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Journal of the American College of Nutrition, Vol. 22, No. 3, 239-246 (2003)
Published by the American College of Nutrition

Original Research

Female Rats Are Protected against Oxidative Stress during Copper Deficiency

Isabelle Bureau, PhD, Elyett Gueux, Andrzej Mazur, PhD, Edmond Rock, PhD, Anne-Marie Roussel, PhD, FACN and Yves Rayssiguier, PhD, FACN

Unité Maladies Métaboliques et Micronutriments, INRA-CRNH, Saint Genès Champanelle (I.B., E.G., A.M., E.R., Y.R.), LBSO
Laboratoire de Biologie du Stress Oxydant, Faculté de Pharmacie, UJF, Domaine de la Merci, La Tronche (A.-M.R.), FRANCE

Address correspondence to: Yves Rayssiguier, PhD, FACN, Unités Maladies Métaboliques et Micronutriments, INRA-CRNH, 63122 Saint Genès Champanelle, FRANCE. E-mail: rayssiguier{at}clermont.inra.fr


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Background: Copper deficiency induces a dramatic decrease of superoxide dismutase activity and leads to alteration of antioxidant defense systems.

Methods and Objective: Experiments were conducted in weanling male, intact and ovariectomized female rats, fed either a copper-adequate or copper-deficient diet for seven weeks, in order to determine whether endogenous estrogen could modulate oxidative stress and the severity of copper-deficiency.

Results: Feeding male rats a copper-deficient diet induced typical signs of copper deficiency, such as decreased hepatic copper, growth retardation, anemia, heart hypertrophy, pancreas atrophy and hypercholesterolemia. Furthermore, copper deficiency increased the amount of lipid peroxidation products in the heart, liver and pancreas following in vitro iron induction. Although levels of hepatic copper in copper-deficient females were similar to those of their male counterparts, the females were partially protected from the adverse effects of the deficiency (no growth retardation, less severe anemia, lesser extent of lipid peroxidation). Thus, female rats are provided with a greater degree of protection against oxidative damage than males. However, females did not appear to be protected against pancreas atrophy, heart enlargement and hypercholesterolemia induced by copper deficiency. This observed partial protection of females was lost after ovariectomy as shown by decreased body weight and hematocrit, heart enlargement and higher tissue peroxidation in ovariectomized females compared to intact females.

Conclusions: The results suggest that the partial protection of copper deficient females is related to the antioxidant properties of estrogens. The protective action of estrogen against oxidative stress is of particular importance when antioxidant defenses are decreased as shown in this experimental model.

Key words: oxidative stress, copper-deficiency, estrogen, gender, antioxidant


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Copper-deficiency leads to an important reduction of antioxidant enzymatic components, such as Cu-Zn superoxide dismutase (SOD) [1,2]. Since antioxidant defense systems are altered, copper-deficient animals could be considered an experimental model of oxidative stress. Increased oxidative stress leads to damage responsible for pathological manifestations. Dietary copper deprivation is associated with numerous severe pathologies [3]. Except for a few experiments, most of the studies on copper-deficiency have been conducted in male rats. In general, female rats appear partially protected against signs of copper-deficiency [4–8]. The mechanism by which female rats are protected may be related to the antioxidant properties of estrogens. Estradiol has been documented as having antioxidant effects [9,10]. This experiment, therefore, aims to determine both the protective effects of female sex hormones against copper deficiency and antioxidant activity of estrogen using an experimental model of oxidative stress.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Animals and Diet
Weanling male and female Wistar rats (56) weighing about 65g each were derived from a colony of laboratory animals (INRA: National Institute of Agricultural Research, Clermont-Ferrand, France). Rats were housed in wire-bottomed cages under conditions of constant temperature (20–22°C) and humidity (45% to 50%) in rooms with a fixed 12-hour artificial light-dark cycle. Rats were randomly divided into six groups according to dietary copper, gender and ovariectomy surgery as follows: group 1: copper-adequate males, group 2: copper-adequate sham-operated females, group 3: copper-adequate ovariectomized females, group 4: copper-deficient males, group 5: copper-deficient sham-operated females, group 6: copper-deficient ovariectomized females. The ovariectomies and sham-operations were undertaken at three weeks [11].

