disturbed spindle formation is an effect of altered ATP production [26], anomalies in meiosis may originate from the effects of MG on mitochondria functions. Consistent with MG action on the mitochondrial proteome [27], MG was found to strongly hamper mitochondrial physiology and intracellular distribution in the mouse oocyte. In accordance with MG perturbation of glutathione regeneration [28], the use of a mitochondrion-targeted redox-sensitive glutaredoxin 1– roGFP2 fusion probe has led us to establish that MG reduces the inner mitochondrial GSH/GSSG-dependent redox potential [20,29]. Interestingly, mitochondrial dysfunction and distribution, reduced ATP and abnormalities of the spindle and chromosome behaviour have been observed in oocytes from a diabetic mouse model [24,30]. Mitochondrial dysfunction could also contribute to the effects on the IVF rate and embryonic development in MG-exposed CEOs (cumulus-enclosed oocytes) as well as to abnormal fetal development observed in mice receiving MG in drinking water [19]. In conclusion, disturbed redox regulation, meiotic progression, DNA damage and epigenetic effects by MG may contribute to reduced oocyte competence when antiglycation defences are weakened or dicarbonyl production
Glyoxalase Centennial: 100 Years of Glyoxalase Research and Emergence of Dicarbonyl Stress
increases as may occur during reproductive aging and metabolic diseases such as diabetes and PCOS.
Protein glycation in physiological ovarian function In addition to protein cross-linking, AGEs can cause tissue injury by binding to multi-ligand transmembrane receptors, known as RAGE (receptor for AGEs) belonging to the immunoglobulin superfamily [31]. The interaction of AGEs with their receptors results in generation of oxidative stress and activation of redox-sensitive transcription factors such as NF-κB (nuclear factor κB) [32]. Malickov´a et al. [33] reported that the FF concentration of sRAGE (soluble RAGE), a circulating isoform of RAGE that can neutralize the ligandmediated damage [34], is severalfold higher compared with serum and other biological fluids. The authors also reported that serum sRAGE levels are negatively correlated with the yield of follicles and oocytes, together with the high follicular sRAGE levels in women with a positive IVF outcome. Bonetti et al. [35] reported that the FF sRAGE concentration being positively correlated to embryo quality in healthy women may represent a marker of oocyte competence useful in the selection of oocytes to be fertilized in order to improve reproductive outcome. Accordingly, a relevant study in a clinical setting reported that FF and serum concentrations of some AGEs, namely pentosidine, CML (Nε -carboxymethyllysine) and the so-called TAGE (toxic AGE) [36], correlated negatively with follicular growth, fertilization and embryonic development [37]. Overall, clinical studies addressing the question of whether concentrations of AGEs and sRAGE in FF may be related to the status of health of human oocytes deserve particular attention in future research.
Potential role of dicarbonyl stress and glyoxalases in ovarian aging According to a recent view of ovarian aging, decreased antioxidant and anti-glycation defences along with mitochondrial dysfunctions are supposed to generate a positivefeedback loop involving oxidative stress, dicarbonyl stress and accumulation of AGEs as causes of persistent molecular damage [3]. Correlation of AGEs with ovarian aging was first reported by the finding of increased levels of pentosidine in human primordial, primary and atretic follicles in premenopausal women [38]. Evidence obtained in the mouse model has led to the hypothesis that the reduced activity and expression of Glo1 observed in aged ovaries might be one of the causes for accumulation of the MG-derived AGE argpyrimidine [39], detected in some ovarian compartments using immunohistochemistry [18]. In the same study, it has been suggested that COL6A2 (collagen type VI α2) is an ovarian protein highly vulnerable to MG during ovarian aging. Subsequent loss of COL6A2 functional activity may induce permanent abnormalities in interfering with ECM (extracellular matrix) function during follicular development
and ovulation so perturbing ovarian function with aging [40]. According to this view, very recent data in human granulosa cells obtained from human FF suggest that long-lived ECM proteins such as fibronectin, rather than soluble AGEs, are more likely to be involved in decline of ovarian function with aging [41]. AGE-modified structural proteins may also account for vascular endothelium dysfunctions in the aged pre-ovulatory follicle with a consequent reduced intake of nutrients and hypoxia conditions known to endanger oocyte maturation and chromosomal constitution in the periovulatory period [42]. According to Stensen et al. [41], RAGE expression on granulosa cells appears to correlate with the chronological age of the patient, implying an up-regulation of the receptor by positive-feedback systems.
Potential role of dicarbonyl stress and glyoxalases in ovarian dysfunction associated with metabolic disorders In disorders with altered glucose metabolism, AGEs are accumulated in various tissues including the ovarian tissue, implicating their role in the pathogenesis of female reproductive abnormalities [10]. From 4 to 10 % of reproductiveage women are estimated to suffer from PCOS, a disease defined by high levels of androgen production, irregular ovulation and cysts in the ovaries associated in some cases with infertility, insulin-resistance and obesity [43]. Both serum and intraovarian AGE levels are considered to be factors contributing to PCOS pathogenesis: increased serum AGE levels are associated with insulin-resistance indices and androgen levels [44,45] and increased AGE localization in the form of CML has been detected in the PCOS ovarian tissue [17]. Intraovarian AGE deposition may account for some PCOS phenotypes, including endothelial dysfunction [46] and anovulation. Indeed, a causative link between AGE signalling and deposition of excess collagen in PCOS tissue has been established and taken as evidence of AGE implication in PCOS symptoms related to ECM perturbation [38]. An important role in the regulation of AGE accumulation in the ovary is played by Glo1: according to recent data in normal and hyperandrogenic rats, an animal PCOS model, the activity of this enzyme seems to be downregulated by a high-AGE diet and androgen levels and upregulated by oestrogen levels [47]. Further evidence for the role of AGEs as contributors to ovarian dysfunction is that serum levels of TAGE above 7.24 units/ml have been established as causing diminished fertility, and correlated positively with altered glucose metabolism, age and factors related to obesity, e.g. dyslipidaemia, hyperglycaemia and insulin resistance [37].
Final remarks The present review of mechanisms underlying glycation damage in the ovary provides a framework to properly C The
C 2014 Biochemical Society Authors Journal compilation
435
436
Biochemical Society Transactions (2014) Volume 42, part 2
Figure 1 Effects of MG on mouse oocytes Spindles in control and oocytes of MF1 mice exposed to 75 μM MG during meiotic maturation. (a) Representative sample of control possessing a normal bipolar MII spindle (green), well-aligned chromosomes (blue) and pericentrin-positive foci at centrosomes at the spindle poles (red, white arrows). (b) Bipolar spindle in MII oocyte with unaligned chromosomes and pericentrin at the spindle pole as well as at one aster at spindle periphery (arrow). Reproduced with permission from [20]: Tatone, C., Heizenrieder, T., Di Emidio, G., Treffon, P., Amicarelli, F., Seidel, T. and Eichenlaub-Ritter, U. (2011) Evidence that carbonyl stress by methylglyoxal exposure induces DNA damage and spindle aberrations, affects mitochondrial integrity in mammalian oocytes and contributes to oocyte ageing. Hum. Reprod. 26, 1843–1859.
