IRON BODY STATUS OF RATS CHRONICALLY EXPOSED TO CADMIUM AND ETHANOL

M. Jurczuk*, M. M. Brzóska, J. Rogalska and J. Moniuszko-Jakoniuk

Department of Toxicology, Medical University of Bialystok, Mickiewicza 2c str., 15-222 Bialystok, Poland

Received 30 August 2002; in revised form 26 November 2002; accepted 10 December 2002


    ABSTRACT
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Aims: The present study was performed to assess the effect of simultaneous long-term exposure to cadmium (Cd) and ethanol on iron (Fe) status of male Wistar rats. Methods: The animals received drinking water containing 50 mg of Cd/l and/or 10% (w/v) ethanol for 12 weeks. Fe and Cd concentrations in serum (blood), certain tissues, urine and feces were determined by atomic absorption spectrometry. The total pool of Fe was calculated as a sum of its content in liver, spleen, kidneys, heart and brain. Fe bioavailability was evaluated based on its apparent absorption. Results: The daily Cd intake ranged from 3.17 to 4.28 mg/kg (Cd group) and from 2.41 to 3.17 mg/kg (Cd + ethanol group); ethanol consumption ranged from 47.5 to 86.9 g/kg/24 h (ethanol group) and from 47.3 to 63.4 g/kg/24 h (Cd + ethanol group). Exposure to Cd or/and ethanol caused serious disturbances in Fe metabolism, as indicated by Fe body depletion. Both substances, applied alone and in combination, reduced the apparent Fe absorption and decreased its total pool in certain organs, and urinary excretion. However, the Cd- and ethanol-induced changes in the tissue Fe concentrations were different. Cd exposure decreased the concentration of Fe in serum, liver, spleen and femur, whereas ethanol decreased it in the spleen. In rats co-exposed to Cd and ethanol, decreased serum, spleen and brain Fe concentrations were all observed. Conclusions: The changes in Fe status in rats co-exposed to Cd and ethanol can be explained by the independent action of the two substances, leading to a decrease in Fe bioavailability, or by their interactions, which involves a modifying effect of ethanol on Cd turnover. The results allow the conclusion that ethanol may increase Cd accumulation, making the organism more susceptible to Fe depletion. Alcoholics thus may be at increased risk of disorders in Fe body status.


    INTRODUCTION
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The data available in the literature and our earlier studies indicate that metabolism and toxicity of cadmium (Cd) can by modified by various factors, including excessive ethanol consumption (Hopf et al., 1990Go; Sharma et al., 1991Go; Moniuszko-Jakoniuk et al., 1999Go, 2001Go; Brzóska et al., 2000Go, 2001Go, 2002Go, 2003Go). The industrial application of Cd leads to contamination of the environment and of dietary products, and this toxic metal is also present in cigarette smoke. Thus, people who drink ethanol excessively may be exposed to Cd at the same time (Schioeler, 1991Go; World Health Organization, 1992Go).

We have previously reported that even short-term, low-level administration of ethanol to Cd-exposed rats influences the turnover of this heavy metal and modifies its effect on the metabolism of some bioelements, including iron (Fe), zinc (Zn) and copper (Cu) (Moniuszko-Jakoniuk et al., 1999Go, 2001Go; Brzóska et al., 2000Go). This prompted us to undertake a study on interactions between Cd and ethanol under their long-term co-administration, including their effect on the metabolism of essential metals. In the present paper, we report on Fe body status. The effects on Zn and Cu body status have already been published (Brzóska et al., 2002Go).

Fe is one of the most essential bioelements and changes in its body status may create serious medical health consequences (Lash and Saleen, 1995Go). The available literature provides much data on the influence of Cd (Groten et al., 1990Go; Kostic et al., 1993Go; Turecki et al., 1995Go; Jurczuk et al., 1997bGo; Oishi et al., 2000Go) and ethanol (Fairweather-Tait et al., 1988Go; Gonzalez-Reimers et al., 1990Go Gonzalez-Reimers et al., 1996; Zhang et al., 1993Go; Valerio et al., 1996Go; Rodriguez-Moreno et al., 1997Go; Sanchez et al., 1998Go) on Fe concentrations in various tissues. However, there have been no reports on the Fe body status under simultaneous exposure to Cd and ethanol. Since both substances have been reported to cause different disturbances in Fe metabolism, and ethanol has been noted to make the organism more susceptible to Cd accumulation, and to some of its effects (Sharma et al., 1991Go; Brzóska et al., 2000Go, 2002Go, 2003Go; Moniuszko-Jakoniuk et al., 2001Go) we hypothesized that simultaneous exposure to Cd and ethanol may lead to disorders in Fe body status, even more serious than those caused by each substance alone.


