The roles of cellular reactive oxygen species, oxidative stress and antioxidants in pregnancy outcomes

The International Journal of Biochemistry & Cell Biology 42 (2010) 1634–1650

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The International Journal of Biochemistry & Cell Biology journal homepage: www.elsevier.com/locate/biocel

Review

The roles of cellular reactive oxygen species, oxidative stress and antioxidants in pregnancy outcomes Kaïs H. Al-Gubory a,∗ , Paul A. Fowler b , Catherine Garrel c a Institut National de la Recherche Agronomique, UMR 1198 Biologie du Développement et Reproduction, Département de Physiologie Animale et Systèmes d’Elevage, F-78350 Jouy-en-Josas, France b Institute of Medical Sciences, Centre for Reproductive Endocrinology & Medicine, Division of Applied Medicine, University of Aberdeen, Foresterhil, Aberdeen AB25 2ZD, UK c Centre Hospitalier Universitaire de Grenoble, Unité de Biochimie Hormonale et Nutritionnelle, Département de Biologie - Toxicologie - pharmacologie, 38043 Grenoble Cedex 9, France

a r t i c l e

i n f o

Article history: Received 23 February 2010 Received in revised form 13 May 2010 Accepted 1 June 2010 Available online 19 June 2010 Keywords: Reactive oxygen species Oxidative stress Antioxidant enzymes Dietary antioxidants Reproduction Pregnancy outcomes

a b s t r a c t Reactive oxygen species (ROS) are generated as by-products of aerobic respiration and metabolism. Mammalian cells have evolved a variety of enzymatic mechanisms to control ROS production, one of the central elements in signal transduction pathways involved in cell proliferation, differentiation and apoptosis. Antioxidants also ensure defenses against ROS-induced damage to lipids, proteins and DNA. ROS and antioxidants have been implicated in the regulation of reproductive processes in both animal and human, such as cyclic luteal and endometrial changes, follicular development, ovulation, fertilization, embryogenesis, embryonic implantation, and placental differentiation and growth. In contrast, imbalances between ROS production and antioxidant systems induce oxidative stress that negatively impacts reproductive processes. High levels of ROS during embryonic, fetal and placental development are a feature of pregnancy. Consequently, oxidative stress has emerged as a likely promoter of several pregnancy-related disorders, such as spontaneous abortions, embryopathies, preeclampsia, fetal growth restriction, preterm labor and low birth weight. Nutritional and environmental factors may contribute to such adverse pregnancy outcomes and increase the susceptibility of offspring to disease. This occurs, at least in part, via impairment of the antioxidant defense systems and enhancement of ROS generation which alters cellular signalling and/or damage cellular macromolecules. The links between oxidative stress, the female reproductive system and development of adverse pregnancy outcomes, constitute important issues in human and animal reproductive medicine. This review summarizes the role of ROS in female reproductive processes and the state of knowledge on the association between ROS, oxidative stress, antioxidants and pregnancy outcomes in different mammalian species. © 2010 Elsevier Ltd. All rights reserved.

Contents 1. 2. 3. 4.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1635 Reactive oxygen species . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1636 Cellular sources of reactive oxygen species . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1637 Physiological role of reactive oxygen species . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1637 4.1. Role of reactive oxygen species in developmental processes and cell survival . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1637 4.2. Role of reactive oxygen species in programmed cell death . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1637

Abbreviations: ROS, reactive oxygen species; O2 , molecular oxygen; 1 O2 , singlet oxygen; • O2 − , superoxide anion; H2 O2 , hydrogen peroxide; H2 O, water; • OH, hydroxyl radical; ONOO− , peroxynitrite; NO, nitric oxide; NOS, nitric oxide synthase; ROOH, peroxy radical; ROH, alcohol, reduced flavin adenine dinucleotide (FADH2 ); ATP, adenosine triphosphate; G6P, glucose-6-phosphate; HMP, hexose monophosphate; G6PD, glucose-6-phosphate dehydrogenase; ICDH, isocitrate dehydrogenase; NADPH/NADP, reduced/oxidized nicotinamide adenine dinucleotide phosphate; OXPHOS, oxidative phosphorylation; MtDNA, mitochondrial DNA; PUFA, polyunsaturated fatty acids; LPO, lipid peroxides; Cu,Zn-SOD or SOD1, copper–zinc superoxide dismutase; Mn-SOD or SOD2, manganese superoxide dismutase; GPX, glutathione peroxidase; CAT, catalase; GSR, glutathione reductase; GST, glutathione S-transferases; GSH/GSSG, reduced/oxidized glutathione; Zn, zinc; Cu, copper; Mn, manganese; Se, selenium; IUGR, intra-uterine growth restriction; HIFs, Hypoxia-inducible factors; (PGC)-1␣, Peroxisome proliferator-activated receptor-␥ coactivator; VHL, Von Hipple-Lindau protein; NRF-1, nuclear respiratory factor 1; NF-␬B, Nuclear factor kappa B; AP1, activator protein-1; Apaf-1, apoptosis protease-activating factor-1; TNF, tumor necrosis factor; FasL, Fas ligand; Bcl-2, B-cell lymphoma 2; BAX, BCL-2-associated X protein. ∗ Corresponding author. Tel.: +33 1 34652362; fax: +33 1 34652364. E-mail address: [email protected] (K.H. Al-Gubory). 1357-2725/$ – see front matter © 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.biocel.2010.06.001

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5.

Antioxidant control of reactive oxygen species production . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1639 5.1. Enzymatic antioxidant systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1639 5.2. Non-enzymatic antioxidant systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1639 5.2.1. Vitamins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1639 5.2.2. Trace elements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1640 5.2.3. Polyphenols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1640 6. Antioxidant systems, establishment and outcome of pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1640 6.1. Antioxidant systems and corpus luteum rescue . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1641 6.1.1. Role of enzymatic antioxidants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1641 6.1.2. Role of non-enzymatic antioxidants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1642 6.2. Antioxidative systems and peri-implantation development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1642 6.3. Antioxidative systems and post-implantation aerobic metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1642 6.4. Antioxidant systems and placental development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1642 7. Antioxidant maternal nutrition and pregnancy outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1643 8. Antioxidant-rich phytonutrients and pregnancy outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1643 9. Oxidative stress and adverse pregnancy outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1643 10. Nutritional and environmental adverse pregnancy outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1644 10.1. Poor dietary nutritional factors and adverse pregnancy outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1644 10.2. Environmental pollutants and adverse pregnancy outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1645 11. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1645 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1645

1. Introduction Cellular reactive oxygen species (ROS) and their control by antioxidants are involved in the physiology of the female reproductive system. Physiological levels of ROS play an important regulatory role through various signalling transduction pathways in folliculogenesis, oocyte maturation, corpus luteum and uterine function, embryogenesis, embryonic implantation and fetoplacental development (Agarwal et al., 2008). Imbalances between antioxidants and ROS production (oxidative stress) is considered to be responsible for the initiation or development of pathological processes affecting female reproductive processes (Agarwal and Allamaneni, 2004; Agarwal et al., 2006). Oxidative stress has been suggested as a causative agent in human pregnancy-related disorders, such as embryonic resorption, recurrent pregnancy loss, preeclampsia, intra-uterine growth restriction (IUGR) and fetal death (Gupta et al., 2007). Nevertheless, the relationship between ROS-induced oxidative stress and such disorders is not clear and cannot be adequately investigated in human pregnancies for self-evident ethical reasons. Furtheremore, there is a lack of fundamental insights regarding cellular, biochemical and molecular adaptive responses to an oxidant environment under both physiological and disease states. Therefore, animal models of both normal and disturbed pregnancies are essential to fill in these important gaps in our knowledge. A thorough understanding of the developmental changes in antioxidant expression, as well as the cellular and molecular mechanisms of antioxidant regulation, in the female reproductive tract is needed. Such studies will provide insights about ROS-mediated antioxidant adaptive responses in normal and disturbed pregnancies and will eventually facilitate treatment of pregnancy-related disorders. ROS are generated as by-products of aerobic respiration and metabolism. Since the purification of superoxide dismutase (SOD) from bovine erythrocytes by McCord and Fridovich (1969), evidence indicates that living organisms have adapted to a coexistence with ROS through the development of highly complex and integrated enzymatic antioxidant mechanisms (Fig. 1). ROS have been linked to numerous biological processes when they are produced at the right levels and they may exert damaging effects when they are over-abundant. Tightly controlled ROS generation is an important constitutive process and is one of the central elements in cell signalling (Khan, 1995; Finkel, 1998), gene expression (Allen and Tresini, 2000) and maintenance of redox homeostasis and signal