Figure 2 Factors contributing to Glo1 down-regulation in ovarian aging and PCOS, as a main factor leading to the dicarbonyl stress that compromises ovarian function by targeting specific hotspots
approach the hypothesis of the involvement of carbonyl stress in ovarian dysfunctions. AGEs may be produced endogenously in the ovary as an effect of widespread spatiotemporal subtle oxidative injury that characterizes some ovarian disorders. In addition, intraovarian dicarbonyl overload may result from hyperglycaemia, insulin-resistance and down-regulation of Glo1 under the influence of oxidative stress or other signalling associated with ovarian hormones (Figure 2). Moreover, AGE deposition in the ovary may be ascribed to exogenous factors, such as tobacco smoking and diet [48,49]. As reported above, ovarian AGEs may interfere with physiological remodelling of ECM during folliculogenesis and endanger oocyte maturation, chromo C The
C 2014 Biochemical Society Authors Journal compilation
somal constitution and developmental capacity by affecting vascularization with consequent hypoxia and reduced intake of nutrients. In the last few years, the dicarbonyl stress theory of ovarian dysfunction has gained much attention by researchers and clinicians. Nevertheless, some concerns can be expressed in relation to the variety of AGEs taken into account in different studies and the methodologies employed to detect them. Immunohistochemistry and ELISA tests used to detect intraovarian AGEs should be validated by a quantitative approach based on LC–MS/MS [50]. This provides a reference methodology to which other methods, such as immunoassay, should be corroborated before the application of AGE measurement to clinical diagnostic use.
Glyoxalase Centennial: 100 Years of Glyoxalase Research and Emergence of Dicarbonyl Stress
Finally, a complete approach to the study of dicarbonyl stress in ovarian functions would require further research into the regulation of the glyoxalase system in oocytes and the follicular microenvironment.
Acknowledgement We thank A.M. D’Alessandro and Giovanna Di Emidio for their valuable contribution to the issues discussed and reviewed in the present article.
Funding This work has been supported by the Ministero dell’Universita` e della Ricera Scientifica (MIUR) (to C.T. and F.A.) and by the German Research Foundation (DFG) [grant number FOR 1041 (to U.E.-R.)].
References 1 Zuccotti, M., Redi, C.A. and Garagna, S. (2012) Study an egg today to make an embryo tomorrow. Int. J. Dev. Biol. 56, 761–764 2 Krisher, R. (2013) In vivo and in vitro environmental effects on mammalian oocyte quality. Annu. Rev. Anim. Biosci. 1, 393–417 3 Tatone, C. and Amicarelli, F. (2013) The aging ovary: the poor granulosa cells. Fertil. Steril. 99, 12–17 4 Agarwal, A., Aponte-Mellado, A., Premkumar, B.J., Shaman, A. and Gupta, S. (2012) The effects of oxidative stress on female reproduction: a review. Reprod. Biol. Endocrinol. 10, 49 5 Mano, J. (2012) Reactive carbonyl species: their production from lipid peroxides, action in environmental stress, and the detoxification mechanism. Plant Physiol. Biochem. 59, 90–97 6 Thornalley, P.J. (2005) Dicarbonyl intermediates in the Maillard reaction. Ann. N.Y. Acad. Sci. 1043, 111–117 7 Thornalley, P.J. (2008) Protein and nucleotide damage by glyoxal and methylglyoxal in physiological systems: role in ageing and disease. Drug Metabol. Drug Interact. 23, 125–150 8 Thornalley, P.J. (1996) Pharmacology of methylglyoxal: formation, modification of proteins and nucleic acids, and enzymatic detoxification – a role in pathogenesis and antiproliferative chemotherapy. Gen. Pharmacol. 27, 565–573 9 Rabbani, N. and Thornalley, P.J. (2012) Methylglyoxal, glyoxalase 1 and the dicarbonyl proteome. Amino Acids 42, 1133–1142 10 Merhi, Z. (2014) Advanced glycation end products and their relevance in female reproduction. Hum. Reprod. 29, 135–145 11 Faddy, M.J., Gosden, R.G., Gougeon, A., Richardson, S.J. and Nelson, J.F. (1992) Accelerated disappearance of ovarian follicles in mid-life: implications for forecasting menopause. Hum. Reprod. 7, 1342–1346 12 Eichenlaub-Ritter, U. (2012) Oocyte ageing and its cellular basis. Int. J. Dev. Biol. 56, 841–852 13 Tatone, C., Amicarelli, F., Carbone, M.C., Monteleone, P., Caserta, D., Marci, R., Artini, P.G., Piomboni, P. and Focarelli, R. (2008) Cellular and molecular aspects of ovarian follicle ageing. Hum. Reprod Update 14, 131–142 14 Young, J.M. and McNeilly, A.S. (2010) Theca: the forgotten cell of the ovarian follicle. Reproduction 140, 489–504 15 Hennet, M.L. and Combelles, C.M. (2012) The antral follicle: a microenvironment for oocyte differentiation. Int. J. Dev. Biol. 56, 819–831 16 Kilhovd, B.K., Giardino, I., Torjesen, P.A., Birkeland, K.I., Berg, T.J., Thornalley, P.J., Brownlee, M. and Hanssen, K.F. (2003) Increased serum levels of the specific AGE-compound methylglyoxal-derived hydroimidazolone in patients with type 2 diabetes. Metabolism 52, 163–167 17 Diamanti-Kandarakis, E., Piperi, C., Patsouris, E., Korkolopoulou, P., Panidis, D., Pawelczyk, L., Papavassiliou, A.G. and Duleba, A.J. (2007) Immunohistochemical localization of advanced glycation end-products (AGEs) and their receptor (RAGE) in polycystic and normal ovaries. Histochem. Cell Biol. 127, 581–589
