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(The FASEB Journal. 2001;15:1181-1186.)
© 2001 FASEB

Acute hypoxia and hypoxic exercise induce DNA strand breaks and oxidative DNA damage in humans

PETER MØLLER1, STEFFEN LOFT, CARSTEN LUNDBY and NIELS VIDIENDAL OLSEN

Department of Pharmacology and Institute of Public Health, The Panum Institute, University of Copenhagen. Department of Neuroanaesthesia, The Neuroscience Center, Copenhagen University Hospital, DK-2200 Copenhagen N, Denmark

1Correspondence: Institute of Public Health (c/o Department of Pharmacology), The Panum Institute, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark. E-mail: fipm{at}farmakol.ku.dk


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The present study investigated the effect of a single bout of exhaustive exercise on the generation of DNA strand breaks and oxidative DNA damage under normal conditions and at high-altitude hypoxia (4559 meters for 3 days). Twelve healthy subjects performed a maximal bicycle exercise test; lymphocytes were isolated for analysis of DNA strand breaks and oxidatively altered nucleotides, detected by endonuclease III and formamidipyridine glycosylase (FPG) enzymes. Urine was collected for 24 h periods for analysis of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), a marker of oxidative DNA damage. Urinary excretion of 8-oxodG increased during the first day in altitude hypoxia, and there were more endonuclease III-sensitive sites on day 3 at high altitude. The subjects had more DNA strand breaks in altitude hypoxia than at sea level. The level of DNA strand breaks further increased immediately after exercise in altitude hypoxia. Exercise-induced generation of DNA strand breaks was not seen at sea level. In both environments, the level of FPG and endonuclease III-sensitive sites remained unchanged immediately after exercise. DNA strand breaks and oxidative DNA damage are probably produced by reactive oxygen species, generated by leakage of the mitochondrial respiration or during a hypoxia-induced inflammation. Furthermore, the presence of DNA strand breaks may play an important role in maintaining hypoxia-induced inflammation processes. Hypoxia seems to deplete the antioxidant system of its capacity to withstand oxidative stress produced by exhaustive exercise.—Møller, P., Loft, S., Lundby, C., Olsen, N. V. Acute hypoxia and hypoxic exercise induce DNA strand breaks and oxidative DNA damage in humans.


Key Words: FPG • high-intensity exercise • ENDO III • reactive oxygen species


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
STRENUOUS EXERCISE MAY increase the production of reactive oxygen species (ROS), leading to a situation of oxidative stress that has been discerned by detection of oxidatively damaged DNA bases and lipid peroxidation products (1) . In humans, the available data suggest that immediately after exercise, the level of oxidative damage to DNA is unchanged whereas DNA damage may appear hours after the exercise (2) . A similar situation has been reported for DNA strand breaks, where DNA strand breaks first appeared hours after an exhaustive running on a treadmill (3) . It has also been reported that a higher level of DNA strand breaks appeared after strenuous bicycling (4) . It appears that in normal healthy subjects, a short bout of maximal exercise is usually not sufficiently strenuous to cause significant effects on biomarkers of oxidative stress immediately after exercise. This is probably because the antioxidant response system can cope with an increased load of ROS generated by a short bout of exhaustive exercise.

It is well known that exposure to low oxygen pressure leads to a complex scenario of both metabolic and physiological changes. The stress induced by hypoxia leads to an imbalance between antioxidant capacity and oxidants, and can consequently be observed by many biomarkers of oxidative stress. Rats exposed to hypobaric oxygen pressure showed a higher level of oxidized glutathione 48 h after exposure to hypoxia (5) . Lipid peroxidation, detected by an elevated malondialdehyde concentration in plasma and a lower level of glutathione in blood, was observed in rats exposed intermittently to hypoxia (equal to 7576 meters) for 6 h daily for 5 consecutive days (6) .

The effects of low oxygen pressure in humans have been investigated in altitude studies for years. A stay at 5500 meters increased breath pentane by 104% after 4 wk, and this effect was ameliorated by pretreatment with vitamin E (7) . Altitude studies performed 1650–3048 meters above sea level for 1–2 wk including exercise programs revealed increased lipid peroxidation and urinary 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) levels compared with levels obtained at lower altitudes (8 9 10) . Although these data indicate that exercise in altitude is accompanied by oxidative stress, they do not discriminate between the effect of exercise and hypoxia.