    MATERIALS AND METHODS
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Animals
Forty inbred male Wistar rats (10 weeks of age), with an initial body weight of about 250 g, were used. The animals were housed under conventional conditions (22 ± 1°C, with a relative humidity of 50 ± 10% and a natural light/dark cycle). They were allowed free access to drinking water and rat chow (LSM dry diet; Fodder Manufactures, Motycz, Poland). The diet was prepared from: corn, wheat, barley, wheat bran, soya-bruised grain, meat starch, skimmed powdered milk, phosphate, fodder-chalk, mineral and vitamin premix, its metabolizable energy being 12.2 MJ/kg. Cd and Fe concentrations in the diet were assessed at 0.211 and 253.8 mg/kg, respectively.

Chemicals
All reagents and chemicals were of analytical grade or higher purity. Ultra-pure water received from a water purification Milli-Q system (Millipore Corporation, USA), trace pure nitric (HNO3) and hydrochloric (HCl) acids (Merck, Germany) as well as Cd and Fe standard solutions (Sigma, USA) assigned for atomic absorption spectrometry (AAS) were used in the analysis.

Experimental design
Randomly selected animals were assigned to four experimental groups of 10 each. The first group received a 50 mg Cd/l CdCl2 solution, the second 10% ethanol, the third one the combination of CdCl2 and ethanol in drinking water uncontaminated with Cd or ethanol. The control group drank redistilled water free of Cd and ethanol.

Daily consumption of drinking water and food of each group was measured during the whole experiment. On the 12th week of the exposure, 24 h faeces was collected in metabolic cages for five consecutive days. On the last day, 24 h urine was also collected. After weighing and overnight starvation, blood was taken by cardiac puncture and the weight of liver, kidneys, spleen, heart, brain, femur and femoral muscle were determined. Soft tissues were washed thoroughly in ice-cold physiological saline [0.9% (w/v) NaCl], the femurs were cleansed of muscle tissue and weighed. An aliquot of blood was allowed to coagulate and serum was separated. The biological samples not used immediately after sampling were frozen at -20°C until further analysis.

The study was permitted by the Local Ethical Committee for animal experiments in Bialystok. Procedures involving the animals and their care conformed to the institutional guidelines, in compliance with national and international laws and Guidelines for the Use of Animals in Biomedical Research (Giles, 1987Go).

Analytical procedures
Cd and Fe analysis. The samples of blood collected in heparinized tubes (assigned for Cd determination) were wet-digested with 5% HNO3 (Razniewska and Trzcinka-Ochocka, 1995Go). Weighed liver and muscle tissue slices (about 1 g) and the whole spleen, brain, heart, femur, right kidney and half of the left kidney as well as representative samples of faeces were submitted to dry mineralization at 450°C in a muffle furnace. After ashing, the samples were dissolved in 10 ml of 1 M HNO3 (soft tissues) or 1 M HCl (femur and faeces). The concentrations of Cd and Fe in such preparations (after appropriate dilution with HNO3 or HCl) as well as Fe in the serum and both metals in urine samples (after appropriate dilution with ultra-pure water) were determined by an AAS method (Zeiss Jena AAS 30; Zeiss, Germany).

Cd was determined by flameless AAS with electrothermal atomization in a graphite cuvette and automatic dosage. The cathode lamp of Cd (Photron) was operated under standard conditions using its respective resonance line of 228.8 nm. Working standards in the range from 0 to 10.0 ng of Cd/ml were prepared from a stock Cd AAS standard solution containing 1005 µg Cd/ml.

The concentration of Fe was measured by a flame (an air–acetylene burner) AAS method. The readings were recorded against suitable Fe standards (Sigma) in the range from 0 to 3.0 µg/ml (prepared from a stock AAS standard solution containing 1020 µg Fe/ml) at the respective resonance line of 248.3 nm.

Internal quality control was employed to keep the measurement processes reliable.

Fe bioavailability. The bioavailability of Fe was evaluated based on its apparent absorption calculated from the following equation: %A = I - EF, where %A is the apparent absorption of Fe; I is the Fe intake; EF is the amount of Fe excreted in faeces during the 5 day observation period.