18 Tatone, C., Carbone, M.C., Campanella, G., Festuccia, C., Artini, P.G., Talesa, V., Focarelli, R. and Amicarelli, F. (2010) Female reproductive dysfunction during ageing: role of methylglyoxal in the formation of advanced glycation endproducts in ovaries of reproductively-aged mice. J. Biol. Regul. Homeost. Agents 24, 63–72 19 Chang, Y.J. and Chan, W.H. (2010) Methylglyoxal has injurious effects on maturation of mouse oocytes, fertilization, and fetal development, via apoptosis. Toxicol. Lett. 193, 217–223 20 Tatone, C., Heizenrieder, T., Di Emidio, G., Treffon, P., Amicarelli, F., Seidel, T. and Eichenlaub-Ritter, U. (2011) Evidence that carbonyl stress by methylglyoxal exposure induces DNA damage and spindle aberrations, affects mitochondrial integrity in mammalian oocytes and contributes to oocyte ageing. Hum. Reprod. 26, 1843–1859 21 Gilchrist, R.B., Lane, M. and Thompson, J.G. (2008) Oocyte-secreted factors: regulators of cumulus cell function and oocyte quality. Hum. Reprod. Update 14, 159–177 22 Su, Y.Q., Sugiura, K. and Eppig, J.J. (2009) Mouse oocyte control of granulosa cell development and function: paracrine regulation of cumulus cell metabolism. Semin. Reprod. Med. 27, 32–42 23 Sutton-McDowall, M.L., Gilchrist, R.B. and Thompson, J.G. (2010) The pivotal role of glucose metabolism in determining oocyte developmental competence. Reproduction 139, 685–695 24 Wang, S., Kou, Z., Jing, Z., Zhang, Y., Guo, X., Dong, M., Wilmut, I. and Gao, S. (2010) Proteome of mouse oocytes at different developmental stages. Proc. Natl. Acad. Sci. U.S.A. 107, 17639–17644 25 Yang, F., Baumann, C. and De La Fuente, R. (2009) Persistence of histone H2AX phosphorylation after meiotic chromosome synapsis and abnormal centromere cohesion in poly (ADP-ribose) polymerase (Parp-1) null oocytes. Dev. Biol. 331, 326–338 26 Yu, Y., Dumollard, R., Rossbach, A., Lai, F.A. and Swann, K. (2010) Redistribution of mitochondria leads to bursts of ATP production during spontaneous mouse oocyte maturation. J. Cell. Physiol. 224, 672–680 27 Rabbani, N. and Thornalley, P.J. (2008) Dicarbonyls linked to damage in the powerhouse: glycation of mitochondrial proteins and oxidative stress. Biochem. Soc. Trans. 36, 1045–1050 28 Mannervik, B. (2008) Molecular enzymology of the glyoxalase system. Drug Metabol. Drug Interact. 23, 13–27 29 Eichenlaub-Ritter, U., Wieczorek, M., Luke, ¨ S. and Seidel, T. (2011) Age related changes in mitochondrial function and new approaches to study redox regulation in mammalian oocytes in response to age or maturation conditions. Mitochondrion 11, 783–796 30 Ratchford, A.M., Chang, A.S., Chi, M.M., Sheridan, R. and Moley, K.H. (2007) Maternal diabetes adversely affects AMP-activated protein kinase activity and cellular metabolism in murine oocytes. Am. J. Physiol. Endocrinol. Metab. 293, E1198–E1206 31 Schmidt, A.M., Yan, S.D., Yan, S.F. and Stern, D.M. (2000) The biology of the receptor for advanced glycation end products and its ligands. Biochim. Biophys. Acta 1498, 99–111 32 Wautier, M.P., Chappey, O., Corda, S., Stern, D.M., Schmidt, A.M. and Wautier, J.L. (2001) Activation of NADPH oxidase by AGE links oxidant stress to altered gene expression via RAGE. Am. J. Physiol. Endocrinol. Metab. 280, E685–E694 33 Malickova, ´ K., Jarosova, ´ R., Rezabek, ´ K., Fait, T., Masata, J., Janatkova, ´ I., Zima, T. and Kalousova, ´ M. (2010) Concentrations of sRAGE in serum and follicular fluid in assisted reproductive cycles: a preliminary study. Clin. Lab. 56, 377–384 34 Fujii, E.Y. and Nakayama, M. (2010) The measurements of RAGE, VEGF, and AGEs in the plasma and follicular fluid of reproductive women: the influence of aging. Fertil. Steril. 94, 694–700 35 Bonetti, T.C., Borges, Jr, E., Braga, D.P., Iaconelli, Jr, A., Kleine, J.P. and Silva, I.D. (2013) Intrafollicular soluble receptor for advanced glycation end products (sRAGE) and embryo quality in assisted reproduction. Reprod. Biomed. Online 26, 62–67 36 Sato, T., Iwaki, M., Shimogaito, N., Wu, X., Yamagishi, S. and Takeuchi, M. (2006) TAGE (toxic AGEs) theory in diabetic complications. Curr. Mol. Med. 6, 351–358 37 Jinno, M., Takeuchi, M., Watanabe, A., Teruya, K., Hirohama, J., Eguchi, N. and Miyazaki, A. (2011) Advanced glycation end-products accumulation compromises embryonic development and achievement of pregnancy by assisted reproductive technology. Hum. Reprod. 26, 604–610 38 Papachroni, K.K., Piperi, C., Levidou, G., Korkolopoulou, P., Pawelczyk, L., Diamanti-Kandarakis, E. and Papavassiliou, A.G. (2010) Lysyl oxidase interacts with AGE signalling to modulate collagen synthesis in polycystic ovarian tissue. J. Cell. Mol. Med. 14, 2460–2469 C The
C 2014 Biochemical Society Authors Journal compilation
437
438
Biochemical Society Transactions (2014) Volume 42, part 2
39 Shipanova, I.N., Glomb, M.A. and Nagaraj, R.H. (1997) Protein modification by methylglyoxal: chemical nature and synthetic mechanism of a major fluorescent adduct. Arch. Biochem. Biophys. 344, 29–36 40 Iwahashi, M., Muragaki, Y., Ooshima, A. and Nakano, R. (2000) Type VI collagen expression during growth of human ovarian follicles. Fertil. Steril. 74, 343–347 41 Stensen, M.H., Tanbo, T., Storeng, R. and Fedorcsak, P. (2014) Advanced glycation end products and their receptor contribute to ovarian ageing. Hum. Reprod. 29, 125–134 42 Yeh, J., Kim, B.S. and Peresie, J. (2008) Ovarian vascular endothelial growth factor and vascular endothelial growth factor receptor patterns in reproductive aging. Fertil. Steril. 89 (Suppl.), 1546–1556 43 Diamanti-Kandarakis, E. (2008) Polycystic ovarian syndrome: pathophysiology, molecular aspects and clinical implications. Expert Rev. Mol. Med. 10, e3 44 Kaya, C., Erkan, A.F., Cengiz, S.D., Dunder, ¨ I., Demirel, O.E. and Bilgihan, A. (2009) Advanced oxidation protein products are increased in women with polycystic ovary syndrome: relationship with traditional and nontraditional cardiovascular risk factors in patients with polycystic ovary syndrome. Fertil. Steril. 92, 1372–1377 45 Diamanti-Kandarakis, E., Piperi, C., Kalofoutis, A. and Creatsas, G. (2005) Increased levels of serum advanced glycation end-products in women with polycystic ovary syndrome. Clin. Endocrinol. 62, 37–43
