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Keywords:

  • life history evolution;
  • mate choice;
  • ROS;
  • redox signalling;
  • sexual selection

Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Oxidative stress modulating the first steps of life
  5. Oxidative challenges during adulthood
  6. Oxidative stress and reproduction
  7. Oxidative stress and the reproductive investment in signalling
  8. Sexual selection and germline oxidation
  9. Oxidative stress and age-related declines in life functions
  10. Avenues for future research
  11. Acknowledgements
  12. References

1. Oxidative stress is usually defined as an imbalance arising when the rate of production of reactive oxygen species (ROS) exceeds the capacity of the antioxidant defence and repair mechanisms, leading to oxidative damage to biomolecules, but the concept can be expanded to include the disruption of reduction : oxidation (redox) reactions involved in cellular signalling. In this review, we consider how the need to circumvent oxidation may shape the phenotypes of organisms throughout their life and that of their offspring, underpinning a diverse range of life-history trade-offs.

2. A recent explosion of interest in this field has shown that both ROS production and the capacity of animals to deal with it change from early development through to adulthood, and vary with environmental conditions and lifestyle. Oxidative stress may both stimulate and be caused by reproduction, although direct evidence of either process is surprisingly weak. Many forms of secondary sexual traits may signal the individual’s oxidative balance to potential mates, but the underlying mechanisms are still debated.

3. Germline cells may be especially vulnerable to oxidative stress, leading to transgenerational effects on offspring viability and possible consequences for the evolution of mate choice.

4. Both antioxidant defences and the ability to repair oxidative damage tend to decline with old age, contributing to cellular and whole organism senescence. This increasing vulnerability to oxidative stress, although little studied, appears especially marked in sexually selected traits.

5. Challenges for the future include the incorporation of longitudinal approaches into experiments that analyse oxidative balance over an individual’s lifetime (preferably under near-natural conditions), the exploration of the genetic basis for trade-offs involving oxidative stress, the assimilation of current redox signalling knowledge, and the study of the consequences of heritable oxidative damage to germline DNA.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Oxidative stress modulating the first steps of life
  5. Oxidative challenges during adulthood
  6. Oxidative stress and reproduction
  7. Oxidative stress and the reproductive investment in signalling
  8. Sexual selection and germline oxidation
  9. Oxidative stress and age-related declines in life functions
  10. Avenues for future research
  11. Acknowledgements
  12. References

Chemical reduction : oxidation (redox) reactions have been central to life from its origin. However, aerobic cell respiration inevitably leads to the formation of pro-oxidative by-products (reactive oxygen and nitrogen species, ROS and RNS, respectively) that can cause oxidative and nitrosative damage to DNA, proteins and lipids when not fully quenched by the antioxidant machinery (Hulbert et al. 2007). Since the effects of RNS are far less documented, we will concentrate in this review on the effects of ROS. An imbalance between the production of ROS and the capacity of the antioxidant and repair machineries to deal with the consequences is commonly defined as oxidative stress (Costantini 2008). In a broader sense, it has been recently redefined as the disruption of the normal redox signalling processes of the cell, leading to a plethora of negative effects on homeostasis (Jones 2006). Nonetheless, it should be noted that some physiological mechanisms require certain ROS levels to work [review in Hurd & Murphy (2009)]. Hence, the view of ROS as exclusively damaging compounds must be treated with caution. In this review, we will demonstrate how oxidative stress and ROS can be selective forces acting on the design of almost any phenotypic trait, promoting critical trade-offs throughout an individual’s life history from development to death.

Oxidative stress modulating the first steps of life

  1. Top of page
  2. Summary
  3. Introduction
  4. Oxidative stress modulating the first steps of life
  5. Oxidative challenges during adulthood
  6. Oxidative stress and reproduction
  7. Oxidative stress and the reproductive investment in signalling
  8. Sexual selection and germline oxidation
  9. Oxidative stress and age-related declines in life functions
  10. Avenues for future research
  11. Acknowledgements
  12. References

Is development a period of high oxidative stress?

It has been suggested that early development is a life stage where oxidative stress levels are high due to the presumed link between the high metabolic activities required for growth and ROS generation (Monaghan, Metcalfe & Torres 2009), but evidence to support this hypothesis has only appeared recently. In developing zebra finches Taeniopygia guttata, the resistance of erythrocytes to a ROS-induced hemolysis was negatively related to growth rate during a phase of compensatory growth following an initial period of growth suppression (Alonso-Álvarez et al. 2007b). ROS-induced hemolysis would reveal the past exposure of cell membranes to ROS and overall status of blood antioxidants (e.g. Zou, Agar & Jones 2001). Similarly, juvenile rats had reduced expression of enzymatic antioxidants in aortic and pancreatic cells if induced to go through a post-natal phase of compensatory growth after protein restriction during gestation (Tarry-Adkins et al. 2008, 2009). The effect was linked to increased levels of oxidatively damaged DNA residues in urine (Tarry-Adkins et al. 2008, 2009). In a wild population of Soay sheep Ovis aries, lipid oxidative damage (plasma levels of malondialdehydes; MDA) was higher in lambs than in any age class of adult, and was positively related to growth rate over the first 4 months of life (Nussey et al. 2009). All these studies support the cited hypothesis. However, in damselflies Lestes viridis growth rate manipulation revealed that body levels of the antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT) were actually highest during a phase of accelerated growth (De Block & Stoks 2008). This could still suggest some compensatory mechanism against a ROS challenge, but it should have been linked to high ROS production or oxidative damage (Monaghan, Metcalfe & Torres 2009), which was unfortunately not assessed.

In addition to phenotypic manipulations, genomic studies have allowed exploration of the genetic basis of the hypothesis. For example, the Ames strain of dwarf mice has reduced rates of growth and growth hormone (GH) synthesis as well as an extended lifespan, associated with an increase in antioxidant production. GH administration to Ames mice resulted in a reduction in the activity of antioxidant enzymes and an alteration in glutathione (GSH) levels (a key intracellular antioxidant) in several non-blood tissues (Brown-Borg & Rakoczy 2003), suggesting that GH might suppress components of the oxidative stress pathway. Moreover, Rosa et al. (2008) found a positive relationship between growth rate, oxygen consumption and ROS production in muscles of different GH-transgenic genotypes of zebra fish Danio rerio, together with an indication of a reduction in the expression of the catalytic subunit of glutamate-cysteine ligase, i.e. an enzyme involved in GSH synthesis. Both the interference with the antioxidant system and the increased ROS production suggest that an elevation of growth rate due to GH would increase levels of oxidative stress. But GH has many other different effects on physiology, so the mechanisms relating GH to oxidative stress are still unclear. Moreover, there was no difference between GH genotypes of zebra fish in the level of oxidative stress (measured as lipid hydroperoxides) (Rosa et al. 2008), so the evidence for a genetic link between growth and oxidative stress remains inconclusive.