Total Fe content in organs. Based on Fe concentrations in soft tissues, its total content in the main storage organs, i.e. liver and spleen and the total pool in the studied organs (liver, spleen, kidneys, heart, brain) were calculated.

Blood-ethanol concentration. The concentration of ethanol in the blood was analysed by a headspace gas chromatography technique according to the producer recommendation with own modification. The Hewlett-Packard 5890 chromatograph (Series II) was used.

Statistical methods
Data are expressed as means ± SEM. Differences between the four experimental groups were evaluated using the non-parametric Mann–Whitney U-test, as data were not normally distributed according to the Kolmogorov–Smirnov test. A P < 0.05 was considered significant. A linear Pearson’s correlation was performed for the relationship between Cd accumulation and Fe tissue concentrations. All statistical calculations were done using STATISTICA version 5.0 computer program.


    RESULTS
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Consumption of food and body weight gain
Control rats consumed an average of 24.5 ± 1.1 g/day of LSM food during the 12 week experiment. The food consumption of the Cd-treated groups was similar to that of the control. There was a decreasing tendency of food uptake in the ethanol group, but when ethanol was combined with Cd, this decrease became larger and statistically significant (-30%, P < 0.05) compared with both control and Cd-exposed groups (data not shown). As a consequence, separate administration of Cd and ethanol had no effect on body weight gain, whereas co-exposure resulted in a retarded body weight gain (-39% by the end of treatment; P < 0.001; Table 1Go).


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Table 1. Body weight gain, average drinking water consumption, and cadmium (Cd), ethanol and iron (Fe) intakes
 
Fluid consumption and Cd and ethanol intake
The administration of Cd alone or ethanol alone significantly decreased the fluid consumption (P < 0.001) which was further reduced when the two substances were given in combination (-40% vs control; Table 1Go). As a consequence, daily Cd and ethanol intakes in the co-exposed groups were also reduced by 37 and 18%, respectively (P < 0.01), when expressed in mg/24 h, as compared to their separate administration (Table 1Go). However, expressed in mg/kg body weight/24 h, ethanol intake was not impaired, and Cd intake was reduced by only 24%, in the Cd + ethanol group.

Blood-ethanol concentration
The blood-ethanol concentration of the control and Cd-treated groups was within the low physiological range, below 5 mg/l. This concentration was significantly (P < 0.001) higher, if still negligible, in the ethanol group (11.6 ± 2.0 mg/l), while it was within the control range in the co-exposed group.

Iron body status
Dietary intake and apparent Fe absorption. Owing to the decreased food ingestion, the rats co-exposed to Cd and ethanol had lower Fe intake than the control (by 30%, P < 0.05) and Cd (by 28%, P < 0.05) groups (Table 1Go). Control rats absorbed about 11% of the Fe consumed, as assessed on the basis of its apparent absorption (Fig. 1Go). The apparent Fe absorption in the Cd, ethanol and Cd + ethanol groups was reduced (P < 0.001) by 50, 33 and 49%, respectively, compared with controls (Fig. 1Go).



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Fig. 1. Effects of cadmium (Cd), ethanol, and their combination, on apparent iron (Fe) absorption. Values are means ± SEM (bars) of 10 animals/group. *P < 0.05 (Mann–Whitney U-test) compared with the control groups.

 
Fe concentrations in serum and tissues. Exposure of rats to Cd resulted in a decrease in Fe concentrations in serum (by 19%, P < 0.05), liver (by 39%, P < 0.001), spleen (by 61%, P < 0.001) and femur (by 22%, P < 0.001) (Table 2Go). The Fe concentration in the kidney, heart, brain and femoral muscle was in the range of the respective control values. The administration of ethanol alone resulted in a decrease (by 32%, P < 0.001) in the spleen Fe concentration, while Fe concentration in the serum and other tissues did not change (Table 2Go). In the rats simultaneously treated with Cd and ethanol, a reduction was observed in Fe concentration in serum (by 19%, P < 0.001), spleen (by 49%, P < 0.001) and brain (by 24%, P < 0.05; Table 2Go). Some of these changes in the co-exposed animals differed from those observed in the Cd or ethanol groups. Cd alone or ethanol alone had no effect on the brain Fe concentration, but their co-administration decreased the Fe level of brain. On the other hand, Cd alone reduced the Fe content of the liver and femur Fe, but these changes were no longer evident when Cd was combined with ethanol.