C The
C 2014 Biochemical Society Authors Journal compilation
46 Christakou, C., Economou, F., Livadas, S., Piperi, C., Adamopoulos, C., Marinakis, E. and Diamanti-Kandarakis, E. (2011) Strong and positive association of endothelin-1 with AGEs in PCOS: a causal relationship or a bystander? Hormones 10, 292–297 47 Chatzigeorgiou, A., Kandaraki, E., Piperi, C., Livadas, S., Papavassiliou, A.G., Koutsilieris, M., Papalois, A. and Diamanti-Kandarakis, E. (2013) Dietary glycotoxins affect scavenger receptor expression and the hormonal profile of female rats. J. Endocrinol. 218, 331–337 48 Cerami, C., Founds, H., Nicholl, I., Mitsuhashi, T., Giordano, D., Vanpatten, S., Lee, A., Al-Abed, Y., Vlassara, H., Bucala, R. and Cerami, A. (1997) Tobacco smoke is a source of toxic reactive glycation products. Proc. Natl. Acad. Sci. U.S.A. 94, 13915–13920 49 Krajcovicova-Kudl ´ ackov ´ a, ´ M., Sebekova, ´ K., Schinzel, R. and Klvanova, ´ J. (2002) Advanced glycation end products and nutrition. Physiol. Res. 51, 313–316 50 Thornalley, P.J. and Rabbani, N. (2014) Detection of oxidized and glycated proteins in clinical samples using mass spectrometry: a user’s perspective. Biochim. Biophys. Acta 1840, 818–829
Received 14 February 2014 doi:10.1042/BST20140023
Dicarbonyl stress and glyoxalases in ovarian function Carla Tatone*1 , Ursula Eichenlaub-Ritter† and Fernanda Amicarelli* *Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy †Faculty of Biology, Gene Technology Microbiology, University of Bielefeld, 33501 Bielefeld, Germany
Biochemical Society Transactions
www.biochemsoctrans.org
Abstract The ovary is the main regulator of female fertility. Changes in maternal health and physiology can disrupt intraovarian homoeostasis thereby compromising oocyte competence and fertility. Research has only recently devoted attention to the involvement of dicarbonyl stress in ovarian function. On this basis, the present review focuses on clinical and experimental research supporting the role of dicarbonyl overload and AGEs (advanced glycation end-products) as key contributors to perturbations of the ovarian microenvironment leading to lower fertility. Particular emphasis has been given to oocyte susceptibility to methylglyoxal, a powerful glycating agent, whose levels are known to increase during aging and metabolic disorders. According to the literature, the ovary and the oocyte itself can rely on the glyoxalase system to counteract the possible dicarbonyl overload such as that which may occur in reproductive-age women and patients with PCOS (polycystic ovarian syndrome) or diabetes. Overall, although biochemical methods for proper evaluation of dicarbonyl stress in oocytes and the ovarian microenvironment need to be established, AGEs can be proposed as predictive markers and/or therapeutic targets in new strategies for improving reproductive counselling and infertility therapies.
Introduction Although reproductive success is related to positive outcome of intrauterine fetal growth, it begins in the ovary with the production of a healthy euploid oocyte. The oocyte is a longlived cell marked by an extraordinary biological competence: upon fertilization, it completes DNA haploidization, reprogrammes the sperm chromatin into a functional pronucleus, gives rise to totipotency and activates the embryonic genome supporting basic processes in the early embryo [1]. Normal ovarian function is crucial to the ovulation of a competent oocyte and makes the ovary the main regulator of female fertility. Disruptions of intraovarian homoeostasis through changes in maternal health and physiology can compromise oocyte quality, leading to reduced fertility and epigenetic defects that affect the long-term health of the offspring [2]. Recently, much evidence has suggested that ovarian function and oocyte quality are influenced by toxic by-products of cellular metabolism that could accumulate in the ovary when imbalance of detoxifying activity occurs [3]. Although the implication of ROS (reactive oxygen species) in both ovarian physiology and ovarian dysfunctions is largely known [4], the interest in the possible role of so-called dicarbonyl stress has been growing for less than a decade. Dicarbonyl stress is a condition under which reactive carbonyls, low-molecularKey words: advanced glycation end-product (AGE), female fertility, oocyte aging, ovarian aging, oxidative stress, polycystic ovarian syndrome (PCOS). Abbreviations: AGE, advanced glycation end-product; CML, Nε -carboxymethyl-lysine; COC, cumulus oocyte complex; COL6A2, collagen type VI α2; ECM, extracellular matrix; FF, follicular fluid; Glo, glyoxalase; IVF, in vitro fertilization; MG, methylglyoxal; MII, metaphase II; PCOS, polycystic ovarian syndrome; RAGE, receptor for AGEs; sRAGE, soluble RAGE; TAGE, toxic AGE. 1 To whom correspondence should be addressed (email [email protected]).