transduction pathways involved in cell function, growth, differentiation and death (Valko et al., 2007). Dietary antioxidants play important roles in protecting cells from ROS damage. Both dietary and enzymatic antioxidants are components of interrelated and systems that interact with each other to control ROS production, thereby ensuring adequate defences against oxidative stress (Machlin and Bendich, 1987). Nutritional deficiencies in protein and/or micronutrient antioxidant vitamins and trace minerals may impair cellular antioxidant capacities because proteins provide the amino acids needed for the synthesis of antioxidant enzymes. In addition, many micronutrients form part of the active site necessary for the antioxidant enzyme function or act as cofactors in the regulation of antioxidant enzymes. Exposure to environmental chemicals is inevitable as it occurs through the consumption of contaminated food, water and beverage. Nutritional and environmental factors play a major role in programming the susceptibility of offspring to disease (Luo et al., 2006). Commonly known or suspected causes of preterm birth or low birth weight, such as nutritional and environmental factors, are sources of oxidative stress (Luo et al., 2006). Oxidative stress programming may operate either directly through the modulation of gene expression or indirectly through the adverse effects of oxidized molecules, such as lipids and proteins, at critical developmental windows (Luo et al., 2006). Preconception nutrition plays a major role in programming the offspring susceptibility to disease, which may be mediated by macro- and micronutrient deficiencies and oxidative stress (Chavatte-Palmer et al., 2008). Research is essential to determine the maternal antioxidant micronutrient requirements needed to improve fetal survival in undernourished populations or in populations at high risk of micronutrient deficiency and low birth weight. This review summarizes the role of ROS and antioxidants in female reproductive processes and pregnancy outcomes among different mammalian species. A discussion is devoted to the importance of cellular enzymatic antioxidants and dietary antioxidants in female reproductive functions and pregnancy outcomes. The review also examines the available evidence for the involvement of cellular ROS-induced oxidative stress in pregnancy-related disorders. Antioxidant and prooxidant biochemical markers have becoming increasingly important for the design of a strategy for prevention or management of oxidative diseases and could be used as useful tools in estimating the risk of oxidative damage and

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Fig. 1. Schematic representation of reactive oxygen species (ROS) production and key cellular antioxidant enzymatic pathways. The production of • O2 − by a single electron donation to O2 is the initial step in the formation and propagation of ROS within and out of the cell. Formation of • O2 − leads to a cascade of other ROS. Mammalian cells are equipped with a variety of antioxidant mechanisms to control ROS production and propagation. The major enzymes, SOD1, SOD2, CAT, GPX, GSR, G6PD and ICDH represent co-coordinately operating network of defences against oxidative stress-induced functional alteration and tissue damage. Molecular oxygen (O2 ); superoxide anion (• O2 − ); hydrogen peroxide (H2 O2 ); water (H2 O); hydroxyl radical (• OH); peroxynitrite (ONOO–); nitric oxide synthase (NOS); nitric oxide (NO); copper–zinc containing SOD (Cu,Zn-SOD or SOD1); manganese containing SOD (Mn-SOD or SOD2); catalase (CAT); glutathione peroxidase (GPX); glutathione reductase (GSR); glucose6-phosphate dehydrogenase (G6PD); isocitrate dehydrogenases (ICDH); reduced/oxidized glutathione (GSH/GSSG); reduced/oxidized nicotinamide adenine dinucleotide phosphate (NADPH/NADP).

associated pregnancy disorders. Screening technologies, especially proteomics, will be useful approaches for the discovery of peptide and/or protein molecular changes and oxidative stress biomarker associated with normal and complicated pregnancies. 2. Reactive oxygen species The reactive oxygen species (ROS), superoxide anion radical (• O2 − ), hydrogen peroxide (H2 O2 ) and hydroxyl radical (• OH), are ubiquitous, highly reactive, diffusible molecules that are generated within the cell as by-products of aerobic respiration and metabolism. The generation of • O2 − by a single electron donation to molecular oxygen (O2 ), resulting in a very reactive unpaired electron state, is the initial step in the formation and propagation of ROS within and out of the cell. Indeed, • O2 − radical is the precursor of most ROS and could be a mediator in oxidative chain reactions. Dismutation of • O2 − produces H2 O2 (McCord and Fridovich, 1969), which in turn may be reduced to water and O2 . Unlike • O2 − , H2 O2 is stable and can cross cell membrane. In the presence of iron, H2 O2 and • O2 − interact in a Haber–Weiss reaction (Halliwell, 1978; Kehrer, 2000) to generate • OH, which is thought to be responsible of oxidative damage (Halliwell and Gutteridge, 1989). The Haber–Weiss cycle consists of the following reactions: Fe3+ + • O2 − → Fe2+ + O2 Fe2+ + H2 O2 → Fe3+ + OH− + • OH

(Fentonreaction)

The net reaction: •O − 2

+ H2 O2 → • OH + OH− + O2

Nitric oxide (NO) and peroxynitrite (ONOO− ) are important cellular radical species. The generation of NO from l-arginine by the action of NO synthase (NOS) is an important biochemical process, as NO acts as a regulator of many cellular events (Moncada et al., 1991) such as programmed cell death, or apoptosis. Protein S-nitrosylation inhibits the activity of enzymes known to be Snitrosylated by NO (Stamler, 1994), such as the effector enzyme of apoptotic DNA fragmentation (Nicholson et al., 1995) and caspase-3 (Li et al., 1997). Decreased caspase-3 S-nitrosylation was associated with an increase in caspase activity (Mannick et al., 1999). Mitochondria are endowed with a NOS (mtNOS) and NO are produced by mitochondria (Ghafourifar and Richter, 1997; Giulivi, 1998) and have emerged as an inhibitor of apoptosis in a wide range of mammalian cells (Yoon et al., 2002; Jee et al., 2003; Preutthipan et al., 2004). Prooxidant action of NO is often attributed to reactive nitrogen intermediates rather than NO itself. NO may react with • O2 − in a reaction controlled by the rate of diffusion of both radicals to form ONOO− (Koppenol et al., 1992; Garrel and Fontecave, 1995) as follows: NO + • O2 − → ONOO− ONOO− can diffuse freely within and out of the cell, and react with lipids, proteins and DNA, leading to cell membrane-lipid peroxidation (Radi et al., 1991), DNA damage (Inoue and Kawanishi, 1995) and apoptosis (Marla et al., 1997). The balance between NO and • O2 − may help to define the prooxidant action of NO in the

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biological tissues (Violi et al., 1999). Elevated concentrations of NO and • O2 − would promote ONOO− production (Packer et al., 1996) and cellular oxidative damage (Kirkinezos and Moraes, 2001). 3. Cellular sources of reactive oxygen species The mitochondrial respiratory system is the major source of and H2 O2 and a target for their damaging effects (Richter, 1992). Mitochondrial oxidative phosphorylation (OXPHOS) is the process by which adenosine triphosphate (ATP) is formed as a result of the transfer of electrons from NADH or FADH2 to O2 (Brown, 1992). During OXPHOS, electrons are transferred from electron donors such as NADH+ to electron acceptors such as O2 in redox reactions. The mitochondrial respiratory chain consists of four multimeric complexes (complexes I–IV), coenzyme Q (CoQ) and cytochorome C (Cyt C). Electrons are transferred from the reducing equivalent (NADH–FADH2 ) to molecular O2 through the mitochondrial respiratory chain, generating water at complex IV. During the electron transfer, • O2 − radicals are generated at complexes I and III. It has been shown that complex I impairment increases ROS production (Pitkanen and Robinson, 1996; Luo et al., 1997; Jezek and Hlavatá, 2005). It is of interest to note that at non-phosphorylating state 4 with low respiratory rate and high membrane potential, i.e. resting state, mitochondria produce more ROS as compared to the phosphorylating state 3 with ATP production and higher respiration and low membrane potential, i.e. active state (Korshunov et al., 1997). Mitochondria are also the main intracellular source of NO (Ghafourifar and Richter, 1997; Giulivi, 1998) and ONOO− (Packer et al., 1996). Enzymatic pathways, such as NADPH oxidase, xanthine oxidase, cyclooxygenases, lipoxygenases, monooxygenase (Dröge, 2002) and cytochrome P450 systems (Zangar et al., 2004) are the potential extramitochondrial ROS sources. Outside mitochondria, ROS are also generated during biotransformation of xenobiotics and drugs, inflammation, UV exposition, ionic irradiation and lipid peroxidation of plasma membrane and other membrane-lipid structures (Jezek and Hlavatá, 2005). •O − 2