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Table 2. Effects of cadmium (Cd), ethanol, and their combination on iron (Fe) concentration in the serum, certain tissuesa and urine
 
Urinary Fe excretion. Exposure to Cd or/and ethanol decreased (P < 0.001) the urinary Fe excretion by 77–79% compared to the control value (Table 2Go).

Total Fe content in the organs. Fe content in liver and spleen as well as its total pool in the organs examined of Cd-exposed rats was decreased (P < 0.001 in all cases) by 44, 66 and 49%, respectively (Fig. 2Go). In the ethanol group, a decrease was observed in the spleen (by 29%, P < 0.01) and in the total Fe content of the organs investigated (by 16%, P < 0.05) (Fig. 2Go). The rats simultaneously exposed to Cd and ethanol and those treated with Cd alone showed similar directions of changes, but of different intensity, in Fe content in the liver, spleen and in the total pool of the element in several organs. Fe content in the liver, spleen and its total pool in the organs under co-exposure to Cd and ethanol were reduced by 28 (P < 0.01), 60 (P < 0.001) and 39% (P < 0.001), respectively, compared with the control.



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Fig. 2. Effects of cadmium (Cd), ethanol, and their combination, on iron (Fe) content of certain organs. The whole Fe pool is defined as a sum of its content in liver, spleen, kidneys, heart and brain. Values are means ± SEM (bars) of 10 animals/ group. P < 0.05 (Mann–Whitney U-test) compared with the control (*), Cd ({dagger}) and ethanol ({ddagger}) groups.

 
Cd body burden
Cd concentrations in blood and in tissues accumulating the most Cd and in which the most important changes in Fe concentrations were observed are presented in Table 3Go. The effect of ethanol on Cd turnover in this experimental model has already been reported in detail and discussed in a separate paper (Brzóska et al., 2002Go).


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Table 3. Effects of cadmium (Cd), ethanol, and their combination on cadmium concentration in the blood and certain tissuesa
 
Relationship between tissue Fe concentrations and Cd accumulation
A negative relationship was noted between Fe concentrations in the liver (r = -0.6009, P < 0.0001), spleen (r = -0.7215, P < 0.0001) and femur (r = -0.5860, P < 0.0001), and Cd accumulation in these tissues. There was no correlation between Fe and Cd concentrations in other tissues. Moreover, the total pool of Fe in organs negatively correlated with Cd accumulation in the body reflected in its total content in organs (r = -0.8429, P < 0.0001).


    DISCUSSION
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The aim of the present work was to investigate the Fe body status in rats with long-term exposure to Cd and ethanol. The experimental protocol applied by us is to constitute a model of conditions that may take place in human life.

The rats drinking water containing 50 mg Cd/l (with or without ethanol) received 2.41–4.28 mg of Cd/kg/day. This dose seems to be rather high, considering that the estimated daily Cd intake of the population (even in areas polluted by Cd) is only a few hundred micrograms per day (World Health Organization, 1992Go). In creating this experimental model, we have taken into consideration that gastrointestinal absorption of Cd in rats (about 2%) is lower than in humans and may be influenced by various factors (World Health Organization, 1992Go; Ohta and Cherian, 1995Go; Peraza et al., 1998Go). Thus, the body burden of Cd, reflected by its concentration in the blood and kidney, and urinary excretion, is a better indicator of the intensity of exposure than its intake. Cd concentrations in the blood, kidney and urine of rats continuously intoxicated with 50 mg Cd/l (presented in this paper and previously reported; see Brzóska et al., 2002Go, 2003Go) were comparable with levels reported in Cd workers and heavy smokers (World Health Organization, 1992Go; Bem et al., 1993Go; Chalkley et al., 1998Go; Rydzewski et al., 1998Go).

The treatment with ethanol may be tantamount to its misuse in man. The daily consumption of ethanol in the rats drinking water containing 10% (w/v) ethanol was equivalent to about 0.7 l/day of 40% vodka in men (Wisniewska-Knypl and Wronska-Nofer, 1994Go). Since the rate of ethanol oxidation in rats (0.3 g/kg/h) is three times faster than in humans, the animals need a higher dose of ethanol to produce comparable toxic effects.

Since the rats simultaneously treated with Cd and ethanol developed stronger aversion to drinking, than those exposed separately to either substance, they also consumed less Cd and ethanol. The difference in Cd intake is very important to note and has been taken into account in the interpretation of the present results. Alcoholics can have a lower Cd intake than abstinent or social drinkers, as they frequently consume reduced amounts of food, which is the main source of exposure to this heavy metal in the general population. Thus, our experimental model may relate to the human situation.