The genetic and environmental components of oxidative stress during development have rarely been assessed. A cross-fostering experiment with kestrels Falco tinnunculus found that more of the ROS variation in blood was associated with the nest in which a chick was born than with the nest in which it was reared, whereas only the rearing nest explained variation in antioxidant defences (Costantini & Dell’Omo 2006). This suggests that variation in ROS production was primarily of genetic origin [a view supported by a recent study of lizards Ctenophorus pictus (Olsson et al. 2008)], while antioxidant levels were more a consequence of environmental conditions. A similar result for a high environmental cause of variation in blood antioxidants was found in a cross-fostering study of juvenile great tits Parus major (Norte et al. 2009). Nonetheless, it has been shown recently that resistance to ROS-induced haemolysis is heritable in yellow-legged gull Larus michahellis chicks (Kim et al. 2010a).

Adaptations to high ROS generation during development

As development could impose high ROS levels, it can be hypothesized that animals should have evolved mechanisms to counteract their effects during this period. The stage of development at which the embryo starts to generate its own (i.e. not maternally derived) antioxidant enzymes depends on the species and the enzyme in question. In juvenile Daphnia magna, SOD, CAT and glutathione peroxidise (GPx) activities all increase with age to reach a stable level in early adulthood (before a later decline) (Barata et al. 2005). Meanwhile, in vertebrates such as the frog Xenopus laevis embryos have high SOD and CAT activities from a very early stage, and relatively high GPx levels (Rizzo et al. 2007). However, GSH and its associated enzymes glutathione reductase (GR) and glutathione transferase (GST) are initially absent, and their activity only increases close to hatching (Rizzo et al. 2007). It has therefore been suggested that different enzymes are used to combat the ROS produced at different developmental stages, with the GSH system being formed only when the animal is about to first be subjected to environmental stressors (Rizzo et al. 2007). Similar patterns have been found in fishes (Fontagne et al. 2008) and mammals (Khan & Black 2003).

The effect of these ontogenetic changes on oxidative stress has, however, been little studied. In mammals, birth is potentially a time of increased oxidative stress, since the neonate abruptly commences pulmonary respiration while no longer receiving the mother’s antioxidant protection. In one of the few studies that actually measured ROS levels, Gaál et al. (2006) showed that these are higher in the blood of new born calves than in their mothers, while levels of SOD are initially lower. However, the overall antioxidant capacity of neonate plasma is higher than that of adults, possibly because of greater concentrations of other antioxidants, so that levels of lipid oxidative damage (as measured by MDA concentration in erythrocytes) at birth are no higher (Gaál et al. 2006). After birth the blood concentration of antioxidant enzymes usually increases with age (Gaál et al. 2006), but so may the production of ROS due to the effects of growth. The dynamics of oxidative stress over early life are thus hard to predict.

Oxidative challenges during adulthood

  1. Top of page
  2. Summary
  3. Introduction
  4. Oxidative stress modulating the first steps of life
  5. Oxidative challenges during adulthood
  6. Oxidative stress and reproduction
  7. Oxidative stress and the reproductive investment in signalling
  8. Sexual selection and germline oxidation
  9. Oxidative stress and age-related declines in life functions
  10. Avenues for future research
  11. Acknowledgements
  12. References

Oxidative stress during adult life will not only arise from endogenous metabolism, but also from oxidative challenges induced by environmental conditions. The impact of ecological factors on oxidative balance has received little attention, but it is likely that this will be a fruitful area of future research. We will here mention those factors currently known to influence oxidative stress.

Locomotor activity

The hypothesis that physical activity affects oxidative balance is strongly supported [reviewed in Powers & Jackson (2008)]. The exact link between activity, respiration and ROS production is, however, not straightforward. Moderate activity does not necessarily result in more ROS production because it tends to shift the mitochondria from a state with lower ADP levels and high superoxide and hydrogen peroxide production (the state IV or resting state) to a state with high ADP levels but lower ROS production (the state III or active state)(Navarro et al. 2004). However, thanks to human exercise medicine, we know that intense physical exercise causes an increase in ROS production (Powers & Jackson 2008), which may lead to a temporary increase in oxidative stress (Aguilo et al. 2005; Radak et al. 2008; Ristow et al. 2009). Similar findings have been reported in salmon, migrating birds and honeybees (Costantini, Dell’Ariccia & Lipp 2008; Williams, Roberts & Elekonich 2008; Welker & Congleton 2009).

The body can immediately respond to extra ROS generation during an activity bout by increasing the production of antioxidant enzymes in tissues and mobilizing dietary antioxidants (Aguilo et al. 2005). This increase is temporary, to match the ROS surge, and tends to drop again within hours of its cessation (Aguilo et al. 2005). However, if the activity occurs in regular bouts (as in physical training), then the animal can build up its protection against oxidative damage (Leaf et al. 1999). This is because training often results in a greater baseline production of antioxidant enzymes in muscles (Chandwaney et al. 1998), although this response does not always occur (Selman et al. 2002; Vaanholt et al. 2008). Frequent muscular activity could also enhance repair mechanisms. In rat liver, regular treadmill exercise led to a decline in DNA oxidative damage in both nucleus and mitochondria and changes in the activity of the DNA damage repair enzyme OGG1, which could explain such a decline (Nakamoto et al. 2007). This can be viewed as an example of hormesis – whereby exposure to moderate levels of a stressor leads to increased capacity to combat it in the future (Radak et al. 2008).