4. Physiological role of reactive oxygen species An important feature of the signal transduction is that the first messenger molecules, such as hormones, growth factors, cytokines, and neurotransmitters, bind to specific cell membrane receptors and subsequent release of second messenger molecules into the cytoplasm. The second messenger generation process involves various cellular components like specific receptors, transducers, adaptor proteins, protein kinases, and protein phosphatases, and eventually leads to the induction of physiological responses such as gene expression, cell proliferation, differentiation and survival or death. Cellular ROS have been implicated in the initiation of developmental and differentiation events (Sohal et al., 1988; Allen and Balin, 1989; Allen and Venkatraj, 1992). There is increasing evidence that ROS can function as second messengers in mammalian cells (Khan, 1995; Remacle et al., 1995; Finkel, 1998; Thannickal and Fanburg, 2000) to regulate signal transduction pathways that control gene expression and posttranslational changes of proteins (Palmer and Paulson, 1997; Allen and Tresini, 2000) involved in cell function, growth, differentiation and death (Dröge, 2002; Valko et al., 2007). 4.1. Role of reactive oxygen species in developmental processes and cell survival Hypoxia is fundamental in developmental control of O2 homeostasis (Iyer et al., 1998) and is thought to be essential for early embryonic and placental development and growth (Dunwoodie,

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2009), at least in part via regulation of peri-implantation angiogenesis in humans (De Marco and Caniggia, 2002), sheep (Nau et al., 2002) and mice (Daikoku et al., 2003). Recently, it has been shown that normal placental trophoblast apoptosis may be initiated by hypoxia and oxidative stress (Sharp et al., 2010). Hypoxia-inducible factors (HIFs) are among the well-defined transcription proteins that have been identified to be regulated by the intracellular redox state (Chandel et al., 1998; Haddad, 2002). Their expression and activity are tightly controlled by cellular ROS concentration (Fig. 2). HIF-1, the major O2 homeostasis regulator, is a heterodimer composed of two subunits: the oxygen-sensitive HIF-1␣ and constitutively expressed HIF-1␤. Under normoxic conditions, HIF-1␣ is degraded by the proteasome. Under hypoxic conditions, HIFhydroxylases are inactive and HIF-1␣ is stabilized which allows the formation of a transcriptionally active heterodimeric protein. This complex can translocate to the nucleus to permits the activation of genes essential to cellular adaptation to low O2 conditions, including the transcriptional activation of erythropoietin, vascular endothelial growth factor, glucose transporter 1 and glycolytic enzymes (Semenza, 1999). These responses enhance the delivery of O2 to cells and facilitate the production of ATP and they are known to play crucial roles in embryonic development and early placentation (Harvey et al., 2002). Peroxisome proliferator-activated receptor-␥ coactivator (PGC)-1␣ is a nuclear receptor coactivator identified in a wide range of organ and tissues where it plays a key role in the regulation of cellular and developmental O2 homeostasis (Iyer et al., 1998) and promotes mitochondrial biogenesis and respiration (Puigserver et al., 1998; Wu et al., 1999). Upon hydroxylation, HIF-1␣ is targeted by the von Hippel–Lindau (VHL) protein to ubiquitination and proteasomal degradation (Maxwell et al., 1999). Substantial evidence indicates that PGC-1␣ serves as a key regulator of mitochondrial biogenesis in mammals through its coactivating effects on key transcription factor designated nuclear respiratory factor 1, or NRF-1 (Kelly and Scarpulla, 2004). It has been shown that PGC-1␣-induced mitochondrial biogenesis results in increased O2 consumption, leading to a decrease in intracellular O2 availability to HIF-hydroxylases, and this in turn stabilizes HIF-1␣ (O’Hagan et al., 2009). HIF-1␣ activation facilitates the elevated generation of ATP after mitochondrial biogenesis by matching the increased O2 demand with an increase in O2 supply (O’Hagan et al., 2009). Mitochondria provide ATP for GSH production during oocyte maturation and also participate in the regeneration of NADPH and GSH during early development (Dumollard et al., 2009). Nuclear factor (NF) kappa B (NF-␬B) and activator protein-1 (AP1) are redox-sensitive transcription factors (Schreck et al., 1992; Manna et al., 1998; Haddad, 2002) that regulate gene expression (Muller et al., 1997). Inflammatory cytokines, such TNF-␣, and/or ROS could activate NF-␬B (Meyer et al., 1994; Di Donato et al., 1997) and AP-1 (Meyer et al., 1994; Martin et al., 1997; Kyriakis, 1999). NF-␬B plays a crucial role in immune responses and inflammation (Baeuerle and Baltimore, 1996), through regulation of gene expression of a large number of cytokines and other immune response genes (Kabe et al., 2005). NF-␬B may act as a protector of embryos exposed to embryopathic stresses, possibly, because of the ability of NF-␬B to prevent the induction of programmed cell death, as well as to activate cell proliferation (Torchinsky and Toder, 2004). In addition, NF-␬B controls cell survival through the enhancement of anti-apoptotic gene transcription (Nakano et al., 2006). 4.2. Role of reactive oxygen species in programmed cell death Programmed cell death, or apoptosis, is fundamental in homeostatic maintenance of biological systems. Apoptosis serves to eliminate cells during early embryonic development (Pierce et al., 1989) and plays an important role in maintaining homeostasis of

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Fig. 2. A schematic overview of the potential signalling pathways involved in reactive oxygen species (ROS)-mediated regulation of cell function or death. Hypoxia and extracellular inflammatory signals induce the intracellular accumulation of ROS. Mitochondrial ROS-mediated signalling allows hypoxia-inducible factor-1 alpha (HIF-1␣) stabilization, nuclear translocation and transcriptional activation. Under physiologically normoxic conditions, HIF-1␣ is rapidly broken down following binding of von Hippel–Lindau tumor suppressor protein (pVHL), which targets HIF-1␣ for degradation by the ubiquitin–proteasome pathway. Peroxisome proliferator-activated receptor-␥ coactivator (PGC)-1␣ induces mitochondrial biogenesis, leading to increased oxygen (O2 ) consumption, decrease in intracellular O2 availability to HIF-hydroxylases, and stabilization of HIF-1␣. NF-␬B resides in the cytoplasm in an inactive complex with the inhibitor I kappa B (I␬B). ROS stimuli cause release of I␬B for proteasomal degradation and allow NF-␬B to enter the nucleus, bind to DNA control elements to induce gene expression. Apoptosis may be initiated intrinsically by the mitochondrial pathway or extrinsically through membrane-associated death receptors Mitochondrial-mediating pathway involves loss of mitochondrial membrane potential and cytochrome c release leading to activation of caspase-9 followed by downstream effector caspase-3 activation and ultimately leads to DNA cleavage. In the extrinsic pathway, ligand-type cytokine molecules of the tumor necrosis factor-␣ (TNF) family such as TNF-␣ and Fas ligand (FasL) trigger apoptotic signalling by ligating cognate receptors on the cell surface. ROS can also activate NF-␬B and, hence, NF-␬B-dependent genes such as IL-2 and TNF-␣. The extrinsic pathway involves stimulation of pathways leading to activation of upstream caspase-8. Activated caspase-8 is in turn able to trigger a biochemical cascade leading stimulation of effector caspase-induced DNA cleavage. ROS may act as an extracellular intermediate directly stimulating the mithochondria and/or Fas cell death pathways.

the uterine endometrium during embryo implantation (von Rango et al., 1998; Pampfer and Donnay, 1999; Tassell et al., 2000; Fei et al., 2001; Zhang and Paria, 2006). ROS have been recognized as key molecules, which can selectively modify proteins and therefore regulate cellular signalling including apoptosis. In response to different stimuli, apoptosis may be initiated intrinsically by the mitochondrial pathway or extrinsically through membraneassociated death receptors (Fig. 2). Mitochondria contribute to apoptosis signalling via the ROS production (Mignotte and Vayssiere, 1998). ROS are involved in the initiation and promotion of apoptosis (Simon et al., 2000), at least through specific metabolic and signal transduction cellular

components (Carmody and Cotter, 2001). Cytochrome c is an electron transporting protein that resides within the intermembrane space of the mitochondria, where it plays a critical role in the process of OXPHOS and production of cellular ATP. Cytochrome c release from the mitochondria into the cytoplasm activates caspase (Rossé et al., 1998) catalyzed by a complex known as apoptosome (Cain et al., 2002). This is a central event in apoptosis induction (Fig. 2) and appears to be mediated by ROS (Petrosillo et al., 2003). ROS originating from the mitochondrial electron transport chain can trigger a transient burst of mitochondrial ROS production via ROS activation of the mitochondrial permeability transition (MPT) pore (Zorov et al., 2000), a phenomenon termed