Biochem. Soc. Trans. (2014) 42, 433–438; doi:10.1042/BST20140023
mass toxic by-products of cellular metabolism, in particular glycolysis, increase to levels perturbing molecular functions and cell metabolism [5]. By interacting with proteins, DNA and lipids, dicarbonyls generate AGEs (advanced glycation end-products), that with their prolonged half-life gradually accumulate contributing to the pathogenesis of diseases across different organ systems. The AGEs can be considered as both triggers and results of oxidative stress. By promoting the last step of advanced glycation, oxidative stress is a key factor in the production of AGEs which in turn activate signalling pathways potentiating spatiotemporal widespread oxidative stress [3]. Dicarbonyls include MG (methylglyoxal), a highly reactive α-oxoaldehyde deriving from spontaneous degradation of glycolytic intermediates and from other non-enzymatic and enzymatic pathways [6,7]. MG acts as a powerful glycating agent and exerts deleterious effects on mitochondrial respiration, proliferation, survival and redox balance [8]. Most endogenous MG is metabolized to innocuous products by Glo1 (glyoxalase I) that, working in tandem with Glo2 (glyoxalase II), ensures an enzymatic defence crucial to proteome protection against MG-mediated glycation [9]. Only recently have studies in humans and animal models provided evidence for correlation of dicarbonyl stress with ovarian dysfunction, i.e. ovarian aging and PCOS (polycystic ovarian syndrome) [10]. In this context, our purpose in the present review is to provide an overview of current literature that may be helpful to understand possible critical aspects and issues that would deserve attention in order to establish the relevance of dicarbonyl stress to female fertility. C The
C 2014 Biochemical Society Authors Journal compilation
433
434
Biochemical Society Transactions (2014) Volume 42, part 2
Ovarian function: a brief overview The mammalian ovary is endowed with a finite pool of follicles, highly specialized structures formed during fetal life or soon after birth in a few species. The single follicle is the fundamental unit of the ovary and is composed of an oocyte arrested at the diplotene stage of meiosis I surrounded by granulosa cells. During reproductive life, primordial follicles are periodically recruited into the growth phase under the influence of intraovarian factors. The majority of growing follicles are lost in atresia, and a small cohort of antral follicles is recruited for further growth, dominance and ovulation under the cyclic stimulation of gonadotropins. As a result, the oocyte/follicle pool declines exponentially with age, with a marked increase in the rate of disappearance from 37–38 years of age onwards. When the follicle pool reaches a critical size, cycles become irregular, ovulation arrests and menopause occurs [11]. These quantitative changes are associated with a reduced quality of oocytes reaching ovulation, a factor that represents an early marker of reproductive aging [12,13]. Behaving as post-mitotic cells that can be required to start growing after 10–50 years, primordial ovarian follicles are likely to be exposed to environmental factors related to aging of the ovarian somatic compartment. Primordial and primary follicles within the avascular ovarian cortex rely on passive diffusion of nutrients and growth factors from the surrounding stroma. In the secondary stage, theca cells are recruited from the surrounding stroma and participate in providing a vascular network to the growing follicle [14]. During the final stages of growth, the oocyte is surrounded by cumulus cells and is bathed by FF (follicular fluid) present in the pre-ovulatory follicle antrum delimitated by mural granulosa cells. Being both an exudate of plasma and a product of granulosa cells, FF composition may well reflect the metabolic status of a single follicle, the oocyte quality and the whole ovarian function [15]. Thus FF samples recovered from IVF (in vitro fertilization) patients represent an important source of molecules and follicle cells useful for the study of dicarbonyl stress in the human ovary.
Oocyte sensitivity to dicarbonyl stress Direct and indirect evidence support the hypothesis that the mammalian ovary experiences dicarbonyl stress during aging, diabetes and PCOS [3,16,17,18]. As a result, increased intraovarian levels of dicarbonyls might negatively affect oocyte competence during its prolonged stay in the ovary and especially during the final stage of oogenesis when the fully grown oocyte has to establish the molecular and energetic reserve to sustain resumption of meiosis, a process critical for the ovulation of an euploid oocyte [19,20]. Relevant to pre-ovulation events is the metabolic activity of the COC (cumulus oocyte complex), an intrafollicular niche where oocyte and cumulus cells act as a single metabolic unit [21]. Although glycolysis is active in the COC, the oocyte itself is unable to metabolize glucose and requires glycolysis in cumulus cells that then send pyruvate to the oocyte for C The
C 2014 Biochemical Society Authors Journal compilation
oxidative phosphorylation. On the other hand, glycolysis in cumulus cells is stimulated by the oocyte in the prematuration phase [22]. Since oocyte competence is highly influenced by glucose concentration inside the COC and FF [23], it is reasonable to speculate that glycolysis-derived MG passing from cumulus cells to the oocyte through gap junctions may pose a risk of dicarbonyl stress during prematuration events. In vivo and in vitro studies have shown that supraphysiological MG concentrations affect mouse oocyte maturation, fertilization and embryonic development [19,20]. The finding that Glo1 and Glo2 genes are expressed in both mouse cumulus cells and oocytes reveals the importance of anti-glycation defence in the production of a competent oocyte. The relevance of the glyoxalase system seems to decrease following maturation when reduced mRNA levels were observed. However, since Glo1 protein has been detected in mouse MII (metaphase II) oocytes by means of proteomic analysis [24], further investigation is needed to clarify changes in anti-glycation defence during oogenesis. MG is also found to cause oocyte apoptosis and DNA damage in the form of double-strand breaks that represent a high risk to genome integrity during oogenesis [20,25]. Moreover, the presence of abnormal chromatin condensation in maturing oocytes exposed to MG has suggested possible epigenetic effects. The influence of MG on meiotic maturation in vitro has been investigated in two different studies. According to these investigations, meiotic arrest and delay at meiosis I observed in MG-exposed oocytes result from anomalies in spindle formation and chromosome congression (Figure 1). Although there is no induction of aneuploidy, it can be proposed that the increased oocyte susceptibility to MG observed in aged oocytes may contribute to meiotic disturbances by acting synergistically with other aberrations [12,23]. Since disturbed spindle formation is an effect of altered ATP production [26], anomalies in meiosis may originate from the effects of MG on mitochondria functions. Consistent with MG action on the mitochondrial proteome [27], MG was found to strongly hamper mitochondrial physiology and intracellular distribution in the mouse oocyte. In accordance with MG perturbation of glutathione regeneration [28], the use of a mitochondrion-targeted redox-sensitive glutaredoxin 1– roGFP2 fusion probe has led us to establish that MG reduces the inner mitochondrial GSH/GSSG-dependent redox potential [20,29]. Interestingly, mitochondrial dysfunction and distribution, reduced ATP and abnormalities of the spindle and chromosome behaviour have been observed in oocytes from a diabetic mouse model [24,30]. Mitochondrial dysfunction could also contribute to the effects on the IVF rate and embryonic development in MG-exposed CEOs (cumulus-enclosed oocytes) as well as to abnormal fetal development observed in mice receiving MG in drinking water [19]. In conclusion, disturbed redox regulation, meiotic progression, DNA damage and epigenetic effects by MG may contribute to reduced oocyte competence when antiglycation defences are weakened or dicarbonyl production
Glyoxalase Centennial: 100 Years of Glyoxalase Research and Emergence of Dicarbonyl Stress
increases as may occur during reproductive aging and metabolic diseases such as diabetes and PCOS.