Thus while either a single exercise bout or one that is prolonged and continuous without a break for recovery both lead to oxidative damage, regular and intermittent exercise can be beneficial (Radak et al. 2008). Recent work suggests that it is the ROS themselves that are produced by activity that are essential for this hormetic effect (Gomez-Cabrera, Domenech & Vina 2008; Ristow et al. 2009). The effect seems to be mediated by the involvement of low ROS levels in complex redox signalling pathways in the muscle (Powers & Jackson 2008). Thus the removal of ROS (either by dietary antioxidants or by abolishing ROS production with the inhibitor allopurinol) obstructs the exercised–induced upregulation of antioxidant enzymes (Gomez-Cabrera, Domenech & Vina 2008; Ristow et al. 2009). Therefore, while dietary antioxidants can promote short-term benefits by reducing the oxidative damage that can occur during physical activity (Larcombe et al. 2008; Ristow et al. 2009), it is possible that they may also prevent hormesis in the longer term, so that the body is less protected against future exercise-induced ROS. Hence, ROS must be here viewed not only as potentially damaging molecules, but also as regulating agents.

These studies suggest that animals engaged in regular but intermittent intense activity develop antioxidant defences to combat real damage (Williams, Roberts & Elekonich 2008). However, the fact that these defences are not automatically present but must be induced by exercise suggests that they are indeed costly. Moreover, seasonal long-distance migrants may have a lifestyle where prolonged periods with only low levels of daily exercise are followed by continuous muscular activity for many hours. Conversely, we must presume that birds such as swifts Apus spp., which remain in flight continuously for many months after leaving the nest, have evolved the means to cope with unremitting muscular exercise that in other species (even racing pigeons Columba livia, selected for sustained flying ability) causes oxidative stress (Costantini, Dell’Ariccia & Lipp 2008). A comprehensive interspecific analysis that relates life style to oxidative balance is now overdue.

Dietary and seasonal variability

It has been hypothesized that diet composition favours or inhibits oxidative stress. The role of dietary restriction in reducing oxidative stress has been the subject of much research on classical model species (Mair & Dillin 2008), and recent studies suggest that differences in the limitation of specific amino acids may play a key role (Gomez et al. 2009; Grandison, Piper & Partridge 2009). In particular, methionine (Met) in the diet stimulates reproduction and immunity, but its degradation produces methionine sulfoxide that is a dangerous pro-oxidative compound that must be efficiently repaired (Ruan et al. 2002; Minniti et al. 2009). Nonetheless, Grandison, Piper & Partridge (2009) have recently shown that Met does not accelerate ageing in fruitflies, dietary effects being mostly dependent on the exact proportion of several aminoacids. While it is unknown whether similar effects of aminoacid content on oxidative stress are found in wild animals, dietary antioxidants are predicted to vary seasonally in different animals due to changes in both the availability of different food types and in diet choice decisions. As an example, Catoni, Peters & Schaefer (2008a) calculated that badgers Meles meles could have more than a two-fold difference in total dietary antioxidant intake over the course of the year (being lowest in summer), with polyphenols (predominantly in leaves) being most important in summer and anthocynanins (fruit) in autumn/winter. Given that different dietary antioxidants can have widely differing capacities to combat ROS, and act in different cell compartments (e.g. vitamin C and polyphenols in cytoplasm, whereas vitamin E and carotenoids in membranes), this will mean that dietary antioxidants may show great seasonal variation in effectiveness (Catoni, Peters & Schaefer 2008a). While there is evidence that animals are able to choose food types that are rich in antioxidants (Catoni, Peters & Schaefer 2008a; Catoni, Schaefer & Peters 2008b; Schaefer, McGraw & Catoni 2008), it is not yet known whether they can select between different antioxidant-rich food types so as to maintain the optimal balance of antioxidant types throughout the year. Finally, seasonal variation in oxidative damage [e.g. as observed in the blood of land iguanas Conolophus subcristatus (Costantini et al. 2009)] may be due to changes in dietary antioxidant intake, changes in environmentally induced ROS production, or both.

Oxygen availability

Animals that are subjected to hypoxia, as a result of either their regular behaviour (e.g. air-breathers that undergo long dives) or hibernation/aestivation, should face short-term exposure to high levels of ROS production when the tissues become re-oxygenated. Some frogs, snakes and fishes have been shown to exhibit anticipatory increases in antioxidant defences in different tissues through upregulation of enzymes during anoxia (i.e. before the ROS are produced) (Hermes-Lima & Zenteno-Savín 2002). However, this is not a general rule – other species (e.g. the freshwater turtle Trachemys scripta elegans) appear to routinely maintain their antioxidant enzymes at high levels so that further upregulation is not needed, while aestivating desert spadefoot toads Scaphiopus couchii intriguingly decrease their antioxidant enzyme capacity (Hermes-Lima & Zenteno-Savín 2002).

Temperature

Changes in environmental temperatures may also cause oxidative stress, although if they are predictable and/or gradual then there is the potential for adaptive mitigation. Animals may respond to temperature challenges by upregulating antioxidant enzymes in tissues (Selman et al. 2000) and mobilizing dietary antioxidants (Eraud et al. 2007), although this may have knock-on effects such as a decrease in carotenoid-based sexual signals (see below), independent of energetic intake (Eraud et al. 2007). Spotted Wolffish Anarhichas minor acclimate to cold temperatures without increases in oxidative damage (i.e. carbonyl levels and lipid perooxidation), by increasing levels of both antioxidant defences (reduced GSH) and repair mechanisms that degrade oxidatively damaged proteins (proteasome activity) in muscles (Lamarre et al. 2009).

Geography and spatial location

Both antioxidant defences and oxidative damage have been shown to exhibit geographical variation, for instance, in land iguana populations across the Galápagos archipelago (Costantini et al. 2009) and in mussels Mytilus edulis within the Baltic Sea (Prevodnik et al. 2007). Spatial variation may perhaps be related to variation in the level of environmental stress: Prevodnik et al. (2007) suggest that osmoregulatory costs experienced by mussels living in different salinities influences both their ‘background’ oxidative balance and their ability to cope with new stressors such as pollutants. Spatial variability may also be associated with availability of dietary antioxidants. In Adelie penguins Pygoscelis adeliae, dietary isotopes in blood, which reveal foraging grounds, were related to plasma oxidative damage (hydroperoxide amounts), suggesting that penguins foraging in coastal areas feed on a diet depleted in antioxidants (Beaulieu et al. 2010).