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ROS-induced ROS release (RIRR). Generated ROS can be released into cytosol and could potentially function as a second messenger to activate RIRR in neighboring mitochondria. The mitochondrionto-mitochondrion ROS-signalling constitutes a positive feedback mechanism for enhanced ROS production leading to potentially significant mitochondrial and cellular injury (Zorov et al., 2006). In the extrinsic pathway, ligand-type cytokine molecules of the tumor necrosis factor-␣ (TNF) family such as TNF-␣ and Fas ligand (FasL) trigger apoptotic signalling (Rath and Aggarwal, 1999) by ligating cognate receptors on the cell surface (Fig. 2). ROS can also activate NF-␬B and, hence, NF-␬B-dependent genes such as IL-2 and TNF-␣ (Burdon, 1995). The extrinsic pathway involves stimulation of pathways leading to activation of upstream caspase-8. Activated caspase-8 is in turn able to trigger a biochemical cascade leading stimulation of effector caspase-induced DNA cleavage. ROS may act as an extracellular intermediate directly stimulating the mithochondria and/or TNF-␣–Fas cell death pathways (Burdon, 1995). The Bcl-2-family proteins are key regulators of mitochondrialrelated apoptosis pathways (Tsujimoto and Shimizu, 2000). Bcl-2 interacts with Bax and blocks Bax-induced apoptosis (Oltvai et al., 1993). One possible role of Bcl-2 protein in prevention of apoptosis is to block cytochrome c release from mitochondria (Yang et al., 1997). Inhibition of apoptosis by Bcl-2 and Bcl-xL anti-apoptotic proteins is associated with protection against ROS and/or a shift of the cellular redox potential to a more reduced state (Fleury et al., 2002). 5. Antioxidant control of reactive oxygen species production Intracellular ROS production and propagation are controlled by highly complex and integrated antioxidant systems. Mammalian cells have evolved a variety of interrelated enzymatic antioxidant mechanisms (Fig. 1) which enable them to cope with oxidative environments (Hayes and McLellan, 1993; Michiels et al., 1994). Besides enzymatic systems, the thiol tripeptide glutathione (GSH) is considered to be pivotal in protecting cells from ROS-induced oxidative damage (Schafer and Buettner, 2001). Cells within the body are also protected from ROS-induced oxidative damage by various non-enzymatic dietary antioxidants (Machlin and Bendich, 1987). 5.1. Enzymatic antioxidant systems SODs constitute the first enzymatic step that plays a vital role in the control of cellular • O2 − production by catalyzing the dismutation of • O2 − into H2 O2 and O2 (McCord et al., 1971). Copper–zinc containing SOD (Cu,Zn-SOD or SOD1) is a dimeric protein, essentially located in the cytoplasm. Manganese containing SOD (Mn-SOD or SOD2) is a homotetrameric protein, located in the mitochondria (Weisiger and Fridovich, 1973). Extracellular SOD (EC-SOD or SOD3) is a Cu- and Zn-containing tetrameric glycoprotein (Marklund, 1982; Marklund et al., 1982). The dismutation reaction of SODs may represent as follows: 2• O2 − + 2H+ → H2 O2 + O2 The control of H2 O2 production is the second enzymatic step that plays a vital role against ROS propagation. Glutathione peroxidases (GPXs) are a family of enzymes divided to two groups, selenium (Se)-independent and Se-dependent enzymes, present in the cytoplasm and the mitochondria (Mills, 1957), and catalase which found within peroxisomes (Chance et al., 1979), both catalyze the conversion of H2 O2 to H2 O. The H2 O2 can be removed by

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CAT and GPX, respectively, as follows: H2 O2 + H2 O2 → O2 + 2H2 O H2 O2 + 2GSH → 2H2 O + GSSG GSR catalyzes the reduction of the oxidized form of glutathione (GSSG) to the reduced glutathione (GSH) with NADPH as the reducing agent (Chance et al., 1979). Therefore, GSR is essential for the glutathione redox cycle that maintains adequate levels of reduced GSH necessary for the maintenance of cells in a reduced state. In the reduced state of glutathione, the thiol group of cysteine is able to donate a reducing equivalent (H+ + e− ) to other unstable molecules, such as ROS. In donating an electron, GSH reacts with another reactive GSH to form GSSG. The thiol tripeptide GSH (␥-glutamylcysteinylglycine) is the major cellular non-enzymatic antioxidant, as well as being a cofactor for GPX activity. GST plays an important role in detoxifying reactive metabolites by catalyzing their conjugation with GSH. They are involved in the intracellular transport of compounds and their delivery to sites for subsequent transformation and/or excretion (Kaplowitz, 1980). Glucose-6-phosphate dehydrogenase (G6PD) is a cytosolic ratelimiting enzyme of the pentose phosphate metabolic pathway that supplies reducing energy to cells by maintaining NADPH (Kirkman, 1971). Since NADPH is necessary for the regeneration of GSH and plays important role in the maintenance of the catalytic activity of CAT (Kirsch and De Groot, 2001), G6PD-produced NADPH pathway is crucial in the defense against the ROS damaging effects (Pandolfi et al., 1995). The isocitrate dehydrogenase (ICDH) catalyzes oxidative decarboxylation of isocitrate to 2-oxoglutarate and requires either NAD+ or NADP+ , producing NADH and NADPH, respectively. The maintenance of the cellular redox state is one of the primary functions of mitochondrial (Jo et al., 2001) and cytosolic (Lee et al., 2002) NADP+ -dependent ICDH through supply of NADPH for the GSH-dependent antioxidant enzyme systems. The key antioxidant enzymes, namely SOD1, SOD2, CAT, GPX, GSR, G6PD and ICDH are therefore specifically compartmentalized within the cell and represent co-coordinately operating network of defenses against ROS propagation, oxidative stress and tissue damage (Fig. 1). 5.2. Non-enzymatic antioxidant systems Antioxidant vitamins are among the major dietary antioxidants that directly scavenge ROS, providing a major source of protection against the damaging effects of ROS (Sies and Stahl, 1995; Rock et al., 1996; Johnson et al., 2003). Trace elements are vitally important because they form part of the active site necessary for the antioxidant enzyme functions or act as cofactors in the regulation of antioxidant enzymes (Bettger, 1993; Dashti et al., 1995). Polyphenols, ubiquitous in a diet high in vegetables and fruits, are particularly important because of their beneficial effects on health as natural antioxidants (Scalbert et al., 2005). 5.2.1. Vitamins Vitamin E, fat-soluble antioxidants, is a family of ␣-, ␤-, ␥-, and ␦-tocopherols and corresponding four tocotrienols (Herrera and Barbas, 2001). The most active form of the vitamin E homologues is ␣-tocopherol which protects cell membranes from oxidation by reacting with ROS and lipid radicals produced in the lipid peroxidation chain reaction (Traber et al., 2007). Carotenoids are fat-soluble antioxidants. The major carotenoids are ␤-carotene, lutein, ␣-carotene, zeaxanthin, cryptoxanthin and lycopene. The most widely distributed carotenoid in plant species is ␤-carotene (Bendich and Olson, 1989) which is the main source of provitamin A. Both ␤-carotene and lycopene are important biological

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compounds that can inactivate electronically excited molecules, a process termed quenching, and may also participate in free radical reactions (Stahl et al., 1997). Vitamin C (ascorbic acid), a watersoluble antioxidant, can scavenge ROS and protects against DNA damage. Ascorbic acid interacts with the tocopheroxyl radical and regenerates the reduced tocopherol (Machlin and Bendich, 1987). Furthermore, vitamins C and E are able to interact in association with GSH-related enzymes to control the production of lipid peroxidation products (Machlin and Bendich, 1987). 5.2.2. Trace elements Minute quantities of trace elements are required for normal metabolism, development and physiology of the organism (Mertz, 1981). This makes them among the most important factors in maintaining health, reproduction and fertility in domestic animals and human (Ferrando, 1972; Hidiroglou, 1979; Bedwal and Bahuguna, 1994). Trace elements also have indirect antioxidant and detoxifying properties and are therefore essential in the defense systems against ROS-induced cellular damage. Indeed, Cu, Zn, Mn and Se are particularly of utmost importance as they are essential constituents of enzymatic antioxidant systems, namely Cu,Zn-SOD (SOD1), MnSOD (SOD2) and Se-GPX. 5.2.3. Polyphenols Polyphenols, naturally occurring in vegetables, fruits and plantderived beverages such as tea, red wine, and extra virgin olive

oil, are a wide variety of organic molecules (Scalbert et al., 2005). They are characterized by the presence of several groups involved in phenolic structures and include the flavonoids and phenolic acids. Commonly occurring flavonoids are catechins, resveratrol, quercetin, anthocyanins and hesperitin derivatives, and phenolic acids such as phytic, caffeic acid and chlorogenic acids. Phytic acid, by virtue of chelating free iron, is a potent inhibitor of • OH radical formation by the Fenton reaction (Graf et al., 1987) and accelerates O2 -mediated Fe2+ depletion and suppresses iron-mediated oxidative processes and lipid peroxidation (Graf and Eaton, 1990). 6. Antioxidant systems, establishment and outcome of pregnancy During the oestrous/menstrual cycle, the ovarian follicles, the corpus luteum (CL) and the uterus exhibit extremely rapid cellular proliferation, growth and development to ensure hormonal environment suitable for early embryonic development and the establishment of pregnancy (Fig. 3). The establishment of pregnancy requires a receptive uterus able to respond to a variety of biochemical and molecular signals produced by the developing conceptus (embryo and extra-embryonic membranes), as well as specific interactions between the uterine endometrium and the extra-embryonic membranes, the trophectoderm (Schlafke and Enders, 1975; Bazer and Roberts, 1983). Before embryonic implantation, the uterine endometrium must be adequately prepared to