The objective of this study was to investigate whether altitude hypoxia makes normal healthy individuals more prone to generate DNA strand breaks and oxidative DNA damage after a single bout of exhaustive exercise. The oxidative DNA damage 8-oxodG was measured by HPLC; DNA strand breaks, endonuclease III (ENDO III) -sensitive sites, and formamidopyrimidine DNA glycosylase (FPG) -sensitive sites were detected by the single cell gel electrophoresis (comet assay) (11) . Both ENDO III and FPG are DNA glycosylase enzymes that hydrolyze the N-glycosylic bond between the deoxyribose and a damaged base. The types of DNA damage detected by ENDO III are a broad spectrum of oxidatively damaged pyrimidines; the FPG glycosylase detects oxidative purine lesions (12) .


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Subjects and experimental protocol
Twelve healthy subjects (5 females and 7 males), aged 26.1 ± 4.9 years, with a maximal VO2 uptake rate of 3.9 ± 0.6 l/min, a body weight of 73.5 ± 9.5 kg, and a height of 179 ± 15 cm (means ± SD) were included in the study. The subjects entered the study after having given their written informed consent. The study was approved by the local ethical committee of Copenhagen county. Separated by an interval of 7 days, identical test protocols were performed on two locations: sea level experiments were carried out at the Copenhagen Muscle Research Center, and high-altitude studies at the Capanna Regina Margherita on the mountain of Monte Rosa, Italy (4559 meters above sea level). The subjects arrived at the high-altitude laboratory in the afternoon by helicopter after an overnight stay at Zermatt, Switzerland. Experiments were started on the next day (19 h after the arrival to the altitude laboratory). Each morning the subjects were scored for acute mountain sickness (AMS) according to the Lake Louise symptom score (13) . Each symptom—headache, gastrointestinal symptoms, fatigue, and/or weakness, dizziness/lightheadedness, and difficulty of sleeping—was assessed on a scale from 0 to 3 (maximal attainable score=15).

The exercise protocol started by a 5 min warm-up at 120 watt and 80 rpm on a Monark 848 cycle ergometer (Monark, Sweden), followed by a submaximal exercise test for 5 min, electing ~50% of the estimated maximal oxygen uptake (VO2max) at sea level. Immediately thereafter, the maximal exercise test was started. The start load was estimated from the submaximal exercise and the workload was increased by 40 watts every 90 s until exhaustion. The VO2max and heart rate (HR) were recorded. The VO2max situation was accepted if the oxygen uptake reached a plateau, the plasma lactate concentration was above 8 mmol/l, or the respiratory exchange rate was above 1.15. The HR was measured with a Polar Vantage XL (Oy, Finland); oxygen saturation was recorded continuously by a Nellcor pulse oximeter (Haywar) with the sensor attached to a fingertip. Gas exchange was recorded every 15 s with a MedGraphic CPX/d system (St. Paul, MN).

Twenty-four hour urine collections were obtained before and after the exercise protocol both at sea level and at high altitude. The first urine collection at high altitude was commenced immediately after arrival. The subjects were instructed to empty their bladder before start of the urine collection. In both environments, blood samples were obtained before, immediately after, 1 day (24 h), and 2 days (48 h) after the exercise session.

Isolation of lymphocytes
Ten milliliter venous blood were placed in Vacutainer®CPTTM with sodium heparin (Becton Dickinson and Company, Rutherford, NJ) and centrifuged 1650 g for 20 min at room temperature. The plasma/lymphocyte layer was removed, washed in cold RPMI 1640 media (Gibco, Grand Island, NY), and centrifuged at 400 g for 15 min at 4°C. Most of the supernatant was removed and the pellet was resuspended in cold RPMI 1640 media supplemented with 50% bovine calf serum and 10% dimethyl sulfoxide. At sea level, the lymphocytes were stored at -70°C until analysis. At high altitude, the lymphocytes were stored in liquid nitrogen and thereafter transferred to -70°C at the return to Denmark. The possible influence of storage in liquid nitrogen was investigated in a separate experiment including blood samples from 5 donors.