Oxidative stress and reproduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Oxidative stress modulating the first steps of life
  5. Oxidative challenges during adulthood
  6. Oxidative stress and reproduction
  7. Oxidative stress and the reproductive investment in signalling
  8. Sexual selection and germline oxidation
  9. Oxidative stress and age-related declines in life functions
  10. Avenues for future research
  11. Acknowledgements
  12. References

Oxidative stress should not only shape adaptations to the environment that allow survival, but should also influence reproduction. Here we address the hypotheses that oxidative stress: (i) constrains reproduction, (ii) favours reproduction, but also that (iii) reproduction increases oxidative stress. The last link might be at the basis of the classical evolutionary trade-off between reproductive investment early in life and the subsequent rate of senescence. We will conclude this section by evaluating the current support for a genetic basis for this trade-off.

Oxidative stress constrains reproduction

The negative impact that oxidative stress may exert on reproduction has been broadly established in mammalian models (Agarwal, Saleh & Bedaiwy 2003; Kaur, Kalia & Bansal 2006). In non-model species, studies have shown how pollutants that cause oxidative damage also impair fecundity or fertility [e.g. in bonnet monkeys Macaca radiata (Subramanian et al. 2006) and red deer Cervus elaphus (Reglero et al. 2009)]. Laboratory studies have also shown that male three-spined sticklebacks Gasterosteus aculeatus with a greater intake of dietary antioxidants and that had less oxidative damage were more attractive to females and were better able to both care for their young and survive the breeding season (Pike et al. 2007a,c). However, evidence of negative impacts of oxidative stress on the reproductive capacity of non-polluted wild organisms is scarce (Bize et al. 2008; Petes, Menge & Harris 2008), although the benefits of dietary antioxidants on fecundity have been documented in a broad range of animal species, suggesting that oxidative stress may in some way constrain reproduction [see Bize et al. (2008) and references therein].

The genetic architecture of these ROS-induced constraints is poorly understood, but could usefully be addressed through a quantitative genetics approach using captive populations. In this vein, a positive genetic correlation between resistance to ROS-induced haemolysis at the age of sexual maturity and number of breeding events throughout life has recently been reported in zebra finches (Kim et al. 2010b).

Oxidative stress stimulates reproduction

It has been proposed that environments that generate high levels of ROS would have favoured the appearance of sexual reproduction among eukaryotes. Damage to germ line DNA is often due to exogenous or endogenous sources of oxidative stress (Lodish et al. 2004), and this damage can be offset by the recombination occurring during meiosis (Michod 1995). Therefore, sexual reproduction could have evolved as a response to a pro-oxidative environment. The alga Volvox carteri can switch between asexual/sexual reproduction, and reproduces asexually when antioxidants are abundant (Nedelcu & Michod 2003) but sexually when in the presence of pro-oxidants (hydrogen peroxide) (Nedelcu, Marcu & Michod 2004).

On the other hand, low levels of ROS act as redox signals promoting many developmental pathways, including specific aspects of reproduction. The most studied radicals involved in redox signalling are probably the superoxide radical and nitric oxide [reviewed in Hurd & Murphy (2009)]. These are not only metabolic by-products, but are also generated as signalling molecules by certain enzymes [NADPH oxidases and nitric oxide synthases (NOS), respectively] (Hurd & Murphy 2009). In some microbial fungi, the presence of NADPH oxidases, and hence, high levels of superoxide radical, have been associated with the development of structures involved in asexual or sexual reproduction (Aguirre et al. 2005). In mammals, NADPH oxidases are present in most part of the reproductive system (Bedard & Krause 2007), suggesting that superoxide signalling may be critical for reproduction. A certain level of nitric oxide (NO) is necessary for mammalian spermatozoid maturation and activation (Revelli et al. 2002). Conversely, it has been shown that high NO levels in the brain of mice inhibit gonadotropin secretion (Clasadonte et al. 2008), which affects the production of sexual steroids. All these findings suggest a direct control of free radicals on the reproduction of vertebrates, which could be modulated by enzymes but also subject to the overall oxidative state of the organism. This again illustrates the role of ROS as regulating agents instead of damaging compounds.

Reproduction increases oxidative stress

Every stage of the reproductive cycle may potentially induce oxidative stress. The cyclic production of oocytes over time could lead to an increased cumulative risk of ovarian oxidative damage (Behrman et al. 2001), and ovulation does indeed induce a rise in the level of oxidative damage in the DNA of ovarian epithelial cells both in ewes and laying hens (Murdoch & Martinchick 2004; Murdoch, Van Kirk & Alexander 2005). Bertrand et al. (2006) showed that the number of eggs produced by zebra finches was negatively correlated with the change in resistance to ROS-induced haemolysis during the breeding period, the relationship disappearing when the birds were supplied with dietary carotenoids. The relationship between oxidative status and egg production may not only be related to the number of eggs, but also to their quality. In red-legged partridges Alectoris rufa, females producing eggs with higher hatching probabilities also had higher levels of lipid peroxidation in their erythrocytes by the end of reproduction (Alonso-Álvarez et al. 2010).

Among mammals, gestation can lead to oxidative stress in the placenta due to increased mitochondrial activity and consequent ROS formation; this can ultimately compromise the life of the mother (Myatt & Cui 2004; Redman & Sargent 2005). Most human-based studies are of severe pathological cases (i.e. pre-eclampsia) (Redman & Sargent 2005), but even healthy women with a ‘normal’ pregnancy experience higher levels of systemic oxidative damage (i.e. lipid hydroperoxides in plasma) than non-gestating women (Toescu et al. 2002). Rearing offspring could also generate oxidative stress. For instance, a decline in the level of uncoupling proteins in the mitochondria of brown adipose tissue has been reported in lactating rodents [Speakman (2008) and references therein], and low levels of uncoupling seem to be responsible for elevated ROS production (Hulbert et al. 2007). Finally, captive zebra finches that were engaged in more breeding attempts showed a weaker resistance to ROS-induced hemolysis (Alonso-Álvarez et al. 2006).

While these correlational studies support the idea that reproductive effort exacerbates oxidative stress, more conclusive evidence comes from experiments. Stimulation of reproduction (either by dietary supplements or by hormonal manipulation) made Drosophila less resistant when exposed to an herbicide with pro-oxidant properties (paraquat) (Salmon, Marx & Harshman 2001; Wang, Salmon & Harshman 2001). In captive zebra finches, those parents that were made to rear experimentally enlarged broods showed weaker resistance to ROS-induced hemolysis (Alonso-Álvarez et al. 2004) and lower activity of antioxidant enzymes in muscles (Wiersma et al. 2004) than control birds. Note, however, that none of these studies directly measured oxidative damage, nor were they carried out in the wild, and so we still lack conclusive evidence of a link between reproductive effort and oxidative stress under realistic environmental conditions.