Animals were fed the appropriate diets for seven weeks. The semi-purified diet contained (in g/kg diet) 650 sucrose, 200 casein, 50 corn oil, 50 alphacel, 3 DL-methionine and 2 choline bitartrate, 35 modified AIN-76 mineral mix formulated in our laboratory to omit cupric carbonate, and 10 AIN-76 A vitamin mix (ICN Biomedicals, Orsay, France). The copper-deficient diet contained 0.6 µg Cu/g food. The copper-adequate diet was prepared by adding copper carbonate to the copper-deficient mixture to produce a final concentration of 6.0 µg Cu/g (control). All rats were fed ad libitum, with distilled de-ionized drinking water.

Non-fasted animals were killed after being anesthetized with sodium pentobarbital (40 mg/kg body wt ip). Blood was collected into heparinized tubes, and plasma was obtained by low-speed centrifugation (2000g). Hematocrit was determined by centrifugation in a capillary tube system to obtain packed cells. Organs (liver, pancreas, heart) were rapidly removed, weighed, placed in liquid nitrogen and stored at -80°C. All procedures were in accordance with the Institute’s guide for care and use of laboratory animals.

Analytical Procedures
Mineral analysis: copper and iron were determined in liver and diets by atomic absorption spectrophotometry (Perkin Elmer 560).

Lipid peroxidation: liver, heart, and pancreas, tissue homogenates were prepared on ice in a ratio of 1g wet tissue to 9 mL 150 mmol/L KCl using a Polytron homogenizer. Thiobarbituric acid-reactive substances (TBARS) were measured in tissue homogenates supplemented with 20 mmol/L butyl hydroxy toluene (BHT) as previously described [12]. TBARS were also determined in BHT-free tissue homogenates after lipid peroxidation induced by 10 µmol/L FeSO4-250 µmol/L ascorbate for 30 minutes in a 37°C water bath in an oxygen-free medium, using a standard of 1,1,3,3-tetraethoxypropane. The coefficients of variation were 4.32% and 2.10% respectively for the basic and stimulated methods.

Plasma analysis: cholesterol was measured in plasma by enzymatic procedures (Biomérieux, Charbonnières-les-bains, France). The coefficient of variation was 0.70%.

Statistical Analysis
Data are expressed as means + SEM. Male and intact female data were first analyzed. Female versus ovariectomized female was then studied in another statistical analysis. Two-way analysis of variance (ANOVA), defined as p < 0.05, was used to determine the main effects (copper level, sex and ovariectomy) and interaction (copper level x sex; and copper level x ovariectomy). All data were also subjected to one-way analysis of variance (ANOVA). When significant F ratios were found, the individual means were compared by protected Least Significance Difference (PLSD) test (p < 0.05). Statview program was used for statistical analysis (Statistical Software, France).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
ACKNOWLEDGMENTS
 REFERENCES
 
Effect of Gender
Body and tissue weights, hematocrit, and plasma cholesterol for male and intact female rats are presented in Table 1. Consequences of copper-deficiency on growth were different in males and females. Indeed, copper-deficiency induced a decrease in male body weight. In contrast, identical body weights were found in copper-adequate and copper-deficient females. In both genders, hearts were hypertrophied by copper-deficiency. Gender affected pancreas size, and all copper-deficient females exhibited atrophy of pancreas. Regardless of the gender, hematocrit was decreased by copper-deficiency. However, the effect of the deficient diet on hematocrit was different in male and female rats. Plasma cholesterol level was elevated by copper-deficiency. As expected, animals fed the copper-deficient diet exhibited a tenfold decrease in hepatic copper level compared to animals fed the copper-adequate diet (Table 2). Liver copper concentration was significantly higher in copper-adequate females compared to copper-adequate males. However, regardless of gender, all copper-deficient rats exhibited similar copper tissue concentrations. Hepatic iron concentration was significantly increased by copper-deficiency in all rats. When females were fed copper-adequate and copper-deficient diets, they exhibited higher iron levels than males. The highest iron concentration was found in copper-deficient females.