Detection of DNA strand breaks and oxidative DNA damage
The procedure of the comet assay was the same as has been described previously (14) . The isolated lymphocytes were mixed with 90 µl low melting point agarose and applied on a fully frosted microscope slide that had been covered with 90 µl high melting point agarose. The cells were lysed overnight in lysis solution (1% Triton X-100, 2.5 mM NaCl, 0.1 Na2EDTA, 10 mM Tris, pH=10) and rinsed three times in buffer (40 mM HEPES, 0.1 M KCl, 0.5 mM EDTA, 0.2 mg/ml BSA, pH=8). To detect oxidative DNA damage and DNA strand breaks, the nucleoids were incubated in with either ENDO III, FPG, or buffer for 45 min at 37°C (enzymes were a kind gift from Serge Boiteaux, UMR217 Center National de la Recherche Scientifique et Commissariat a l’Energie Atomique, France). Immediately after the enzyme treatment, the nucleoids were immersed to an alkaline solution (0.3 M NaOH, 1 mM Na2EDTA, pH>13) for 40 min and electrophoresed for 20 min in the same alkaline solution (procedures were carried out in a 4°C cold room). The electrophoresis solution was recycled at a rate of 3.6 l/h. After electrophoresis, the lymphocytes were washed twice in Tris buffer (0.4 M Tris-HCl, pH=7.5) and stained with YOYO-1 in PBS (Molecular Probes, Eugene, OR) and viewed in an Olympus fluorescence microscope. A detailed description of the scoring of damage has been described previously (15) . Fifty images from each slide were scored visually as belonging to one of five classes of DNA damage, from score 0 (round images) to score 4 (most of the DNA had migrated from the head to the tail). An average level of DNA damage was calculated by multiplying the number of cells in a class by the score number. A total of 100 cells were scored, thus, the level of DNA damage range from score zero (undamaged) to score 400 (highly damaged).

Analysis of urine samples
The 8-oxodG content in each of the urine collections was determined as described previously (16) . The volume of urine was measured immediately after termination of urine collections and 10 ml aliquots were frozen in liquid nitrogen for later analysis. Due to the arrival time at high altitude, the collection of urine amounted to ~19 h before exercise. For the statistical analysis, we estimated the 8-oxodG in these as 24 h urine samples by linear extrapolation.

Statistics
The data were analyzed by a multifactorial ANOVA based on repeated measurements with substitution of missing values. In a two-factor ANOVA analysis, we used 85 degrees of freedom because the original data material included 86 samples. Essentially similar results were obtained by a one-way multifactorial ANOVA, with place and time as the factors. The statistical analysis of one-way ANOVA was aided by using Statistica® for Windows version 5.1 F, StatSoft, 1997 (Tulsa, OK).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Table 1 depicts HR, VO2max, and arterial oxygen saturation before and after exercise at sea level and high altitude. Compared with sea level, resting HR increased and maximal HR decreased. The VO2max at high altitude was lower compared with sea level values. Arterial oxygen saturation at rest and after exercise in hypoxia was lower compared with sea level. The AMS score was 4.7 ± 2.7 (mean ±SD) on day 2 and gradually decreased in the ensuing days of hypoxia (day 3: 2.9±1.6, day 4: 2.5±2.1). There were no significant correlations between the AMS score and 8-oxodG, levels of DNA strand breaks, ENDO III-sensitive sites, or FPG-sensitive sites (r2<0.04, data not shown).


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  		Table 1. Heart rate, maximal oxygen uptake, and arterial oxygen saturation

Figure 1 depicts the level of DNA strand breaks, ENDO III-sensitive sites, and FPG-sensitive sites. Hypoxia increased the level of DNA strand breaks on all the days at altitude. ENDO III-sensitive sites were increased on day 3 at altitude compared with sea level and pre-exercise level. FPG-sensitive sites remained unchanged. Urine samples collected during the first day of hypoxia had a higher 8-oxodG content compared with the sea level values (Fig. 2 ).