To conclude, the physiological mechanism(s) that might link reproductive effort and oxidative stress are not fully documented. While increased effort should imply an increase in metabolic rates, which might lead to high ROS production [and hence the potential for oxidative imbalance (Alonso-Álvarez et al. 2004; Wiersma et al. 2004)], an elevated metabolic rate does not necessarily result in greater ROS production, since this also depends on a number of other factors such as the lipid composition of cell membranes or the degree of protein uncoupling in the mitochondria (Barja 2007; Hulbert et al. 2007).

Oxidative stress and antagonistic gene-based signalling pathways

A well-known mechanism connecting oxidative stress with the trade-off between reproduction and self-maintenance is the insulin/insulin-like growth factor signalling pathway (IIS) [reviews in Tatar, Bartke & Antebi (2003); Partridge & Bruning (2008)]. Within this pathway, the forkhead box (FOXO) proteins and their analogues (e.g. DAF-16 in the nematode Caenorhabditis elegans) regulate metabolism, development and fertility, but also oxidative stress resistance (Tatar, Bartke and Antebi 2003; Partridge & Bruning 2008). In vertebrates, FOXO proteins up-regulate genes favouring the repair of oxidatively damaged DNA and antioxidant enzymes (i.e. Mn-SOD), but down-regulate genes promoting the progression of the cell cycle (Tatar, Bartke & Antebi 2003; Partridge & Bruning 2008). The trade-off between reproduction and self-maintenance is not absolute: female (but not male) mice mutants for the insulin-like growth factor type 1 receptor (IGF-1R) live 33% longer than wild-type controls partly through increased tolerance to oxidative stress, but without showing a detectable alteration in fecundity or reproductive senescence (Holzenberger et al. 2003). However, this may depend on the conditions under which the animals are living, as is evident from an intriguing study of the long-lived Indy (for I’m Not Dead Yet) strain of Drosophila melanogaster. This strain has a mutation that alters the normal trade-off between the benefits of increased ATP production and the consequent costs of greater ROS production. Since a step increase in electron-transfer chain (ETC) activity produces a linear increase in ATP production but an exponential increase in ROS production, the cells of Indy flies can produce the same amount of ATP for less ROS by having a greater number of mitochondria running at a lower rate of ETC activity (Neretti et al. 2009). However, Indy mutants suffer a disproportionately reduced fecundity when the food supply is reduced (Marden et al. 2003), which highlights the importance of measuring ecological trade-offs in appropriate environments.

Other relevant components of the IIS pathway in invertebrates are Juvenile Hormone (JH; a gonadotropin) and the yolk precursor protein vitellogenin (Vg) (Seehuus et al. 2006). In insects, the gene encoding for JH promotes sexual development and egg production (Parthasarathy et al. 2009), but can also reduce tolerance to oxidative stress and lifespan (Salmon, Marx & Harshman 2001; Seehuus et al. 2006). Interestingly, JH often upregulates Vg synthesis (Bownes 1994). Since Vg acts as an antioxidant, reducing protein oxidation (Seehuus et al. 2006), this antioxidant activity could serve to counteract the oxidative stress promoted by JH. Nonetheless, experimental work is still required to demonstrate this hypothesis.

Oxidative stress and the reproductive investment in signalling

  1. Top of page
  2. Summary
  3. Introduction
  4. Oxidative stress modulating the first steps of life
  5. Oxidative challenges during adulthood
  6. Oxidative stress and reproduction
  7. Oxidative stress and the reproductive investment in signalling
  8. Sexual selection and germline oxidation
  9. Oxidative stress and age-related declines in life functions
  10. Avenues for future research
  11. Acknowledgements
  12. References

In sexually reproducing species, a key component of reproductive investment is the production of secondary sexual traits (SSTs). It has been proposed that SST production may increase oxidative stress (von Schantz et al. 1999). This hypothesis has been tested over the last decade in the context of the handicap principle, which suggests that some traits evolve as reliable signals of individual quality due to their cost of production, with only the best individuals being able to afford the cost of elaborate SST (Zahavi & Zahavi 1997). Oxidative stress could thus constitute the currency in which this cost is paid. The question then arises about how SST construction induces oxidative stress.

The role of testosterone

As the investment in sexual signals is often male-biased, male sexual hormones, which control the development of primary and also SSTs, might play a significant role in any cost associated with the signal production (i.e. Zahavi & Zahavi 1997). Folstad & Karter (1992) argued that testosterone (T), the major androgen in vertebrates, induces immunosuppression, producing an obligate cost for those males expressing sexual signals (the ‘immunocompetence handicap hypothesis’). Alonso-Álvarez et al. (2007a) refined the idea by predicting that T may also impair the antioxidant machinery (see also von Schantz et al. 1999). They argued that T increases metabolic rate, shifting the balance between ROS generation and antioxidants. In support of this, stimulation of T synthesis led to increased H202 and lipid peroxidation in rat testes (Gautam et al. 2007), zebra finches whose T levels were artificially elevated had weaker resistance to a ROS-induced haemolysis than controls (Alonso-Álvarez et al. 2007a), and injecting their eggs with T produced male (but not female) chicks with lower plasma antioxidant levels (Tobler & Sandell 2009). Moreover, wild male red grouse Lagopus lagopus scoticus whose T levels were experimentally increased showed high circulating antioxidant levels but also higher lipid peroxidation in plasma (Mougeot et al. 2009), although similar manipulations of red-legged partridges produced mixed responses (Alonso-Álvarez et al. 2008, 2009). Finally, captive three-spined sticklebacks implanted with the hormone showed higher acrolein levels (a proxy of lipid peroxidation) in both liver and spleen (Kurtz et al. 2007).

Testosterone may also induce pro-oxidative mechanisms unrelated to metabolic rates. In mammals, it has been shown that high sustained T levels activate NADPH oxidases in vascular endothelia, increasing superoxide and NO levels that lead to hypertension (Reckelhoff 2005). In contrast, female sex steroids (estrogens) appear to enhance antioxidant defences (Halifeoglu et al. 2003; Borrás et al. 2010) and reduce ROS production in mitochondria (Borrás et al. 2010). The role played by sex hormones in the oxidative balance of invertebrates is as yet unexplored.

