Review
Animal response to drastic changes in oxygen availability and physiological oxidative stress

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Abstract

Oxygen is essential for most life forms, but it is also inherently toxic due to its biotransformation into reactive oxygen species (ROS). In fact, the development of many animal and plant pathological conditions, as well as natural aging, is associated with excessive ROS production and/or decreased antioxidant capacity. However, a number of animal species are able to tolerate, under natural conditions, situations posing a large potential for oxidative stress. Situations range from anoxia in fish, frogs and turtles, to severe hypoxia in organs of freeze-tolerant snakes, frogs and insect larvae, or diving seals and turtles, and mild hypoxia in organs of dehydrated frogs and toads or estivating snails. All situations are reminiscent of ischemia/reperfusion events that are highly damaging to most mammals and birds. This article reviews the responses of anoxia/hypoxia-tolerant animals when subjected to environmental and metabolic stresses leading to oxygen limitation. Abrupt changes in metabolic rate in ground squirrels arousing from hibernation, as well as snails arousing from estivation, may also set up a condition of increased ROS formation. Comparing the responses from these diverse animals, certain patterns emerge. The most commonly observed response is an enhancement of the antioxidant defense. The increase in the baseline activity of key antioxidant enzymes, as well as ‘secondary’ enzymatic defenses, and/or glutathione levels in preparation for a putative oxidative stressful situation arising from tissue reoxygenation seem to be the preferred evolutionary adaptation. Increasing the overall antioxidant capacity during anoxia/hypoxia is of relevance for species such as garter snakes (Thamnophis sirtalis parietalis) and wood fogs (Rana sylvatica), while diving freshwater turtles (Trachemys scripta elegans) appear to rely mainly upon high constitutive activities of antioxidant enzymes to deal with oxidative stress arising during tissue reoxygenation. The possibility that some animal species might control post-anoxic ROS generation cannot be excluded.

Introduction

Oxygen (O2) is an essential gas for most life forms. However, formation of reactive oxygen species (ROS) is associated with the development of many animal and plant pathological conditions as well as natural aging (Beckman and Ames, 1998, Halliwell and Gutteridge, 1999). The term ROS includes superoxide radical (O2radical dot), hydrogen peroxide (H2O2), hydroxyl radical (radical dotOH), singlet oxygen, ozone, lipid peroxides, nitric oxide (NO) and peroxynitrite (ONOO, also classified as a reactive nitrogen species (RNS) formed by the reaction of NO and O2radical dot). Singlet oxygen,radical dotOH and ONOO are the most relevant chemical agents in the direct induction of oxidative damage in biological systems. Endogenous antioxidant defenses of enzymatic and non-enzymatic nature are crucial for the control of ROS/RNS-mediated oxidative damage of biomolecules, including proteins, RNA, DNA and membrane polyunsaturated lipids (Beckman and Ames, 1997, de Zwart et al., 1999, Stadtman and Levine, 2000).

Organisms have many sites of ROS formation including the ‘leaky’ mitochondrial respiratory chain (1–4% of O2 consumed by mammalian mitochondria is converted to ROS), NADPH-oxidase of phagocytes, P450 systems, soluble oxidases and the autoxidation of many small molecules. Key enzymatic players in the defense mechanism against ROS include catalase, superoxide dismutases (Mn- and CuZn-SOD), glutathione (GSH) reductase (GR), selenium-dependent glutathione peroxidase (Se-GPX), selenium independent GPX, glutathione S-transferases (GST), glutaredoxin, thioredoxin and thioredoxin reductase. Non-enzymatic defenses of endogenous and dietary sources include GSH, vitamin E, ascorbate, carotenoids, polyphenols, uric acid and bilirubin. These defenses work in concert to keep ROS (and consequently the several toxic by-products of oxidative damage, such as aldehydes) at non-threatening levels in the cells (Ahmad, 1995, Halliwell and Gutteridge, 1999, Wilhelm Filho et al., 2000).

When the rate of ROS formation is excessive it can overwhelm the antioxidant capacity of organisms, creating oxidative stress (Sies, 1986). Organisms are able to adapt themselves to some chronic situations of high exposure to ROS by increasing the expression of antioxidant enzymes and many other forms of defense/response and repair of oxidative damage (Demple, 1999, Halliwell and Gutteridge, 1999). Indeed, it is currently known that over 100 genes are activated upon exposure of mammalian cells to ROS (Allen and Tresini, 2000).

Furthermore, the secrets of the molecular machinery leading to ROS-activation of defense mechanisms are currently intensively explored. Many efforts in the last decade have shown that ROS and RNS, particularly H2O2 and NO, are second messengers in many transduction signaling pathways (such as those involving tyrosine kinase membrane receptors, Ras, MAP kinases, protein kinase C and nuclear factor κB (NFκB)) mediating responses to oxidative stress and pathological/paracrine stimuli (Kamata and Hirata, 1999, Allen and Tresini, 2000). Endogenous generation of ROS is also involved in transduction pathways connected to the mechanisms of O2 sensing and consequent physiological response (Kietzmann et al., 2000, Semenza, 2000).

Section snippets

Ischemia and reperfusion: mammals vs. anoxia-tolerant animals

This article reviews the antioxidant response of animals to certain situations of physiological oxidative stress; specifically, in anoxia/hypoxia-tolerant animals when subjected to wide variations of O2 tensions. Many species of insects, mollusks, fish, amphibians and reptiles are able to survive periods ranging from hours to months without O2. There are many studies on the behavioral, physiological, biochemical and molecular mechanisms of adaptation to life without O2 (for relevant

Anoxia tolerance in garter snakes and antioxidant defenses

In the early 1990s, in collaboration with Kenneth B. Storey and Janet M. Storey, from Carleton University (Ottawa, Canada), we started to investigate the biochemical mechanism for the tolerance of certain animals to the stress of reoxygenation following anoxia exposure. Our initial working hypothesis was the presence of a very powerful enzymatic antioxidant system that could withstand a putative post-anoxic overgeneration of ROS.