Fig. 3. Diagram of the mammalian female reproductive organs, early embryonic development and implantation. The processes of recruitment, development and selection of one or more ovulatory follicles are specific for particular species and breeds. Aspects of the ovarian function and the development of the blastocyst from ovulation to implantation common to many mammalian species are (1) following ovulation, the corpus luteum (CL) develops from an ovarian follicle during the luteal phase of the menstrual cycle or oestrous cycle, (2) oestradiol (E2) produced by the developing ovarian follicles interacts with progesterone produced by the CL to prepare endometrium receptivity necessary for embryo implantation, (3) the meeting of the oocyte and sperm, and subsequent fertilization, take place in the ampulla of the oviduct, (4) following early embryo development within the oviduct, morula migrates to the uterus where implantation occurs, (5) the appearance of a fluid-filled inner cavity (blastocoel) accompanied by cellular differentiation: the surface cells become the trophoblast and give rise to the extra-embryonic tissues, including the placenta, and the inner cell mass gives rise to the embryo, and finally (6) shedding of the zona pellucida, followed by orientation, apposition, attachment and adhesion of the blastocyst to the endometrium. If the blastocyst is not present, the CL will regress and the uterus starts the cycle again. The timing and chronological events of implantation differs among mammalian species irrespective of the length of gestation (for review see Wimsatt, 1975). In contrast to humans, horses, primates and rodetnts in which implantation occurs shortly after the hatching of the blastocyst, the blastocyst in domestic ruminants and pigs elongates before implantation and this unique developmental event does not occur in laboratory rodents, or humans.

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a highly receptive state of development and differentiation via the sequential action of steroid hormones. Oestrogens produced by the developing ovarian follicles interact with progesterone produced by the CL to prepare uterine receptivity and embryo implantation. The CL is essential throughout pregnancy in the mouse, rat, hamster, rabbit, dog, sow and goat, but for less than full term in cat, guinea pig, sheep, cow, horse, macaque and human (Ryan, 1969). In some species where the CL is not necessary to maintain the entire duration of pregnancy, the placenta becomes a predominant source of progesterone. The timing of this change varies between species: relatively early in pregnancy in the human (Csapo et al., 1972) and ovine (Al-Gubory et al., 1999) or during later gestation in the bovine (Estergreen et al., 1967). The CL (Behrman et al., 2001) and the placenta (Myatt and Cui, 2004; Garrel et al., 2010) are highly exposed to ROS due to their extensive blood vasculature and steroidogenic activity. Rescue of the CL from ROS-induced luteal regression, as well as uterine, embryonic, feto-placental antioxidant adaptation to ROS-induced oxidative stress during pregnancy are now considered as key events for the establishment and outcome of pregnancy. Evidence has accumulated to suggest that ROS and antioxidant enzyme systems are important component of the mammalian reproductive functions, such as ovarian follicular development, ovulation, fertilization, luteal steroidogenesis, endometrium recep-

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tivity and shedding, embryonic development, implantation and early placental growth and development (Table 1). 6.1. Antioxidant systems and corpus luteum rescue Rescue of the CL from luteolysis and maintenance of progesterone production play a crucial role in the establishment of a uterine cellular receptivity suitable for implantation, survival and development of pre-implantation embryos and subsequent pregnancy progression (Schlafke and Enders, 1975). Progesterone is also implicated in the regulation of the immune system during the establishment of pregnancy (Siiteri et al., 1977). Both the endocrine system and the immune system interact closely during early pregnancy (Dosiou and Giudice, 2005). Inadequate progesterone production has been proposed as a cause of embryonic losses in human (Porter and Scott, 2005) and ruminants (Diskin and Morris, 2008). 6.1.1. Role of enzymatic antioxidants Antioxidant enzymes have been suggested to be involved in the maintenance of CL steroidogenesis and in the rescue of CL from luteolysis when pregnancy occurs in various mammalian species. This includes (1) the changes in SOD1 and SOD2 activities in the

Table 1 Physiological roles of reactive oxygen species (ROS) and antioxidant enzymes in female reproductive processes and pregnancy outcomes in various mammalian species. Remarks

Suggested role

Species

Reference

H2 O2 stimulates uterine contractions High GSH levels in the oocyte

Peri-partum regulation of prostaglandin production Reduction of disulfide bonds and sperm nucleus decondensation during fertilization Regulation of vascular permeability at the initiation of implantation Regulation of follicular development, ovulation and luteal functions Control of decidual cell differentiation

Rat Hamster

Cherouny et al. (1988) Perreault et al. (1988)

Mouse

Laloraya et al. (1989a,b)

Rat

Laloraya et al. (1989a,b)

Rat

Devasagayam et al. (1990)

Regulation of uterine oedema and cell proliferation

Rat

Laloraya et al. (1991)

Regulation of blastocyst tissue mass by apoptosis

Mouse

Pierce et al. (1991)

Role of O2 in the mechanism of gonadotropin-induced ovulation Protective role for GSR in the GSH redox cycle

Rat

Sato et al. (1992)

Mouse

Gardiner and Reed (1995)

Endometrium shedding

Human

Sugino et al. (1996)

Blastocyst hatching

Mouse

Thomas et al. (1997)

Protection against • O2 − during implantation

Mouse

Ho et al. (1998)

Detoxification of toxic compounds

Human

van Lieshout et al. (1998)

Protection against deleterious H2 O2 action

Rat

Baiza-Gutman et al. (2000)

Protection against ROS toxicity in the feto-placenal system Control of H2 O2 and stimulation of placental differentiation Regulation of luteal function

Human

Qanungo and Mukherjea (2000)

Human

Jauniaux et al. (2000)

Human

Sugino et al. (2000)

Control of H2 O2 during fertilization

Cow

Lapointe and Bilodeau (2003)

Rescue of CL from apoptosis

Sheep

Al-Gubory et al. (2004)

Control of uterine contraction

Human

Warren et al. (2005)

Role in embryonic brain and heart development

Mouse

Borchert et al. (2006)

Control of H2 O2 and cell death during placental development

Sheep

Garrel et al. (2010)

Uterine preparation for blastocyst implantation

Mouse

Ni et al. (2009)

High levels of • O2 − in day-5 uterus pregnancy Growing and ovulated follicles exhibit high SOD activity Increased SOD activity during uterine deciduoma development Levels of • O2 − and SOD exhibit marked changes in the uterus during the oestrous cycle Blastocoel fluid contains amounts of H2 O2 toxic to malignant pretrophectodermal cells Inhibition of ovulation by SOD in hCG-treated animals Recovery of GSH after depletion in two-cell and blastocyst-stage embryos Decreased SOD activity and increased lipid peroxide in the endometrium of the late secretory phase Rised • O2 − levels and concomitant drop in SOD activity in peri-implantation blastocyst SOD1 knock-out females exhibit marked increase in post-implantation embryo death Early expression of GST isoenzymes in embryonic tissues High uterine peroxidase activity at the time of blastocyst attachment Enhanced CAT, SOD and GPX activities in placental and fetal tissues Enhanced CAT and GPX, acivities, and GSH levels in placental tissue High SOD1 expression and activity in corpus luteum during early pregnancy Enhanced CAT and GPX, activities and GSH levels in oviduct during the oestrous cycle Enhanced SOD1, GPX and GST activities in corpus luteum during early pregnancy H2 O2 or • O2 − reduce oxytocin-induced myometrial contractility Silencing of GPX4 expression induces microencephaly and improper heart development Enhanced GPX and GSR activities and concomitant drop in Bax expression in early developing placentomes High GSTm2 expression in the uterine epithelium during pre-implantatin period