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  		Figure 1. Levels of DNA strand breaks (A), ENDO III-sensitive sites (B), and FPG-sensitive sites (C) before and after exercise at sea level (open bars) and in altitude hypoxia (solid bars). Bars indicate the mean and the 95% confidence interval. *P < 0.001 compared with sea level value. #P < 0.05 and ##P < 0.01 compared with pre-exercise level. {pi}P < 0.05 compared with sea level and pre-exercise value.



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  		Figure 2. Urinary 8-oxodG excretions at sea level (open bars) and altitude hypoxia (solid bars). Bars indicate the mean and the 95% confidence interval. *P < 0.01 compared with sea level value.

At high altitude, exercise further aggravated the induction of strand breaks compared with pre-exercise levels (Fig. 1) . In contrast, normoxic exercise had no significant effect on DNA strand breaks. A significantly decreased level of FPG-sensitive sites was seen 24 h after the exercise at sea level, but not after hypoxic exercise.

At sea level the lymphocytes were stored at -70°C, whereas they were stored in liquid nitrogen at the mountain and then transferred to -70°C after the return to Denmark. The freezing media were the same. We set up an experiment to test the effect of the different storage conditions on DNA strand breaks and oxidative DNA damage in lymphocytes isolated in normoxic conditions from five normal subjects that were not included in the experimental protocol. Scores of the DNA damage (means ±SD) after storage in -70°C (DNA strand breaks: 23±17, endonuclease III-sensitive sites: 1±7, FPG-sensitive sites: 117±41) were not different from scores of samples stored in liquid nitrogen for a week and transferred to -70°C before analysis (DNA strand breaks: 24±14, endonuclease III-sensitive sites 6±13, FPG-sensitive sites 131±19).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
This study investigated the effect of low ambient oxygen tension on biomarkers of oxidative stress before and after maximal exercise. The results demonstrate for the first time that acute hypoxia increases the level of DNA strand breaks and oxidative DNA damage and that exhaustive exercise produces more DNA strand breaks in hypoxic subjects than in normoxic subjects. It is possible we would have observed a larger difference between pre- and postexercise levels of DNA strand breaks if the training condition of the subjects had been poorer. Previously it has been shown that well-trained subjects have less formation of DNA strand breaks after exercise (17) . We did not detect any change in the level of urinary 8-oxodG after exercise. This agrees with reports showing that 8-oxodG and FPG-sensitive sites were the same before and after normoxic exercise (18) . It may reflect that the present exercise protocol was not strenuous enough. High urinary concentration of 8-oxodG is probably detected only after exercise at intensities accompanied by muscle soreness. Previously we had found that vigorous exercise 10 h daily for 30 days resulted in higher urinary 8-oxodG level (19) . Also, elevated content of 8-oxodG in the quadriceps femoris muscle was detected in subjects that performed 200 eccentric muscle actions at an intensity being 60% of the maximum isometric contraction (20) .

Our data indicate that acute hypoxia is associated with oxidative stress. Increased levels of DNA strand breaks and oxidative DNA damage are normally regarded as a signal of an ongoing pathological process, although we cannot distinguish between early or late phases of the process (21) . A common source to the production of oxidative DNA damage and DNA strand breaks is by generation of excess amounts of ROS. Enhanced production of ROS has been shown in vitro in chicken cardiomyocytes, and cultured Hep3B cells exposed to acute hypoxia (22 , 23) . In rats exposed to 10% oxygen, there was an increased production of ROS in the cells of the mesenteric microcirculation (24) . Moreover, evidence from in vitro experiments shows that hypoxia evokes an inflammatory response in vascular tissue and human peripheral blood mononuclear cells, determined by augmentation of the expression of inflammatory mediators such as tumor necrosis factor {alpha} (TNF-{alpha}), interleukins (IL-1, IL-6, IL-8), inducible nitric oxide synthase, and adhesion molecules (25 26 27 28) . Other in vitro experiments have shown that hypoxia increases lipopolysaccharide-induced activity of human alveolar macrophages (29 , 30) . The inflammatory processes are likely to be involved in the pathogenesis of hypoxia-related diseases such as high-altitude pulmonary edema (HAPE) and high-altitude cerebral edema. In subjects with HAPE, very high levels of IL-6 and C-reactive protein (CRP) have been measured in serum (31) and of IL-6 in bronchoalveolar fluid (32) . In subjects without HAPE, altitude hypoxia for 1–3 days caused moderate increases in serum levels of IL-6 (33 34 35) , IL-1 receptor antagonist, and CRP (34) . The human cellular immune system seems to react promptly in response to hypoxia: hypobaric hypoxia (380 Torr) for 20 min markedly increased circulating levels of lymphocytes, CD16+ natural killer cells, and CD14+ monocytes (36) .