Protein glycation in physiological ovarian function In addition to protein cross-linking, AGEs can cause tissue injury by binding to multi-ligand transmembrane receptors, known as RAGE (receptor for AGEs) belonging to the immunoglobulin superfamily [31]. The interaction of AGEs with their receptors results in generation of oxidative stress and activation of redox-sensitive transcription factors such as NF-κB (nuclear factor κB) [32]. Malickov´a et al. [33] reported that the FF concentration of sRAGE (soluble RAGE), a circulating isoform of RAGE that can neutralize the ligandmediated damage [34], is severalfold higher compared with serum and other biological fluids. The authors also reported that serum sRAGE levels are negatively correlated with the yield of follicles and oocytes, together with the high follicular sRAGE levels in women with a positive IVF outcome. Bonetti et al. [35] reported that the FF sRAGE concentration being positively correlated to embryo quality in healthy women may represent a marker of oocyte competence useful in the selection of oocytes to be fertilized in order to improve reproductive outcome. Accordingly, a relevant study in a clinical setting reported that FF and serum concentrations of some AGEs, namely pentosidine, CML (Nε -carboxymethyllysine) and the so-called TAGE (toxic AGE) [36], correlated negatively with follicular growth, fertilization and embryonic development [37]. Overall, clinical studies addressing the question of whether concentrations of AGEs and sRAGE in FF may be related to the status of health of human oocytes deserve particular attention in future research.
Potential role of dicarbonyl stress and glyoxalases in ovarian aging According to a recent view of ovarian aging, decreased antioxidant and anti-glycation defences along with mitochondrial dysfunctions are supposed to generate a positivefeedback loop involving oxidative stress, dicarbonyl stress and accumulation of AGEs as causes of persistent molecular damage [3]. Correlation of AGEs with ovarian aging was first reported by the finding of increased levels of pentosidine in human primordial, primary and atretic follicles in premenopausal women [38]. Evidence obtained in the mouse model has led to the hypothesis that the reduced activity and expression of Glo1 observed in aged ovaries might be one of the causes for accumulation of the MG-derived AGE argpyrimidine [39], detected in some ovarian compartments using immunohistochemistry [18]. In the same study, it has been suggested that COL6A2 (collagen type VI α2) is an ovarian protein highly vulnerable to MG during ovarian aging. Subsequent loss of COL6A2 functional activity may induce permanent abnormalities in interfering with ECM (extracellular matrix) function during follicular development
and ovulation so perturbing ovarian function with aging [40]. According to this view, very recent data in human granulosa cells obtained from human FF suggest that long-lived ECM proteins such as fibronectin, rather than soluble AGEs, are more likely to be involved in decline of ovarian function with aging [41]. AGE-modified structural proteins may also account for vascular endothelium dysfunctions in the aged pre-ovulatory follicle with a consequent reduced intake of nutrients and hypoxia conditions known to endanger oocyte maturation and chromosomal constitution in the periovulatory period [42]. According to Stensen et al. [41], RAGE expression on granulosa cells appears to correlate with the chronological age of the patient, implying an up-regulation of the receptor by positive-feedback systems.
Potential role of dicarbonyl stress and glyoxalases in ovarian dysfunction associated with metabolic disorders In disorders with altered glucose metabolism, AGEs are accumulated in various tissues including the ovarian tissue, implicating their role in the pathogenesis of female reproductive abnormalities [10]. From 4 to 10 % of reproductiveage women are estimated to suffer from PCOS, a disease defined by high levels of androgen production, irregular ovulation and cysts in the ovaries associated in some cases with infertility, insulin-resistance and obesity [43]. Both serum and intraovarian AGE levels are considered to be factors contributing to PCOS pathogenesis: increased serum AGE levels are associated with insulin-resistance indices and androgen levels [44,45] and increased AGE localization in the form of CML has been detected in the PCOS ovarian tissue [17]. Intraovarian AGE deposition may account for some PCOS phenotypes, including endothelial dysfunction [46] and anovulation. Indeed, a causative link between AGE signalling and deposition of excess collagen in PCOS tissue has been established and taken as evidence of AGE implication in PCOS symptoms related to ECM perturbation [38]. An important role in the regulation of AGE accumulation in the ovary is played by Glo1: according to recent data in normal and hyperandrogenic rats, an animal PCOS model, the activity of this enzyme seems to be downregulated by a high-AGE diet and androgen levels and upregulated by oestrogen levels [47]. Further evidence for the role of AGEs as contributors to ovarian dysfunction is that serum levels of TAGE above 7.24 units/ml have been established as causing diminished fertility, and correlated positively with altered glucose metabolism, age and factors related to obesity, e.g. dyslipidaemia, hyperglycaemia and insulin resistance [37].
Final remarks The present review of mechanisms underlying glycation damage in the ovary provides a framework to properly C The
C 2014 Biochemical Society Authors Journal compilation
435
436
Biochemical Society Transactions (2014) Volume 42, part 2
Figure 1 Effects of MG on mouse oocytes Spindles in control and oocytes of MF1 mice exposed to 75 μM MG during meiotic maturation. (a) Representative sample of control possessing a normal bipolar MII spindle (green), well-aligned chromosomes (blue) and pericentrin-positive foci at centrosomes at the spindle poles (red, white arrows). (b) Bipolar spindle in MII oocyte with unaligned chromosomes and pericentrin at the spindle pole as well as at one aster at spindle periphery (arrow). Reproduced with permission from [20]: Tatone, C., Heizenrieder, T., Di Emidio, G., Treffon, P., Amicarelli, F., Seidel, T. and Eichenlaub-Ritter, U. (2011) Evidence that carbonyl stress by methylglyoxal exposure induces DNA damage and spindle aberrations, affects mitochondrial integrity in mammalian oocytes and contributes to oocyte ageing. Hum. Reprod. 26, 1843–1859.
Figure 2 Factors contributing to Glo1 down-regulation in ovarian aging and PCOS, as a main factor leading to the dicarbonyl stress that compromises ovarian function by targeting specific hotspots
approach the hypothesis of the involvement of carbonyl stress in ovarian dysfunctions. AGEs may be produced endogenously in the ovary as an effect of widespread spatiotemporal subtle oxidative injury that characterizes some ovarian disorders. In addition, intraovarian dicarbonyl overload may result from hyperglycaemia, insulin-resistance and down-regulation of Glo1 under the influence of oxidative stress or other signalling associated with ovarian hormones (Figure 2). Moreover, AGE deposition in the ovary may be ascribed to exogenous factors, such as tobacco smoking and diet [48,49]. As reported above, ovarian AGEs may interfere with physiological remodelling of ECM during folliculogenesis and endanger oocyte maturation, chromo C The
C 2014 Biochemical Society Authors Journal compilation
somal constitution and developmental capacity by affecting vascularization with consequent hypoxia and reduced intake of nutrients. In the last few years, the dicarbonyl stress theory of ovarian dysfunction has gained much attention by researchers and clinicians. Nevertheless, some concerns can be expressed in relation to the variety of AGEs taken into account in different studies and the methodologies employed to detect them. Immunohistochemistry and ELISA tests used to detect intraovarian AGEs should be validated by a quantitative approach based on LC–MS/MS [50]. This provides a reference methodology to which other methods, such as immunoassay, should be corroborated before the application of AGE measurement to clinical diagnostic use.