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  		Table 1. Body and Tissue Weights, Hematocrit and Plasma Cholesterol, Level in Male and Female Rats Fed Either a Copper-Adequate or Copper-Deficient Diet

 

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  		Table 2. Hepatic Copper and Iron Level (µg/g Dry Weight), in Male and Female Rats Fed either a Copper-Adequate or Copper-Deficient Diet

 
After exposure of tissue homogenates to iron-induced lipid peroxidation, heart, pancreas and liver TBARS, as well as non-induced pancreas TBARS, were significantly higher in copper-deficient animals compared to control rats. However, copper deficient females were protected against lipid peroxidation as shown by lower tissue TBARS after iron-induced lipid peroxidation (Table 3). When animals were copper-adequate, TBARS levels were not different in either gender.


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  		Table 3. Tissues Peroxidation b(TBARS nmol/g Wet Weight) in Male and Female Rats fed Either a Copper-Adequate or Copper-Deficient Diet

 
Effect of Ovariectomy
Uteri were weighed in ovariectomized (OVX) and intact females to verify correct ovariectomy. Regardless of diet copper level, uterine weights were significantly decreased in ovariectomized compared to sham-operated females (0.19 + 0.04 vs. 0.02 + 0.01 g/100 g body weight).

Body and tissue weights, hematocrit and plasma cholesterol, in intact and OVX female rats are presented in Table 4. Ovariectomized females fed the copper adequate diet exhibited higher body weights compare to intact females. Copper-deficiency significantly lowered body weight of OVX females, whereas intact females showed no change in body weight. Copper-deficient rats exhibited heart enlargement and pancreas atrophy. However, heart hypertrophy induced by copper-deficiency was significantly higher in OVX rats when compared to intact females. Regardless of ovariectomy, hematocrit was decreased by copper-deficiency. However, the decrease was greater in copper-deficient intact females than copper-deficient OVX females. Copper-deficiency significantly increased plasma cholesterol level.


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  		Table 4. Body and Tissues Weights, Hematocrit and Plasma Cholesterol, in Intact and Ovariectomized Female Rats Fed Either a Copper-Adequate or Copper-Deficient Diet

 
Hepatic copper and iron levels are presented in Table 5. The copper-deficient diet induced a marked decrease in hepatic copper level in both groups. Ovariectomy led to a slight and significantly lower copper level when animals were fed a copper-adequate diet. The OVX rats exhibited lower iron concentration than intact females. Hepatic iron retention induced by copper-deficiency was significantly higher in intact than in OVX females. The lowest iron level was found in copper-adequate OVX females.


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  		Table 5. Hepatic Copper and Iron Level (µg/g Dry Weight), in Intact and Ovariectomized Female Rats Fed Either a Copper-Adequate or Copper-Deficient Diet

 
Except for heart TBARS measured without in vitro incubation, copper deficiency significantly increased heart, pancreas and liver TBARS. When animals were fed the copper deficient diet, ovariectomized females exhibited significantly higher TBARS values in heart and pancreas, while liver TBARS values were unaffected by ovariectomy. In copper-adequate rats, TBARS levels were not affected by ovariectomy (Table 6).


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  		Table 6. Tissues Peroxidation b(TBARS nmol/g Wet Weight) in Intact and Ovariectomized Females Rats Fed Either a Copper-Adequate or Copper-Deficient Diet

 

   DISCUSSION
 
Copper status was assessed by measuring hepatic copper concentration. As expected, the copper-deficient diet resulted in a reduced hepatic copper concentration compared to the copper-adequate diet. In agreement with previous studies, the present investigation showed that feeding male rats a copper-deficient diet induced the typical signs of copper deficiency, such as growth retardation, anemia, heart hypertrophy, pancreas atrophy, and hypercholesterolemia [3]. Furthermore, copper deficiency increased the amount of lipid peroxidation products in the heart, liver and pancreas following in vitro iron induction.