•

−

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rat CL in a manner similar to the change in serum progesterone concentrations throughout pregnancy (Sugino et al., 1993) and pseudopregnancy (Shimamura et al., 1995), (2) the high level of expression of the SOD2, SOD3, and CAT in the bovine CL during early pregnancy (Rueda et al., 1995), (3) the high expression and activity of SOD1 in human CL during early pregnancy (Sugino et al., 2000), and (4) the isolation and identification of SOD1 from the sheep CL of pregnancy (Al-Gubory et al., 2003). Changes in activities of SOD1, SOD2, GPX, GSR and GST in the ovine CL throughout pregnancy (AlGubory et al., 2004) and the oestrous cycle (Al-Gubory et al., 2005) is probably be linked to ROS generated in the luteal cells, and may be involved in the inhibition of apoptosis and maintenance of luteal steroidogenesis. In vitro (Sugino et al., 1998) and in vivo (Takiguchi et al., 2000) experiments demonstrated that rodent placental lactogen (rPL) hormone has stimulatory effects on SOD expression in the rat CL, suggesting that this hormone may play important roles in the maintenance of luteal function by increasing the antioxidant capacities of luteal cells. Treatment of ewes with ovine PL at doses mimicked circulating concentrations of this hormone during pregnancy had no effect on the activity of SOD1, SOD2, GPX, GSR and GST, and failed to prevent or reduce apoptosis (Al-Gubory et al., 2006). These results failed to support the hypothesis that PL hormone may play a role in the maintenance of sheep CL structure and function either by inhibiting apoptosis or by increasing antioxidant status of luteal cells. Antioxidant adaptive response as a mechanism against prostaglandin F2 alpha (PGF2␣ )-induced apoptosis and CL regression would be particularly important to luteal cells exposed to high ROS environments (Garrel et al., 2007). 6.1.2. Role of non-enzymatic antioxidants Non-enzymatic antioxidants, such as carotenoids and ascorbic acid, play important roles in CL function and structure. The bovine and porcine CL of the oestrous cycle and pregnancy are known to have high concentrations of ␤-carotene (Chew et al., 1984) and ascorbic acid (Petroff et al., 1997; Miszkiel et al., 1999). Retinol, retinoic acid and ␤-carotene stimulate progesterone secretion by pig luteal cells in vitro (Talavera and Chew, 1988). ␤-Carotene plays a role in progesterone synthesis through protection of cholesterol side-chain cleavage P450 against ROS-induced oxidative damage in bovine luteal cells (Young et al., 1995). Ascorbic acid luteal content is at its maximum when the bovine CL is fully mature, remains high during pregnancy and decreases as the CL regresses (Petroff et al., 1997). Ovarian levels of tocopherol, carotenoid and ascorbic acid change markedly during the pseudopregnant cycle of the superovulated rat and in response to luteotropic or luteolytic factors (Aten et al., 1992). The synthesis of collagen during bovine luteal development and maturation is supported by luteal ascorbic acid (Luck and Zhao, 1993). Ascorbic acid depletion from ovarian tissue of intact and hypophysectomized rats (Sato et al., 1974), ovarian tissue of pseudopregnant rats (Aten et al., 1992), cultured rat luteal cells (Musicki et al., 1996) and pig CL (Petroff et al., 1998) by PGF2␣ is proposed as an early mechanism of luteal regression by rendering luteal cells susceptible to ROS-induced oxidative stress and apoptosis (Tanaka et al., 2000). 6.2. Antioxidative systems and peri-implantation development The high levels of • O2 − in the uterus of day 5 of mice pregnancy suggest a possible role for this radical in vascular permeability at the initiation of implantation (Laloraya et al., 1989a,b). During pre-implantation mouse embryo development, H2 O2 production and GSH-dependent antioxidant mechanisms are developmentally regulated in the inner blastocyst cell mass and H2 O2 is a potential mediator of apoptosis in the blastocyst (Pierce et al., 1991). Pre- (Nasr-Esfahani et al., 1990) and post-implantation (Gagioti et al., 1995) mouse embryos generate and release ROS. The pre-

implantation development of the mammalian embryo involves blastocyst formation, expansion and hatching from the zona pellucida. An abrupt drop in SOD activity and a concomitant rise in • O − levels occur in mouse blastocyst at the perihatching stage 2 (Thomas et al., 1997). NADPH-dependent • O2 − production pathway associated with the uterus of pregnant mice increases across the pre-implantation stages (Jain et al., 2000). Before implantation, antioxidant enzyme systems are important components of the developing embryo and its receptive uterine endometrium (Harvey et al., 1995; El Mouatassim et al., 1999; Guérin et al., 2001; Orsi and Leese, 2001; Blomberg et al., 2005). Antioxidant control of ROS is important in development through cellular signalling pathways involved in proliferation, differentiation and apoptosis, and ROS-induced oxidative stress can alter embryonic development (Dennery, 2007). The establishment of pregnancy is promoted by a network of signalling molecules that mediate cell-to-cell communications between the receptive endometrium and embryonic trophectoderm. Therefore, information about the expression of mRNA encoding key antioxidant enzymes and the activity of these enzymes in trophectoderm and endometrium is of utmost importance for our understanding of the role of ROS metabolism in mediating pre-implantation and conceptus development. There is now evidence to support regulation of key antioxidant enzymes in the mammalian female genital tract, particularly the involvement of ovarian steroid hormones (Sugino et al., 1996; Jain et al., 1999; Kaneko et al., 2001; Al-Gubory et al., 2008). To evaluate molecular mechanisms of antioxidant regulation by ovarian steroids and other factors present and associated with pregnancy, it will be important to determine the developmental changes in mRNA expression of the antioxidant enzymes in the female reproductive genital tract during the peri-implantation period. 6.3. Antioxidative systems and post-implantation aerobic metabolism The post-implantation period constitutes a critical stage of pregnancy due to high susceptibility of the developing conceptus to ROS-induced oxidative damage. OXPHOS is a vital metabolic pathway that uses energy released by the oxidation of nutrients to produce ATP (Brown, 1992) in order to meet high energy demands of the developing conceptus (Alcolea et al., 2007). The switch from pre-implantation embryonic anaerobic metabolism to post-implantation aerobic one, induced by the establishment of conceptus vascularization and utero-placental blood flow, exposes embryonic and extra-embryonic cells to ROS produced as by-products of enhanced respiratory capacity of embryonic mitochondria and OXPHOS enzymatic activities (Alcolea et al., 2007). These changes take place during the period of organogenesis, when the embryo is vulnerable to environmental teratogens, such as heavy metals, prescribed drugs and pesticides. Miscarriage during the establishment of cellular and biochemical interactions between the uterine endometrium and the developing post-implanting conceptus is associated with increased oxidative stress (Jenkins et al., 2000). Knowledge of antioxidative mechanisms involved in the control of post-implanting conceptus development has not been elucidated. In the future, the characterization of post-implantation antioxidant adaptive responses could improve understanding of early conceptus development and may help in the design of a strategy for prevention and treatment of early pregnancy miscarriage. 6.4. Antioxidant systems and placental development The mammalian fetus develops in an environment where respiration, alimentation, and excretory functions are provided by the placenta. A proportionate increase in uterine blood flow throughout

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gestation is essential for placental and fetal growth. The placenta provides an extensive and intimate interface between the maternal and fetal blood streams to meet these requirements. In addition, the placenta of some species, such as human (Csapo et al., 1972) and sheep (Al-Gubory et al., 1999), assumes a predominant role in progesterone production early in pregnancy. Therefore, placental development and function are prerequisites for an adequate supply of nutrients and oxygen to the fetus and successful establishment of pregnancy. Oxidative stress increases during early pregnancy because the high metabolic rate of the placenta leads to increased generation of ROS. Placental oxidative stress (Myatt and Cui, 2004; Poston and Raijmakers, 2004; Biri et al., 2006) may be a general underlying mechanism that links altered placental function to fetal programming (Myatt, 2006). The depletion of placental antioxidant systems has been suggested as a key factor in early human pregnancy failure (Liu et al., 2006). Adequate placental antioxidant status could prevent those disorders induced by oxidative stress that lead to impairment of placental function and development. Indeed, the effectiveness of antioxidant enzymatic defences against oxidative stress varies with the stage of placental development in humans (Sekiba and Yoshioka, 1979; Takehara et al., 1990; Qanungo et al., 1999; Jauniaux et al., 2000; Qanungo and Mukherjea, 2000) and sheep (Garrel et al., 2010). These previous data suggest that enhanced activities of antioxidant enzymes with gestational ages may act as protective mechanism against oxidative stress during early human and sheep placental development and growth. The effectiveness of antioxidant enzymes may vary with the stage of fetal development. The key antioxidant enzymatic mechanisms have not been determined at specific fetal developmental stages. Studies of antioxidant enzymatic systems are therefore of utmost importance because they may indicate how fetal tissues and organs might respond to oxidative stress during early pregnancy. This future perspective is also of great importance to a more complete understanding of the biochemical, molecular and cell biology of adverse pregnancy complications and outomes.