Glyoxalase Centennial: 100 Years of Glyoxalase Research and Emergence of Dicarbonyl Stress
Finally, a complete approach to the study of dicarbonyl stress in ovarian functions would require further research into the regulation of the glyoxalase system in oocytes and the follicular microenvironment.
Acknowledgement We thank A.M. D’Alessandro and Giovanna Di Emidio for their valuable contribution to the issues discussed and reviewed in the present article.
Funding This work has been supported by the Ministero dell’Universita` e della Ricera Scientifica (MIUR) (to C.T. and F.A.) and by the German Research Foundation (DFG) [grant number FOR 1041 (to U.E.-R.)].
References 1 Zuccotti, M., Redi, C.A. and Garagna, S. (2012) Study an egg today to make an embryo tomorrow. Int. J. Dev. Biol. 56, 761–764 2 Krisher, R. (2013) In vivo and in vitro environmental effects on mammalian oocyte quality. Annu. Rev. Anim. Biosci. 1, 393–417 3 Tatone, C. and Amicarelli, F. (2013) The aging ovary: the poor granulosa cells. Fertil. Steril. 99, 12–17 4 Agarwal, A., Aponte-Mellado, A., Premkumar, B.J., Shaman, A. and Gupta, S. (2012) The effects of oxidative stress on female reproduction: a review. Reprod. Biol. Endocrinol. 10, 49 5 Mano, J. (2012) Reactive carbonyl species: their production from lipid peroxides, action in environmental stress, and the detoxification mechanism. Plant Physiol. Biochem. 59, 90–97 6 Thornalley, P.J. (2005) Dicarbonyl intermediates in the Maillard reaction. Ann. N.Y. Acad. Sci. 1043, 111–117 7 Thornalley, P.J. (2008) Protein and nucleotide damage by glyoxal and methylglyoxal in physiological systems: role in ageing and disease. Drug Metabol. Drug Interact. 23, 125–150 8 Thornalley, P.J. (1996) Pharmacology of methylglyoxal: formation, modification of proteins and nucleic acids, and enzymatic detoxification – a role in pathogenesis and antiproliferative chemotherapy. Gen. Pharmacol. 27, 565–573 9 Rabbani, N. and Thornalley, P.J. (2012) Methylglyoxal, glyoxalase 1 and the dicarbonyl proteome. Amino Acids 42, 1133–1142 10 Merhi, Z. (2014) Advanced glycation end products and their relevance in female reproduction. Hum. Reprod. 29, 135–145 11 Faddy, M.J., Gosden, R.G., Gougeon, A., Richardson, S.J. and Nelson, J.F. (1992) Accelerated disappearance of ovarian follicles in mid-life: implications for forecasting menopause. Hum. Reprod. 7, 1342–1346 12 Eichenlaub-Ritter, U. (2012) Oocyte ageing and its cellular basis. Int. J. Dev. Biol. 56, 841–852 13 Tatone, C., Amicarelli, F., Carbone, M.C., Monteleone, P., Caserta, D., Marci, R., Artini, P.G., Piomboni, P. and Focarelli, R. (2008) Cellular and molecular aspects of ovarian follicle ageing. Hum. Reprod Update 14, 131–142 14 Young, J.M. and McNeilly, A.S. (2010) Theca: the forgotten cell of the ovarian follicle. Reproduction 140, 489–504 15 Hennet, M.L. and Combelles, C.M. (2012) The antral follicle: a microenvironment for oocyte differentiation. Int. J. Dev. Biol. 56, 819–831 16 Kilhovd, B.K., Giardino, I., Torjesen, P.A., Birkeland, K.I., Berg, T.J., Thornalley, P.J., Brownlee, M. and Hanssen, K.F. (2003) Increased serum levels of the specific AGE-compound methylglyoxal-derived hydroimidazolone in patients with type 2 diabetes. Metabolism 52, 163–167 17 Diamanti-Kandarakis, E., Piperi, C., Patsouris, E., Korkolopoulou, P., Panidis, D., Pawelczyk, L., Papavassiliou, A.G. and Duleba, A.J. (2007) Immunohistochemical localization of advanced glycation end-products (AGEs) and their receptor (RAGE) in polycystic and normal ovaries. Histochem. Cell Biol. 127, 581–589
18 Tatone, C., Carbone, M.C., Campanella, G., Festuccia, C., Artini, P.G., Talesa, V., Focarelli, R. and Amicarelli, F. (2010) Female reproductive dysfunction during ageing: role of methylglyoxal in the formation of advanced glycation endproducts in ovaries of reproductively-aged mice. J. Biol. Regul. Homeost. Agents 24, 63–72 19 Chang, Y.J. and Chan, W.H. (2010) Methylglyoxal has injurious effects on maturation of mouse oocytes, fertilization, and fetal development, via apoptosis. Toxicol. Lett. 193, 217–223 20 Tatone, C., Heizenrieder, T., Di Emidio, G., Treffon, P., Amicarelli, F., Seidel, T. and Eichenlaub-Ritter, U. (2011) Evidence that carbonyl stress by methylglyoxal exposure induces DNA damage and spindle aberrations, affects mitochondrial integrity in mammalian oocytes and contributes to oocyte ageing. Hum. Reprod. 26, 1843–1859 21 Gilchrist, R.B., Lane, M. and Thompson, J.G. (2008) Oocyte-secreted factors: regulators of cumulus cell function and oocyte quality. Hum. Reprod. Update 14, 159–177 22 Su, Y.Q., Sugiura, K. and Eppig, J.J. (2009) Mouse oocyte control of granulosa cell development and function: paracrine regulation of cumulus cell metabolism. Semin. Reprod. Med. 27, 32–42 23 Sutton-McDowall, M.L., Gilchrist, R.B. and Thompson, J.G. (2010) The pivotal role of glucose metabolism in determining oocyte developmental competence. Reproduction 139, 685–695 24 Wang, S., Kou, Z., Jing, Z., Zhang, Y., Guo, X., Dong, M., Wilmut, I. and Gao, S. (2010) Proteome of mouse oocytes at different developmental stages. Proc. Natl. Acad. Sci. U.S.A. 107, 17639–17644 25 Yang, F., Baumann, C. and De La Fuente, R. (2009) Persistence of histone H2AX phosphorylation after meiotic chromosome synapsis and abnormal centromere cohesion in poly (ADP-ribose) polymerase (Parp-1) null oocytes. Dev. Biol. 331, 326–338 26 Yu, Y., Dumollard, R., Rossbach, A., Lai, F.A. and Swann, K. (2010) Redistribution of mitochondria leads to bursts of ATP production during spontaneous mouse oocyte maturation. J. Cell. Physiol. 