A range of sexually selected traits may be susceptible to ROS

If metabolic rate is linked to oxidative stress, SSTs whose production requires elevated oxygen consumption should be good candidates to act as signallers of good antioxidant defences. These would include songs (Hasselquist & Bensch 2008), acrobatic displays or aggressive behaviours (Castro et al. 2006; Mowles, Cotton & Briffa 2009), and possibly also pheromones (Johansson & Jones 2007). However, as far we know no study has tried to establish a link between the production of these SSTs and oxidative stress. Instead, studies to date have focused on morphological traits, particularly on pigment-based ornaments. Although it has been proposed that most pigments involved in animal ornaments have antioxidant properties or can be bleached by oxidative stress (McGraw 2005; Catoni, Schaefer & Peters 2008b), here we will focus on those where the link between antioxidant status and intensity of SST expression has at least partially been demonstrated, namely carotenoids and melanins.

Carotenoid-based secondary sexual traits

von Schantz et al. (1999) suggested that SST produced by carotenoids (many yellow–orange–red ornaments) could act as reliable signals of individual quality due to the antioxidant properties of these pigments and the fact that they are only obtained from the diet, that is, they may be limiting resources. Hence, only high quality individuals would be able to face the trade-off between allocating carotenoids to antioxidant defence (homeostasis) or SST production (reproduction). This hypothesis has been extensively tested by evolutionary ecologists, with many correlational or experimental studies finding that animals with a higher carotenoid intake have enhanced SSTs and/or antioxidant defences (reviewed by Pérez-Rodríguez 2009).

However, Hartley & Kennedy (2004) proposed that carotenoids do not serve as functional antioxidant resources in the trade-off, and both a recent metanalysis (Costantini & Møller 2008) and a comparative study of 36 species (Cohen & McGraw 2009) revealed that the correlation between circulating carotenoid levels and markers of oxidative stress is often weak or non-significant in birds, the taxon that has received the greatest attention. The exact role of carotenoids in animal signals has therefore become hotly debated (Pérez-Rodríguez 2009).

Hartley & Kennedy (2004) offered three alternative hypotheses for the link between carotenoid-based signalling and physiological function. First, carotenoid-based SST could signal the capacity of other antioxidant molecules to protect circulating carotenoids from being bleached [named the ‘protection hypothesis’ by Pérez, Lores & Velando (2008)]. Several studies give support to this hypothesis by showing that provision of other antioxidants (e.g. melatonin, or vitamins E and/or C) could enhance carotenoid-based signals (Bertrand, Faivre & Sorci 2006; Pike et al. 2007b; Catoni, Peters & Schaefer 2008a; Pérez, Lores & Velando 2008). Moreover, Pérez, Lores & Velando (2008) found that an increase in circulating carotenoids was restricted to those carotenoid types that gave colour to STTs, suggesting that endogenous carotenoid biotransformation is costly in terms of oxidative stress, so that carotenoid-based SSTs could reveal the capacity of the bearer to pay the cost of carotenoid biotransformation. However, we are far from knowing whether these biochemical transformations actually generate oxidative stress.

As a second hypothesis, Hartley & Kennedy (2004) proposed that carotenoid-based traits may signal other qualities, since they participate in functions apparently unrelated to oxidative stress, such as cell signalling, gene activation, immuno-regulation, tissue repair, morphogenesis, synthesis of visual pigments and cell proliferation. We will name it the ‘alternative function’ hypothesis. However, many of these functions are not fully independent from oxidative stress because alterations in redox signalling systems are part of the oxidative stress concept (Jones 2006). For instance, in the case of immune regulation, carotenoids help prevent damage during inflammatory responses by modulating the production of NO and superoxide radicals, which are also used in destroying pathogens (Halliwell & Gutteridge 2007). The capacity of carotenoids to modulate gene expression may also be mediated by redox-sensitive transcription factors.

Finally, carotenoids may potentially act as pro-oxidants when at very high doses (El Agamey et al. 2004) and hence individuals producing carotenoid-based traits would reveal their capacity to endure this handicap. However, we know of no examples of carotenoids acting as pro-oxidants when ingested at levels within the natural range.

Melanin-based ornaments

Melanins are probably the most abundant pigment in animals and have a broad range of functions, including protection against UV-induced lipid peroxidation and free radical scavenging (Rozanowska et al. 1999). Melanins give colour to ornaments involved in sexual selection but also in the establishment of social status (Tibbetts & Safran 2009). It has been suggested that melanin-based ornaments reliably signal the capacity of the bearer to combat oxidative stress (McGraw 2005; Moreno, J. & Møller 2006). As with carotenoids, alternative physiological mechanisms have been proposed to explain the hypothesis. These include a simple allocation trade-off between antioxidant defence and SSTs (McGraw 2005, 2006): while melanins are synthesized by the organism and hence cannot force a resource trade-off, it has been suggested that their precursors (some essential amino acids and minerals) could meet this theoretical requirement (McGraw 2006). Second, melanogenesis could be particularly sensitive to oxidative stress (Schallreuter et al. 2008), and hence, only individuals with good antioxidant defences would be able to produce high levels of melanin (Moreno, J. & Møller, A.P. 2006). The idea could thus resemble the protection hypothesis (Hartley & Kennedy 2004) for carotenoids. Third, melanin-based traits could signal the overall oxidative stress of the organism due to the role of antioxidants in melanin synthesis (see below) (Galván & Alonso-Álvarez 2008, 2009).

Paradoxically, the last hypothesis assumes that oxidative stress promotes melanin production. Melanization may initially have evolved as a protection mechanism against environmental challenges (Plonka et al. 2009). ROS stimulate melanin synthesis by participating in redox signalling within the melanocyte (Schallreuter et al. 2008), but also decrease the levels of key intracellular antioxidants such as GSH (Smit et al. 2008). Conversely, high GSH levels inhibit the synthesis of eumelanin, one of the two types of melanin producing most black-greyish colours (Galván & Alonso-Álvarez 2008 and references therein). In partial support of this, Galván & Alonso-Álvarez (2008) found that chemically inhibiting GSH synthesis in great tit (Parus major) nestlings led to an increase in the size of the (eumelanin-based) black breast stripe, but also an increase in concentrations of other antioxidants in the blood. They proposed that individuals producing large eumelanin-based traits should compensate for the reduction in GSH by mobilizing alternative antioxidants. In a second experiment, they increased ROS levels in young red-legged partridges by adding a pro-oxidant (diquat) in the drinking water, and observed a decline in GSH levels and an increase in eumelanin-based coloration (Galván & Alonso-Álvarez 2009). A recent study supports the hypothesis as greenfinches (Carduelis chloris) whose GSH levels were chemically inhibited by the same procedure described in Galván and Alonso-Álvarez (2008) produced tail feathers with higher eumelanin content and simultaneously had a higher level of oxidative damage (plasma lipid peroxidation) than controls (Hõrak et al. 2010).