7. Antioxidant maternal nutrition and pregnancy outcomes Maternal dietary composition and intake are important determinants of fetal growth and development, including aspects specific to reproduction and pregnancy outcomes, in both animal and human (Mathews et al., 1999; O’Callaghan and Boland, 1999; Wallace et al., 1999; Ashworth and Antipatis, 2001; Boland et al., 2001; Fall et al., 2003; Moore et al., 2004; MacLaughlin et al., 2005; Borowczyk et al., 2006). Adequate maternal antioxidant status before and during pregnancy could prevent and control those mechanisms induced by poor dietary nutritional factors and associated oxidative stress that are responsible for impairment of implantation, placental function, fetal growth and pregnancy outcomes. Antioxidant vitamins, alone or combined with other supplements, decrease embryonic mortality and improve birth outcomes (Coffey and Britt, 1993; Cederberg et al., 2001). Vitamin E is essential for the development of placental labyrinth trophoblast (Jishage et al., 2001). In abnormal pregnancies, blood ␣-tocopherol concentrations are lower than those in normal pregnancies, suggesting that vitamin E requirements increase throughout pregnancy (Brigelius-Flohé et al., 2002). Combined treatment with vitamins E and C decreases oxidative stress and improves fetal outcomes in an experimental model of diabetic pregnancy (Cederberg et al., 2001). However, it is noteworthy that the association between dietary antioxidant vitamins and birth outcomes is not conclusive in human or animal studies (Tamura et al., 1997; Pusateri et al., 1999; Tarin et al., 2002; Rumbold and Crowther, 2005a,b).

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Supplementation with pharmacological doses of vitamin E during the first trimester of human pregnancy is associated with a decrease in birth weight (Boskovic et al., 2005). Furthermore, supplementing vitamins C and/or E does not prevent preeclampsia in high-risk pregnant women (Beazley et al., 2005; Debier, 2007). High maternal intake of selected dietary antioxidants does not protect the child from development of advanced ␤ cell autoimmunity in early childhood (Uusitalo et al., 2008). One reason for this could be imbalanced administration of vitamins and/or trace elements. Research is therefore still needed to determine maternal antioxidant micronutrient requirements to improve fetal growth and survival in undernourished populations or in populations at high risk of micronutrient deficiency and low birth weight. 8. Antioxidant-rich phytonutrients and pregnancy outcomes The SUpplementationen VItamines et Mineraux AntioXydants (SU.VI.MAX) studies described the advantage of using antioxidant vitamins and minerals in reducing several major health problems in reducing the main causes of premature death in industrialized countries (Hercberg et al., 1998a,b). The idea that no single antioxidant could be deemed more essential than others was also emphasized by the EUROFEDA project (European Research on the Functional Effect of Dietary Antioxidants) set-up under the European Union fifth framework (Astley and Lindsay, 2002). Both EUROFEDA and SU.VI.MAX studies reinforced the link between a high level of consumption of fruit and vegetables and a lowered incidence of chronic diseases and highlighted that the use of supplements could not be justified. Increased intake of fruits and vegetables has been shown to increase ␣-carotene, ␤-carotene and ascorbic acid in plasma of healthy premenopausal women with a family history of breast cancer (Djuric et al., 2006). In recent years, nutritional intervention provides sensible means to develop primary prevention strategies against environmental chemical insults and associated diseases (Hennig et al., 2007). If maternal diet plays a role in preventing adverse pregnancy and birth outcomes, the risk will be reduced by the use of natural phytonutrient preparation from legumes and fruits (Polidori et al., 2009) which are rich in multiple and balanced antioxidant vitamins and essential trace elements. 9. Oxidative stress and adverse pregnancy outcomes There are numerous human pathologies related to the progressive increase in ROS-induced oxidative stress, including atherosclerosis, hypertension, ischemia–reperfusion, inflammation, cystic fibrosis, cancer, type-2 diabetes, Parkinson’s disease, and Alzheimer’s disease (Dlasková et al., 2008; Valko et al., 2007). Oxidative stress has been also proposed as the causative agents of pregnancy-related disorders (Gupta et al., 2007). Oxidative stress plays a key role in the pathophysiology of placentarelated disorders, most notably preeclampsia and intra-uterine growth restriction (IUGR). Preeclampsia, a serious disease specific to human pregnancy, is associated with increased oxidative stress biomarkers (Table 2). Impairment of antioxidant activity, which increases the level of lipid peroxidation products, may cause vascular endothelium damage and result in clinical symptoms of preeclampsia (Sa˘gol et al., 1999). The decreased concentrations of glutathione and reduction in antioxidant vitamin status supports the hypothesis that lipid peroxidation is an important causative factor in the pathogenesis of preeclampsia (Krishna Mohan and Venkataramana, 2007). Placentation in preeclampsia is compromised in the first trimester by maternal and fetal immune dysregulation, abnormal decidualization,

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Table 2 The association between increased oxidative stress biomarkers and preeclampsia. Oxidative marker

Reference

Placenta TNF-␣ levels Placenta HNE-modified proteins immunostaining Plasma leptin levels and placenta leptin mRNA Placenta 8-isoprostane levels Placenta • O2 − concentrations Placental and decidual protein carbonyl Plasma MCP-1, IL-8 and lipid peroxide levels Plasma and placental MDA levels Placenta HNE-modified proteins Serum MDA and leptin levels Serum hCG and H2 O2 levels Plasma TBARS, TNF-␣ and IL-6 Erythrocytes H2 O2 , ONOO− and NO2 − • concentrations Serum Hsp70 levels Plasma protein carbonyl and H2 O2 levels Serum and term placenta H2 O2 levels Plasma IL-6, TNF-␣ and 8-isoprostane concentrations

Wang and Walsh (1996) Morikawa et al. (1997) Mise et al. (1998) Walsh et al. (2000) Sikkema et al. (2001) Zusterzeel et al. (2001) Kauma et al. (2002) Madazli et al. (2002) Shibata et al. (2003) Atamer et al. (2005) Kharfi et al. (2005) Bernardi et al. (2008) Dordevic´ et al. (2008) Molvarec et al. (2008) Tsukimori et al. (2008) Aris et al. (2009) Ouyang et al. (2009)

or both, thereby impairing trophoblast invasion (Founds et al., 2009). A growing body of literature indicates that oxidative stress is closely associated with IUGR (Table 3). IUGR is associated with a late life increased prevalence of metabolic syndrome, a condition associating obesity with hypertension, type-2 diabetes mellitus and cardiovascular disease (Valsamakis et al., 2006). The growth hormone (GH)/insulin-like growth factor (IGF) axis is significantly affected by IUGR and some of these alterations may lead to permanent pathological programming of the IGF axis which may play a role in the future occurrence of insulin resistance and hypertension (Setia and Sridhar, 2009). Utero-placental insufficiency, a decline in oxygen and nutrient supply to the fetus, oxidative stress-induced trophoblast cell death are among the identified disorders associated with IUGR (Scifres and Nelson, 2009). Reproductive system pathologies, such as endometriosis, polycystic ovary syndrome, tubal obstruction and recurrent abortions, are related to the presence of inflammatory cytokines and to high levels of ROS (Iborra et al., 2005). The establishment of pregnancy induces maternal immunopermissiveness to tolerate the conceptus allograft and to organize endometrial molecular and cellular changes aimed at favouring implantation and embryo development (Orsi, 2008). This process is mediated by an extensive array of cytokines, which operate in a highly coordinated and complex network system at both local and systemic levels (Orsi, 2008). Cytokines networks act as mediators of the conceptus–maternal paracrine dialogue associated with apposition, attachment and invasion (Makrigiannakis and Minas, 2007) and play an important Table 3 The association between increased oxidative stress biomarkers and intra-uterine growth restriction (IUGR). Oxidative marker

Reference

Urinary 8-oxodG excretion Amniotic fluid 8-isoprostane concentrations Plasma, umbilical cord blood and placental MDA levels Serum MDA and 4-hydroxyalkenals concentrations Plasma hydroperoxide and carbonyl protein levels Urinary 8-oxodG concentrations Platelet ONOO− and NO2 − • levels

Scholl and Stein (2001) Longini et al. (2005) Biri et al. (2007) Karowicz-Bilinska et al. (2007)

Saker et al. (2008) Potdar et al. (2009) Nanetti et al. (2008)