224, 672–680 27 Rabbani, N. and Thornalley, P.J. (2008) Dicarbonyls linked to damage in the powerhouse: glycation of mitochondrial proteins and oxidative stress. Biochem. Soc. Trans. 36, 1045–1050 28 Mannervik, B. (2008) Molecular enzymology of the glyoxalase system. Drug Metabol. Drug Interact. 23, 13–27 29 Eichenlaub-Ritter, U., Wieczorek, M., Luke, ¨ S. and Seidel, T. (2011) Age related changes in mitochondrial function and new approaches to study redox regulation in mammalian oocytes in response to age or maturation conditions. Mitochondrion 11, 783–796 30 Ratchford, A.M., Chang, A.S., Chi, M.M., Sheridan, R. and Moley, K.H. (2007) Maternal diabetes adversely affects AMP-activated protein kinase activity and cellular metabolism in murine oocytes. Am. J. Physiol. Endocrinol. Metab. 293, E1198–E1206 31 Schmidt, A.M., Yan, S.D., Yan, S.F. and Stern, D.M. (2000) The biology of the receptor for advanced glycation end products and its ligands. Biochim. Biophys. Acta 1498, 99–111 32 Wautier, M.P., Chappey, O., Corda, S., Stern, D.M., Schmidt, A.M. and Wautier, J.L. (2001) Activation of NADPH oxidase by AGE links oxidant stress to altered gene expression via RAGE. Am. J. Physiol. Endocrinol. Metab. 280, E685–E694 33 Malickova, ´ K., Jarosova, ´ R., Rezabek, ´ K., Fait, T., Masata, J., Janatkova, ´ I., Zima, T. and Kalousova, ´ M. (2010) Concentrations of sRAGE in serum and follicular fluid in assisted reproductive cycles: a preliminary study. Clin. Lab. 56, 377–384 34 Fujii, E.Y. and Nakayama, M. (2010) The measurements of RAGE, VEGF, and AGEs in the plasma and follicular fluid of reproductive women: the influence of aging. Fertil. Steril. 94, 694–700 35 Bonetti, T.C., Borges, Jr, E., Braga, D.P., Iaconelli, Jr, A., Kleine, J.P. and Silva, I.D. (2013) Intrafollicular soluble receptor for advanced glycation end products (sRAGE) and embryo quality in assisted reproduction. Reprod. Biomed. Online 26, 62–67 36 Sato, T., Iwaki, M., Shimogaito, N., Wu, X., Yamagishi, S. and Takeuchi, M. (2006) TAGE (toxic AGEs) theory in diabetic complications. Curr. Mol. Med. 6, 351–358 37 Jinno, M., Takeuchi, M., Watanabe, A., Teruya, K., Hirohama, J., Eguchi, N. and Miyazaki, A. (2011) Advanced glycation end-products accumulation compromises embryonic development and achievement of pregnancy by assisted reproductive technology. Hum. Reprod. 26, 604–610 38 Papachroni, K.K., Piperi, C., Levidou, G., Korkolopoulou, P., Pawelczyk, L., Diamanti-Kandarakis, E. and Papavassiliou, A.G. (2010) Lysyl oxidase interacts with AGE signalling to modulate collagen synthesis in polycystic ovarian tissue. J. Cell. Mol. Med. 14, 2460–2469 C The
C 2014 Biochemical Society Authors Journal compilation
437
438
Biochemical Society Transactions (2014) Volume 42, part 2
39 Shipanova, I.N., Glomb, M.A. and Nagaraj, R.H. (1997) Protein modification by methylglyoxal: chemical nature and synthetic mechanism of a major fluorescent adduct. Arch. Biochem. Biophys. 344, 29–36 40 Iwahashi, M., Muragaki, Y., Ooshima, A. and Nakano, R. (2000) Type VI collagen expression during growth of human ovarian follicles. Fertil. Steril. 74, 343–347 41 Stensen, M.H., Tanbo, T., Storeng, R. and Fedorcsak, P. (2014) Advanced glycation end products and their receptor contribute to ovarian ageing. Hum. Reprod. 29, 125–134 42 Yeh, J., Kim, B.S. and Peresie, J. (2008) Ovarian vascular endothelial growth factor and vascular endothelial growth factor receptor patterns in reproductive aging. Fertil. Steril. 89 (Suppl.), 1546–1556 43 Diamanti-Kandarakis, E. (2008) Polycystic ovarian syndrome: pathophysiology, molecular aspects and clinical implications. Expert Rev. Mol. Med. 10, e3 44 Kaya, C., Erkan, A.F., Cengiz, S.D., Dunder, ¨ I., Demirel, O.E. and Bilgihan, A. (2009) Advanced oxidation protein products are increased in women with polycystic ovary syndrome: relationship with traditional and nontraditional cardiovascular risk factors in patients with polycystic ovary syndrome. Fertil. Steril. 92, 1372–1377 45 Diamanti-Kandarakis, E., Piperi, C., Kalofoutis, A. and Creatsas, G. (2005) Increased levels of serum advanced glycation end-products in women with polycystic ovary syndrome. Clin. Endocrinol. 62, 37–43
C The
C 2014 Biochemical Society Authors Journal compilation
46 Christakou, C., Economou, F., Livadas, S., Piperi, C., Adamopoulos, C., Marinakis, E. and Diamanti-Kandarakis, E. (2011) Strong and positive association of endothelin-1 with AGEs in PCOS: a causal relationship or a bystander? Hormones 10, 292–297 47 Chatzigeorgiou, A., Kandaraki, E., Piperi, C., Livadas, S., Papavassiliou, A.G., Koutsilieris, M., Papalois, A. and Diamanti-Kandarakis, E. (2013) Dietary glycotoxins affect scavenger receptor expression and the hormonal profile of female rats. J. Endocrinol. 218, 331–337 48 Cerami, C., Founds, H., Nicholl, I., Mitsuhashi, T., Giordano, D., Vanpatten, S., Lee, A., Al-Abed, Y., Vlassara, H., Bucala, R. and Cerami, A. (1997) Tobacco smoke is a source of toxic reactive glycation products. Proc. Natl. Acad. Sci. U.S.A. 94, 13915–13920 49 Krajcovicova-Kudl ´ ackov ´ a, ´ M., Sebekova, ´ K., Schinzel, R. and Klvanova, ´ J. (2002) Advanced glycation end products and nutrition. Physiol. Res. 51, 313–316 50 Thornalley, P.J. and Rabbani, N. (2014) Detection of oxidized and glycated proteins in clinical samples using mass spectrometry: a user’s perspective. Biochim. Biophys. Acta 1840, 818–829
Received 14 February 2014 doi:10.1042/BST20140023