We started working with red-sided garter snakes Thamnophis

The case of anoxia-tolerant leopard frogs, goldfish and marine gastropods

In order to address the full cycle of anoxia and reoxygenation, we investigated how these conditions would affect the antioxidant capacity of two other species: the leopard frog, Rana pipiens (30-h anoxia and 40-h recovery, at 5 °C; Hermes-Lima and Storey, 1996) and goldfish, Carassius auratus (8-h anoxia and 14-h recovery, at 20 °C; Lushchak et al., 2001). Moreover, the work by Pannunzio and Storey (1998) on anoxia-tolerant marine gastropods helped to build-up on the subject.

Leopard frogs

Anoxia tolerance in turtles

An interesting behavior by antioxidant enzyme activities was found when exposing red-eared slider turtles Trachemys scripta elegans to anoxic submergence (20 h in deoxygenated water at 5 °C). These studies were not only relevant to understand adaptation to reoxygenation following anoxia exposure in underwater hibernation, but also to reoxygenation following extended dives, when circulatory adjustments can cause severe hypoxia in some organs due to the shunting of O2 to vital organs (Storey,

Frozen and alive: adaptations against oxidative stress

Several species of reptiles and amphibians that overwinter in cold climates allow freezing of their tissues as a hibernation strategy. During freezing, ice propagates through extracellular spaces (in some animals it is controlled by ice-nucleating proteins) and blood circulation to organs slowly diminishes until full arrest. If freezing propagates inside cells, it is then fatal to animals (Storey et al., 1996). Over the course of a freezing episode, tissues show the typical vertebrate response

Dehydration tolerance in anurans vs. oxidative stress

There are other situations in which physiological oxidative stress is dealt with in certain animals by means of special adaptations in the antioxidant apparatus. We shall briefly discuss what happens during severe dehydration tolerance in anurans (this section) and estivation in gastropods (see following section).

Amphibians—in contrast to mammals, birds and reptiles—have a highly water permeable integument and may lose of 6–9% of body weight per day (Hillman, 1980). Several semi-aquatic species

Metabolic depression and estivation in land snails

We also analyzed the role of antioxidant enzymes and GSH in the process of estivation and awakening in land snails. These gastropods retreat into their shells, which they seal with a mucous epiphragm to minimize evaporative water loss, whenever environmental conditions dry out. Some species, such as Otala lactea, Helix pomatia, Helix aspersa and Pila ovata, drastically reduce their metabolic rate (to 10–30% of the normal rate; studies performed at 20–30 °C) within few days under estivation (

Hibernation in squirrels and oxidative stress

The idea of physiological oxidative stress following arousal has also been proposed for hibernating Arctic ground squirrels Spermophilus parryii and 13-lined ground squirrels Spermophilus tridecemlineatus. During the 8-month hibernation season, O2 consumption falls to 2% of basal levels. It then rises to 300% of hibernating levels during periodic arousals (Boyer and Barnes, 1999), which happens once every 1–2 weeks for periods of approximately 24 h. Body temperature increases from 2 to 37 °C,

Diving seals and reoxygenation stress

Seals are well adapted to living in the ocean, and breath-hold diving is part of their everyday routine. To maximize the use of the large amounts of O2 stored in blood and tissues during a dive, blood flow is diverted from peripheral organs (muscle and viscera) towards the most O2-sensitive tissues, i.e. the central nervous system (Dormer et al., 1977, Guppy et al., 1986). Coronary blood flow is highly decreased and becomes intermittent during diving. Responses of seal heart reflect the

Gene regulation by ROS in hypoxia and anoxia

The most recent line of studies is related to antioxidant adaptation, role of protein kinases (including PKC, JNK and p38) and differential regulation of gene expression in animals enduring hypometabolic conditions triggered by anoxia and freezing exposure (Hermes-Lima et al., 2001, Storey, 1999, Storey and Storey, 2001). These new molecular biology studies have shown that although overall rates of protein synthesis are depressed under hypometabolism, the synthesis of some proteins and their

General discussions, conclusions and perspectives

Hypoxia, even for brief periods, can be detrimental or fatal to humans and most mammals and birds. However, many species of invertebrates, fish, amphibians and reptiles, as well as some diving mammals are adapted to endure hypoxia or anoxia exposure from periods of hours to months. Much has been elucidated in the past two decades on the biochemical and physiological adaptation mechanisms that make these animals endure O2 deprivation (Ultsch, 1989, Storey and Storey, 1990, Pinder et al., 1992,

Acknowledgements

This work was supported by grants from CNPq, PRONEX (Brazil) and International Foundation for Science (Sweden) to M. Hermes-Lima and from Office of Naval Research (N00014-00-0314, USA), UC Mexus (USA-Mexico) and CIBNOR (PAC6, Mexico) to T. Zenteno-Savı́n. We thank Andréia A.L. Torres, Cassia Polcheira, Marcus V.R. Ferreira and Dr Élida G. Campos (Universidade de Brası́lia) for helping with the manuscript writing and for interesting discussions, as well as four anonymous reviewers for providing

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    This paper was presented at the Workshop on Comparative Aspects of Oxidative Stress in Biological Systems, held in La Paz, Baja California Sur, Mexico, October 17–19, 2001.

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