In addition, an alternative hypothesis can be proposed, which would resemble the toxicity hypothesis proposed by Zahavi & Zahavi (1997) for carotenoids. Since melanin synthesis is a process that generates ROS and pro-oxidative cleavage products (Rozanowska et al. 1999), it is possible that melanogenesis is a cost unaffordable for individuals with inefficient antioxidant defences. However, it is clear that more work is necessary to clarify the connections between these mechanisms before these alternative hypotheses can be properly evaluated.

Sexual selection and germline oxidation

  1. Top of page
  2. Summary
  3. Introduction
  4. Oxidative stress modulating the first steps of life
  5. Oxidative challenges during adulthood
  6. Oxidative stress and reproduction
  7. Oxidative stress and the reproductive investment in signalling
  8. Sexual selection and germline oxidation
  9. Oxidative stress and age-related declines in life functions
  10. Avenues for future research
  11. Acknowledgements
  12. References

Up to this point, we have only considered the influence exerted by oxidation on the soma. Here we will address the evolutionary consequences of oxidative stress for the germline. Recently, Velando, Torres & Alonso-Álvarez (2008) and Dowling & Simmons (2009) hypothesized that individuals of the choosy sex should avoid mates with oxidative-induced damage to germline DNA (see also Blount, Møller & Houston 2001). Oxidative stress imposes changes to DNA that could be transmitted to viable offspring by common genetic inheritance (mutations) and/or by epigenetic inheritance (Velando, Torres & Alonso-Álvarez 2008). These changes will mostly be detrimental: many heritable diseases have been linked to sources of oxidative stress [e.g. radiation, xenobiotics; Velando, Torres & Alonso-Álvarez (2008)]. An individual with oxidized DNA in its germline may be a poor choice of mate not only because of reduced fertility, but also because it may produce less viable offspring (Blount, Møller & Houston 2001; Velando, Torres & Alonso-Álvarez 2008). Furthermore, oxidation of the germline DNA would promote genetic variability in the population by increasing mutation rates, accelerating evolution and favouring the appearance of sexual signals linked to the antioxidant status of the bearer (Velando, Torres & Alonso-Álvarez 2008).

Male germline should be particularly prone to oxidative stress due to the particular spermatozoid characteristics (Velando, Torres & Alonso-Álvarez 2008; Dowling & Simmons 2009). Support for the link between SST and germline oxidative status is now forthcoming: the expression of carotenoid-based ornaments in male great tits has been negatively correlated with lipid peroxidation in sperm (Helfenstein et al. 2010), while manipulation of carotenoid intake in sticklebacks has shown direct links between a male’s sexual coloration, his antioxidant status and his fertility (Pike et al. 2010). It is also possible that sperm competition is mediated by the level of oxidative damage of spermatozoids (Velando, Torres & Alonso-Álvarez 2008; Dowling & Simmons 2009), and that females could develop mechanisms to prevent the fertilization of oocyte by those spermatozoids carrying oxidized DNA. Furthermore, while fertilized oocytes can repair DNA damage during the first embryonic stages (Ashwood-Smith & Edwards 1996), female fruit flies in poor nutritional condition are less able to repair oxidative damage in sperm DNA than females in good condition (Agrawal & Wang 2008), which might favour male mate choice mechanisms that discriminate against females unable to repair oxidized sperm DNA.

Oxidative stress and age-related declines in life functions

  1. Top of page
  2. Summary
  3. Introduction
  4. Oxidative stress modulating the first steps of life
  5. Oxidative challenges during adulthood
  6. Oxidative stress and reproduction
  7. Oxidative stress and the reproductive investment in signalling
  8. Sexual selection and germline oxidation
  9. Oxidative stress and age-related declines in life functions
  10. Avenues for future research
  11. Acknowledgements
  12. References

There is currently much debate over the importance of oxidative stress in the ageing process (Lapointe & Hekimi 2010; Salmon, Richardson & Perez 2010), but a detailed discussion of the biochemical links between oxidative stress, ROS and senescence is beyond the scope of this review. Instead, we will describe how markers of oxidative stress vary with age, partly to aid in the interpretation of results from free-living animals and to emphasize the necessity of longitudinal approaches. Finally, we will address how oxidative-mediated ageing determines breeding senescence and production of SSTs.

Ageing-related variability in oxidative stress markers

Levels of oxidative stress may increase in old age, due to an increase in the rate of ROS production (as mtDNA accumulates more damage) and/or a fall in antioxidant defences. In a longitudinal study in zebra finches, the erythrocyte resistance to a ROS-induced haemolysis increased during first part of life to decline at older ages (Alonso-Álvarez et al. 2006). Similar patterns can also be revealed by cross-sectional studies: oxidative stress [i.e. MDA and oxidized GSH (GSSG) levels in erythrocytes] increased from middle age onwards in red-legged partridges (Alonso-Álvarez et al. 2010). However, such studies can also provide conflicting results: in Daphnia magna SOD, CAT and total GPx activities all declined with age up to the age of 60 days, but were then unexpectedly higher again in 75-day-old individuals, while lipid peroxidation levels (MDA) showed the opposite pattern (Barata et al. 2005). A similar age-related U-shaped pattern has been described in the antioxidant enzymes of rats (Chandwaney et al. 1998). The problem in interpreting these data is that animals sampled in old age (when the cohort is already much diminished in size) would be biased towards the fittest individuals that happen to survive that long – moreover, antioxidant levels may be elevated because of the increased production of ROS, making it difficult to interpret causal patterns from analysis of antioxidant defences alone (Monaghan, Metcalfe & Torres 2009).