Although hepatic copper of female rats fed the copper-deficient diet was similar to that of their male counterparts, females were partially protected from the adverse effects of the deficiency. This was evidenced by the dramatic effects of copper deficiency on growth in male rats whereas identical body weights were found in copper deficient and copper adequate females. Anemia was less severe in females. The effects of copper deficiency on hematocrit were different in male and female rats. The present study demonstrates that lipid peroxidation, following in vitro incubation, expressed as TBARS, was lower in liver, pancreas and heart among copper-deficient females compared to copper-deficient males. Thus, female rats are provided with a greater degree of protection against oxidative damage compared to male rats. However, females did not appeared to be protected against pancreas atrophy, heart enlargement and hypercholesterolemia induced by copper deficiency. Although some studies indicate a higher fatty acid unsaturation index in organs of copper-deficient rats, copper status has no striking effect on the fatty acid composition, and there is no indication of the sexual dimorphism in the effect of the copper deficiency on tissue fatty acid composition [13]. Thus, oxidative stress in copper-deficient animals has been related to decreased antioxidant defenses. The antioxidant role of copper resides in its catalytic function in copper-dependent SOD [1]. Both cytosolic and extra-cellular copper-dependent SOD activity have been characterized [14,15]. Enzyme activity is decreased by diets low in copper [2]. Superoxide dismutation is crucial in limiting oxiradical formation and in controlling lipid peroxidation. Furthermore, other major disturbances of antioxidant enzymes which participate in defense mechanisms occurred in copper-deficiency. Indeed, a decreased activity of catalase and glutathione peroxidase is associated with copper deprivation [3]. Thus, the possibility exists that antioxidants could decrease or prevent some of the pathological consequences of copper deficiency. It is therefore hypothesized that endogenous estrogen, by its antioxidant capabilities, could explain the sexual difference in the expression of copper deficiency.

In the literature, protective effects of estrogen are widely described in both animals and humans [16]. Estrogens, which possess a phenolic hydroxyl group, have an effective antioxidant action and inhibit lipid peroxidation in various models [17, 18]. Little is known regarding antioxidant mechanisms of estrogens in vivo. These estrogens may be able to inhibit the generation of radicals [19], to decrease peroxide levels [20], to prevent iron-induced oxidation [21], to suppress free radical generating systems in rat liver [22] or to induce the expression of "anti-oxidant" protein thiol/disulfide oxido-reductase (such as thioredoxin) [23]. Endogenous estrogen could thus offer some protection to the copper deficient animals through increased antioxidant status. This hypothesis is supported by the present data showing that copper-deficient ovariectomized females displayed an exacerbation of some physical and biochemical indicators associated with copper deficiency and that females, compared to males, were partially protected against the pathological effects induced by copper deficiency. Additional studies are required to determine the effects of supplementing ovariectomized copper deficient rats with estrogens.

There are conflicting accounts in the literature concerning the effects of copper deficiency in females rodents. In one study, intact females were protected against the detrimental effects of copper deficiency. Ovariectomized females were also protected against the severity of copper deficiency. Thus, regardless of whether females were ovariectomized or intact, they were not susceptible to damaging effects of copper deficiency, suggesting that estrogens do not always affect the symptoms associated with copper deficiency [4,5]. Another study demonstrates that female rats were susceptible to cardiac hypertrophy, anemia and decreased body weight induced by copper deficiency. The severity of these effects was, however, found to be to a lesser extent than in males, and estrogens did not influence the susceptibility of female rats to copper deficiency [24]. Thus, it appears likely that the protection noted in copper deficient female rats is not maintained to the same degree when challenged by very severe copper deficiency. Both the amount of fructose and the amount of copper in the diet have been shown to be critical to the severity of copper deficiency. Moreover, the experimental period and strain of rats varied among laboratories and may account for the different degrees of copper deficiency observed and thus for the differential impact of dietary copper deficiency on male and female according to hormonal status [24].

In agreement with previous studies, the present investigation showed that rats placed on a copper-deficient diet become anemic [25]. It has been suggested that one mechanism underlying copper deficiency-anemia is through an impairment in iron metabolism and decreased hemoglobin production. However, red blood cells of copper deficient rats are particularly susceptible to oxidative damage. The shortened survival of erythrocytes apparently results from enhanced susceptibility to peroxidation and contributes to anemia [25]. On the other hand, copper supplementation protects red blood cells against in vitro-induced peroxidation as shown recently in humans [26]. In the present experiment, copper deficiency-induced anemia is strongly expressed in male rats, and the relative protection noted in copper-deficient female rats may be related to the antioxidant properties of estrogens.