role in a wide range of reproductive processes including uterine functions during the ovarian cycle and establishment of pregnancy. Furthermore, perturbations in cytokine signalling are associated with adverse pregnancy outcomes, such as miscarriage, preeclampsia, preterm labor and fetal brain injury (Orsi and Tribe, 2008). A better understanding of the developmental antioxidative/inflammatory events that occur between embryonic implantation and parturition are needed. We predict that such studies will provide insights about ROS-mediated antioxidant adaptive responses in normal and disturbed pregnancy and should facilitate treatment of pregnancy-related disorders. 10. Nutritional and environmental adverse pregnancy outcomes Nutritional and environmental factors play a major role in programming the susceptibility of offspring to oxidative stress and pregnancy-related disorders. Oxidative stress programming may operate either directly through the modulation of gene expression or indirectly through the adverse effects of oxidized molecules, such as lipids and proteins, at critical developmental windows (Luo et al., 2006). The adverse health effects of environmental pollutants are a rising public health concern, and a major threat to sustainable socio-economic development (Luo et al., 2009). Various chemicals, such as heavy metals, xenooestrogen and tobacco, to which the mother is exposed during critical periods of pregnancy, pass across the placental barrier into the fetal blood stream and can be transferred to the fetus (Barr et al., 2007). 10.1. Poor dietary nutritional factors and adverse pregnancy outcomes Antioxidant micronutrient-induced disturbances in the balance between ROS and antioxidants may provide an additional mechanistic explanation of the effects of micronutrient imbalance on programming throughout gestation (Ashworth and Antipatis, 2001). Deficiency in dietary Cu may impact directly on cuproproteins, such as SOD1 (Chung et al., 1988), which have antioxidative functions during fetal development (Jankowski et al., 1993). Maternal Cu deficiency is associated with multiple fetal developmental defects that can affect the central nervous system, cardiovascular and skeletal systems, and result in poor immunocompetence and behavioral abnormalities in the offspring (Keen et al., 2003). Increased ROS levels in the Cu-deficient embryo may cause oxidative damage and contribute to the occurrence of developmental defects (Hawk et al., 2003). Consequences of Cu-deficiency induce lipid oxidation (Radi et al., 1991), DNA strand breaks leading to apoptosis (Zhuang and Simon, 2000), decreased SOD activity, increased • O2 − concentrations and increased ONOO− formation that can lead to nitration of proteins and alterations in protein function and activity (Gow et al., 2004). A decrease in bioavailable NO, resulting from the reaction of • O2 − and NO, can inhibit NOmediated intracellular signalling (Bagi et al., 2004) and adversely affect embryonic and fetal development (Tiboni et al., 2003). In developing countries, maternal under- or poor nutrition are associated with multiple micronutrient deficiencies, a major cause of IUGR and miscarriage (Fall et al., 2003) and deficiencies of Zn, Cu and Mn, have been implicated in human reproductive disorders like infertility, pregnancy wastage, pregnancy induced hypertension, placental abruption, premature rupture of membranes and low birth weight (Pathak and Kapil, 2004). Intra-uterine malnutrition is associated with oxidative stress in small for gestational age neonates born at term to malnourished mothers (Gupta et al., 2004). Recent data (Cetin et al., 2010) indicate that micronutrients may affect fertility, embryogenesis and placentation, and the pro-

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phylactic use of some micronutrients may be useful in preventing adverse pregnancy outcomes. 10.2. Environmental pollutants and adverse pregnancy outcomes Epidemiological and experimental data indicate that the in utero exposure to environmental chemicals and prescribed drugs during pregnancy can mediate early embryonic losses, spontaneous abortion, fetal growth retardation and resorptions, decreased litter size, fetal malformations and low birth weight (Bajaj et ´ al., 1993; Friedler, 1996; Khattak et al., 1999; Buczynska and Tarkowski, 2005), at least in part, via ROS generation which damage cellular macromolecules and/or alter signal traduction (Nicol et al., 2000; Wells et al., 2005). The teratogenicity of such chemicals depends upon their bio-activation by cytochrome P450 enzymes, prostaglandin H synthases and lipoxygenases, leading to ROS-induced oxidative stress, and this in turn affects cellular macromolecules, resulting in in utero embryonic and fetal death (Wells et al., 2005). Many consequences for human and animal reproductive systems are recognized as these chemicals disrupt endocrine function and contribute to alterations in growth and development (Sanderson, 2006). In utero exposure to xenobiotics during development induces oxidative stress and fetal toxicity that may ultimately lead to cancer later on in life (Wan and Winn, 2006). In utero exposure of the developing ovine fetus to prolonged low dose of environmental chemicals adversely affects fetal ovarian development, at least in part, through antioxidative pathways alteration and apoptosis induction (Fowler et al., 2008). Xenobiotic substances are becoming an increasingly major environmental problem in sewage treatment systems and xenobiotics-enhanced oxidative stress may contribute to birth defects (Wells et al., 2009). Environmental heavy metals have the potential to affect reproduction and development at every stage of the reproductive process (Thompson and Bannigan, 2008). Methylmercury (MeHg) is a ubiquitous environmental pollutant to which humans can be exposed by ingestion of contaminated food, especially through the consumption of fish and fish products (Bourdineaud et al., 2008). It is known to have serious adverse effects on the development of the human central nervous system, especially when exposure occurs prenatally (Grandjean et al., 1997). MeHg has been suggested to exert toxicity through multiple mechanisms, including ROS formation (Sarafian and Verity, 1991; Ali et al., 1992; Yee and Choi, 1994), likely due to a less efficient ROS detoxifying system and lower activity of mitochondrial enzymes in tissue from young animals (Dreiem et al., 2005). Prenatal exposure to other heavy metals, importantly lead and cadmium, induces oxidative stress through impairment of the antioxidant defense systems in the brain, liver and kidney of the developing fetuses (Uzbekov et al., 2007; Chater et al., 2008a,b). The xenooestrogen bisphenol-A (BPA), well known endocrine disruptor, is one of the highest volume chemicals produced worldwide. It is used in the production of polycarbonate plastics and epoxy resins used in many consumer products, including baby bottles, drinking water bottles, tupperware, metallic food cans and beverage containers (Vandenberg et al., 2007, Le et al., 2008). Humans are experiencing multiple exposures to BPA each day through water and food contamination (Vandenberg et al., 2007). The contamination by BPA during pregnancy is evidenced by its presence in urine, blood, amniotic fluid and placental and fetal tissues (Vandenberg et al., 2007; Lee et al., 2008). Exposure of rodents to BPA during embryonic/fetal development induces tissue oxidative stress, ultimately leading to underdevelopment of the brain, kidney and testis (Kabuto et al., 2004), and to disturbances of postnatal reproductive functions (Rubin et al., 2001; Hong et al., 2005; Markey et al., 2005) and sex difference in behaviour (Palanza et al., 2008).

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11. Conclusions The association between oxidative stress, the female reproductive system and development of adverse pregnancy outcomes, constitutes important issues in animal and human reproductive medicine. Pregnancy failure resulting in reduced litter size is a common cause of economic loss in the livestock systems. In dairy cattle extensive losses of embryos occur early in pregnancy and only around 40% of cows remain pregnant 28 days after insemination (Santos et al., 2004). Before the end of the first trimester, 30–50% of human conceptions end in spontaneous abortion and most of these losses occur at the time of implantation in association with oxidative stress (Gupta et al., 2007). Environment quality and human and livestock health are closely interrelated. Industrial and intensive farming and agricultural activities in both developed and developing countries contribute to the release of large quantities of pollutants in the environment and have resulted in widespread soil and water contamination. Exposure to these pollutants is inevitable as it occurs through the consumption of contaminated food, water and beverage and by air inhalation. In the future, the greatest concerns of human beings are the ability to feed properly and to have healthy lifestyle. These concerns are dependent on our ability to generate safe nutrients and high quality products while minimizing adverse environmental impacts on reproductive processes arising from chemical by-products. Antioxidant and prooxidant status have been suggested as useful tools in estimating the risk of oxidative damage and associated diseases (Papas, 1996; Dib et al., 2002; Northrop-Clewes and Thurnham, 2007) and have becoming increasingly important because they may help in the design of a strategy for prevention or management of oxidative diseases. The evaluation of pre- and peri-conception oxidative stress (increase in oxidative markers) and antioxidant status (reduce or insufficient antioxidant defense mechanisms) by appropriate and reliable techniques appears of utmost importance for preconception health care in poor perinatal outcome. Antioxidant/prooxidant status varied between individuals due essentially to differences in diet and environmental conditions of living and in lifestyle. In addition, enzymatic and dietary antioxidants are both components of interrelated and complex systems that interact with each other to control ROS production and thereby they ensure defenses against oxidative stress and prevent cellular damage. Therefore, measurement of single components may not be reliable indicator of oxidative stress under physiological and pathological conditions. Measurement of antioxidant and oxidant markers may become more common and reliable tools with the increasing of automated laboratory instruments. Between laboratories standardization of the analytical techniques of measurement of antioxidant status and oxidative stress can be expected to provide reliable tools for clinicians and researchers in the developing field of ROS and antioxidant research and their roles in pregnancy disorders and outcomes. Screening technologies, especially proteomics and molecular histology, could be used to improve our understanding of the biochemical pathways and biological consequences of oxidative stress in female reproductive processes and pregnancy outcomes. References Agarwal A, Allamaneni SSR. Role of free radicals in female reproductive diseases and assisted reproduction. Reprod Biomed Online 2004;9:338–47. Agarwal A, Gupta S, Sikka S. The role of free radicals and antioxidants in reproduction. Curr Opin Obstet Gynecol 2006;18:325–32. Agarwal A, Gupta S, Sekhon L, Shah R. Redox considerations in female reproductive function and assisted reproduction: from molecular mechanisms to health implications. Antioxid Redox Signal 2008;10:1375–403. Alcolea MP, Colom B, Lladó I, García-Palmer FJ, Gianotti M. Mitochondrial differentiation and oxidative phosphorylation system capacity in rat embryo during placentation period. Reproduction 2007;134:147–54.

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