Damage repair systems may also show age-related changes. There is a decline in the expression of genes associated with repair of oxidative damage to DNA in the wing muscles of ageing honeybee workers, which is greater than that seen in queens (Aamodt 2009), but it is unknown whether there is an increase in mutation load in these non-reproductive animals and whether this influences either their lifespan or colony fitness.

Finally, the genetic basis for the decline in antioxidant and repair efficiency is still unclear (Paaby & Schmidt 2009). Selection experiments in Drosophila have produced long lived strains with increased expression of genes associated with antioxidant enzymes, and of levels of those enzymes, but comparisons among strains reveal that the same effect of increased lifespan can be produced by alterations of different genes involved in the antioxidant enzymes (Arking et al. 2000a,b), indicating that there is likely to be little generality in the exact mechanisms by which antioxidant systems are traded off against other life history traits.

Reproductive senescence and age-related decline in sexual signalling

The solution of the evolutionary trade-off between reproduction and self-maintenance may give rise to a decline in reproductive function with age due to oxidative stress. ROS have been shown to induce damage to the germline of mammals, affecting oocytes, spermatozoids and sex-steroid secreting tissues, and leading to an age-related loss of fecundity (Martin & Grotewiel 2006; Angelopoulou, Lavranos & Manolakou 2009). In Drosophila, individuals with a greater capacity for repairing oxidized methionine showed delayed reproductive senescence (Ruan et al. 2002). However, as far as we know, the link between ROS and reproductive ageing has not been established in free-living animals.

As SSTs should be particularly dependent on condition (von Schantz et al. 1999), we might expect that these would be the first traits to show senescence (although it can also be argued that the selection intensity faced by SSTs should result in them being very resistant to senescence). Evidence of links between oxidative status and the senescence of SSTs, as far as we know, only comes from birds and a fish species. In blue-footed boobies Sula nebouxii, old males had duller carotenoid-dependent sexual signals (foot colour) than younger males (Torres & Velando 2007), although their colour can improve following a ‘sabbatical’ rest from breeding (Velando, Drummond & Torres 2010). Moreover, the experimental induction of an inflammatory response, which increases ROS levels, induced greater fading of sexual colours in older males (Torres & Velando 2007). Similarly, older male red-legged partridges showed paler carotenoid-based traits, and were less able to increase the intensity of those traits when stimulated with exogenous testosterone (Alonso-Álvarez et al. 2009). While old male zebra finches did not exhibit paler carotenoid-based signals (red beaks) than younger ones, they were less able to sustain these signals when exposed to an experimental inflammatory insult (Cote et al. 2010), and the fading of the red sexual ornamentation in three-spined sticklebacks was faster in males that had a reduced access to dietary carotenoids (Lindström et al. 2009).

Avenues for future research

  1. Top of page
  2. Summary
  3. Introduction
  4. Oxidative stress modulating the first steps of life
  5. Oxidative challenges during adulthood
  6. Oxidative stress and reproduction
  7. Oxidative stress and the reproductive investment in signalling
  8. Sexual selection and germline oxidation
  9. Oxidative stress and age-related declines in life functions
  10. Avenues for future research
  11. Acknowledgements
  12. References

It is obvious that the integration of oxidative stress into mainstream evolutionary and physiological ecology is still in its infancy, but there is a great potential for exploring its role in shaping the design of life history traits. The emphasis should now be on trying to solve methodological limitations [e.g. of measuring ROS production (Monaghan, Metcalfe & Torres 2009)] and on rigorous testing of the hypotheses that have been posed in recent years.

Future studies should also consider what tissue is used to estimate oxidative stress. In vertebrates, evolutionary ecologists mostly focus on blood because it is easily sampled and avoids killing animals, so allowing repeated measurements from the same individual. Contrarily, gerontologists have traditionally studied tissues without regenerative potential (i.e. post-mitotic tissues such as muscles or neuronal tissue) because they accumulate damage. Although studies of rats show that measures of blood oxidative stress markers strongly correlate with those from post-mitotic tissues (Argüelles et al. 2004; Veskoukis et al. 2009), evolutionary ecologists should increase the range of analysed tissues to understand what is happening in the organism as a whole.

Another crucial point here is to emphasize the need for longitudinal approaches, preferably using free-living animals, to help interpret results from lab experiments. The vast majority of studies of oxidative balance in animals involve a single measurement point taken from animals held in conditions to which they might not be adapted. Even those studies examining changes in oxidative stress with age have often used cross-sectional samplings, so there is little direct evidence for how life history or environmental conditions influence oxidative stress (and vice versa). This is an important limitation since it is clear from this review that different phases of an animal’s life present different challenges in terms of oxidative balance. Moreover, the ultimate consequences of those trade-offs where oxidative stress is involved should be explored over the long term. For instance, although oxidative stress during early development seems to increase the short-term mortality risk (e.g. in human preeclampsia) (Redman & Sargent 2005), the potential long-lasting effects are still unknown (e.g. accelerated aging or reproductive senescence).

The incorporation of redox signalling is also a great challenge for the future. Genomics approaches now offer the possibility of measuring gene expression and so understanding how these signals act in the interplay between different organismal functions. In this context, the impact that growth or breeding effort may impose on the delicate redox signalling machinery remains to be explored. Similarly, the hypothesis that ROS production does not strictly depend on metabolic rates but instead on the interaction between metabolic efficiency and lipid composition of cell membranes and on the degree of protein uncoupling in mitochondria (Barja 2007; Hulbert et al. 2007) should be addressed in both an evolutionary and a developmental context, trying to understand how these parameters change over both evolutionary time and the lifespan of an individual. The tools of quantitative genetics should also be used more widely in order to establish heritabilities and genetic correlations involved in oxidation trade-offs (Olsson et al. 2008; Kim et al. 2010b). Finally, the study of the consequences of oxidative damage to germline DNA for subsequent generations is an exciting future research field, given that it has implications for environmental effects on epigenetic inheritance, sexual selection and rates of evolution.

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  1. Top of page
  2. Summary
  3. Introduction
  4. Oxidative stress modulating the first steps of life
  5. Oxidative challenges during adulthood
  6. Oxidative stress and reproduction
  7. Oxidative stress and the reproductive investment in signalling
  8. Sexual selection and germline oxidation
  9. Oxidative stress and age-related declines in life functions
  10. Avenues for future research
  11. Acknowledgements
  12. References
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