The development of severe damage to the heart induced by dietary copper deficiency has long been recognized [27]. The results obtained showed that copper deficiency induced a cardiac hypertrophy and suggest that copper deficiency caused severe oxidative damage to the heart. Saari and Johnson were the first to notice that antioxidants could decrease or prevent some of the cardiovascular damage of copper deficiency [28,29]. The antioxidant effect of estrogen contributes to the protective effect on the heart as shown by the higher heart hypertrophy in ovariectomized females compared to intact females.

Pancreas atrophy is not significantly different in intact and ovariectomized females, suggesting that the protective effect of estrogen on peroxidative damage is not enough when rats are subjected to severe copper deficiency.

It is well known that lipid metabolism is influenced by sex hormones in animals and humans [30]. In the present experiment, cholesterol plasma levels were higher in male rats compared to females, and ovariectomy resulted in increased plasma cholesterol. In rats, copper deficiency induced hypercholesterolemia and changes in lipoprotein concentration and composition [31]. In the present experiment, hypercholesterolemia is expressed in female rats following copper deficiency. However, plasma cholesterol levels were similar in both copper adequate and copper-deficient females following ovariectomy due to the hypercholesterolemic effect of ovariectomy. Even if expression of hypercholesterolemia induced by copper deficiency is of the same magnitude in copper-deficient male and female rats, consequences may be different. Previous studies have shown that copper deficiency increased the susceptibility of lipoproteins to in vitro peroxidation [31,32]. Estradiol may act as an antioxidant to protect the lipoproteins against oxidation [33], and further studies in copper-deficient animals are needed to assess the influence of endogenous estrogen in protecting the lipoproteins against peroxidation and in reducing the risk of cardiovascular diseases.

Females exhibited iron concentration severalfold higher than in male rats. This is in agreement with other studies [34] and could be due to higher rate of ferritin synthesis [35] and more efficient iron absorption [36]. Iron plays an important role in oxygen radical formation. Thus, conditions of iron overload in various tissues might participate in their damage via a mechanism that involved reactive oxygen species. It is well established that interactions between copper and iron exist. Copper is necessary for the utilization of iron from storage sites, and copper deficiency leads spontaneously to an accumulation of iron in tissues [37]. The aggravating effect of dietary iron on the pathological consequences of copper deficiency has been reported. However, oxidative stress and subsequent pathological changes in copper-deficient rats are not solely due to iron overload. Indeed, the redox state of iron may be important in generating reactive oxygen species [38]. In support of this observation is the finding that, although copper-deficient females exhibited higher concentration of hepatic iron than males, tissue peroxidation was greatly increased in males, but not in females. Similarly, although copper deficient ovariectomized females exhibited lower iron concentration than copper deficient intact females, they were not protected against tissue peroxidation. Therefore, it was suggested that the redox state of hepatic iron played a role in the exacerbation of the symptom of copper deficiency by generating free radicals as shown by ESR [39]. Under these circumstances, estrogen may also provide protective effects by directly modifying iron redox chemistry and, thus, acting as antioxidant. Preventive action of estrogen may also be related to the maintenance of the normal redox status of the cell by partial recovery of the intracellular GSH level [40].

The present study describes the effects of copper deficiency in sucrose-fed rats. The effects of copper deficiency are dependent on the type of dietary carbohydrate consumed, and the aggravating effect of fructose or sucrose is well known [41]. The reason for this aggravating effect is not fully understood. However, fructose may aggravate the consequences of copper deficiency by enhancing oxidative damage [42]. Thus, the possibility exists that estrogen may protect against oxidative damage resulting from a fructose-based diet [43]. In this context it is interesting to note that female rats do not develop sucrose-induced insulin resistance [44].

The protective action of estrogen against oxidative stress may be of particular importance when antioxidant defenses are decreased as shown in this experimental model.


   ACKNOWLEDGMENTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 ACKNOWLEDGMENTS
REFERENCES
 
We are grateful to C. Coudray for his assistance in measuring trace elements and C. Lab for her technical help.

Received February 11, 2002. Accepted January 3, 2003.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 ACKNOWLEDGMENTS
 REFERENCES
 

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