Several investigations indicate that prolonged exercise and high-intensity exercise in normoxic conditions evoke inflammatory processes similar to hypoxia. A short bout of maximal exercise for 5 min had no effect on serum cytokines, whereas sustained exercise at 60–65% of VO2max increased serum levels of IL-6 and TNF-{alpha} (37) . Other studies of exercise with a duration less than 20 min showed unaltered levels of IL-6 and TNF-{alpha} in blood after running (38 , 39) and swimming (40) . This suggests that only exercise with a propensity of forcing damage to the muscle fibers activates an inflammatory response, as evidenced by secretion of cytokines in the blood. The parallel activation of the inflammation system by exhaustive exercise and hypoxia has been shown to exert a higher effect when subjects exercise in hypoxia: hypoxic exercise enhanced the concentration of CD16+ and CD56+ natural killer cells compared with normoxic exercise (41) . Data obtained after 4 days at 4350 meters suggested that exercise exacerbated hypoxia-induced increases in IL-6 (33) .

The mechanism by which hypoxic exercise exacerbates the inflammatory response possible lies in the reduced oxygen delivery to the muscle tissue. In subjects enrolled in our study, maximal workloads at sea level decreased the arterial oxygen saturation. This kind of arterial hypoxemia is widely known to occur during maximal exercise in endurance-trained subjects (42) , and may be secondary to a reduced pulmonary arterial mean transit time of red blood cells because of a high maximal cardiac output, leading to insufficient oxygen diffusion time. The decrease in arterial oxygen saturation was further aggravated during hypoxic exercise, as has been described (43) . Exercise induces a reduction in intracellular muscle PO2 that is aggravated during hypoxic exercise (44) . Thus, further studies with control of oxygenation during exercise are necessary to separate the effect of exercise on the inflammatory response in relation to the greater hypoxemia. Nonetheless, our findings of enhanced levels of DNA strand breaks after hypoxic exercise demonstrate the presence of a factor that is likely to enforce a proinflammatory response to hypoxia. Because single-stranded DNA breaks are a strong and probably the only activator of poly-ADP-ribose polymerase (45) , increased levels of DNA strand breaks may constitute an important link in hypoxia-induced inflammation cascades. The mechanism of poly-ADP-ribose polymerase-mediated toxicity possibly involves an inhibition of mitochondrial function, which alters the cellular energy metabolism and may lead to apoptosis (45) . Because both apoptosis and altered energy metabolism is associated with formation of ROS, poly-ADP-ribose polymerase enzymes may further contribute to the higher level of DNA strand breaks detected during hypoxia.

In conclusion, the present report demonstrates that hypoxia generates DNA strand breaks and oxidative DNA damage in humans. Exercise performed in normoxic conditions had no effect on the generation of DNA strand breaks, whereas hypoxic exercise produced more DNA strand breaks. This implies that during a condition of hypoxic stress, the protection by the antioxidant system is insufficient to avoid generation of DNA strand breaks after exhaustive exercise. By activation of poly-ADP-ribose polymerase, induction of DNA strand breaks by ROS may play an important role in hypoxia-induced inflammation.


   ACKNOWLEDGMENTS
 
This study was supported by grants from the Dameca Foundation and the Lippmann Foundation, Denmark. We thank the Italian Alpine club (CAI Verallo) for hospitality at the Capanna Regine Margherita and Dr. Serge Boiteaux, UMR217 Center National de la Recherche Scientifique et Commissariat a l’Energie Atomique, France, for the endonuclease III and formamidipyridine glycosylase enzymes. The technical assistance of Mrs. Hanne Fenger and Dr. Gesche Jürgens is gratefully acknowledged.

Received for publication October 12, 2000. Accepted for publication December 13, 2000.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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