The growth retardation observed in rats simultaneously exposed to Cd and ethanol is likely to be caused by the reduced fluid and food consumption observed in these animals. The animals developed an aversion to drink water containing Cd or ethanol and especially both substances together, due to their unpalatable tastes. Moreover, ethanol has been reported to cause anorexia and weight loss (Strbak et al., 1998Go; Gupta and Gill, 2000Go). Retardation of body weight gain in co-exposure to Cd and ethanol has also been reported by others (Tandon and Tewari, 1987Go; Gupta and Gill, 2000Go).

Exposure to Cd or ethanol alone, or in combination, caused disorders in Fe metabolism reflected in changes in its bioavailability, concentrations in serum and tissues, as well as in its urinary excretion. These observations suggest an anti-nutritive effect of Cd and/or ethanol on this bioelement. The decreased Fe bioavailability may be one of the reasons for the alterations in the Fe content of the body. The animals co-exposed to Cd and ethanol ate less food and thus had lower Fe intake than that in the other groups. However, this may have had no influence on Fe body status as the intake of Fe in the Cd + ethanol group was sufficient to meet the daily requirement for this bioelement.

As discussed above, both Cd and ethanol led to Fe body depletion, but the changes in tissue Fe concentrations differed depending on the conditions. Thus, exposure to Cd alone resulted in a decrease in Fe concentration in liver, spleen and femur, as well as in the total Fe content of the organs examined. Similar results have previously been reported (Groten et al., 1990Go; Kostic et al., 1993Go; Turecki et al., 1995Go; Jurczuk et al., 1997bGo; Moniuszko-Jakoniuk et al., 1999Go; Oishi et al., 2000Go). Fe depletion has been recognized as one of the mechanisms of Cd-induced anaemia (Sugawara et al., 1988Go; Hogan and Razniak, 1992Go; Jurczuk et al., 1997aGo,bGo,cGo).

Although Fe overload is frequently seen in alcoholics (Duane et al., 1992Go), our studies using the alcoholic rat model revealed Fe body depletion under ethanol’s influence. The maintenance of Fe level in serum and liver, with a simultaneous decrease in spleen (where the turnover of Fe reutilization from damaged erythrocytes is large), may result from the activity of the organism to maintain correct concentrations in organs in which this bioelement is necessary. Moreover, the reduced urinary Fe excretion, which may, at least partly, result from the reduced fluid consumption and in consequence from body dehydration, could mask to some extent the ethanol-induced Fe deficiency. There are some discrepancies in the literature with respect to Fe status in alcoholics and alcoholized animals. The use of ethanol has been reported to cause either Fe deficiency (Nadkarni and Deshpande, 1982Go) or its excessive storage in the body, mainly in the liver (Gonzales-Reimers et al., 1990, 1996Go; Duane et al., 1992Go; Zhang et al., 1993Go; Valerio et al., 1996Go; Sanchez et al., 1998Go).

There is still too little knowledge on the effects of ethanol on Cd-induced biochemical changes, including Fe metabolism (Hopf et al., 1990Go; Moniuszko-Jakoniuk et al., 1999Go; Brzóska et al., 2000Go, 2002Go, 2003Go; Oishi et al., 2000Go). In the present experimental model, both Cd and ethanol influenced the body status of Fe, but the administration of ethanol to Cd-exposed rats generally did not cause a further Fe depletion. It was more likely to result from lower Cd and ethanol intake in co-exposure than during their separate administration. Similar results were observed in apparent Fe absorption and its urinary excretion in all the groups. However, Fe organ deficiency was more pronounced in the rats simultaneously exposed to both substances, in comparison to those exposed to ethanol alone, but was similar to that in the Cd-treated group. The fact that the total Fe pool in organs in the Cd + ethanol group was decreased to the same level as in the Cd group, in spite of lower Cd intake when it was co-administered with ethanol, seems to indicate a modifying influence of ethanol. Decreased Fe absorption was probably the main cause of Fe body depletion. However, it is important to note that gastrointestinal absorption, calculated as the difference between intake and fecal excretion (apparent absorption), does not reflect genuine absorption.

The present results allow the conclusion that the changes in Fe body status in conditions of simultaneous exposure to Cd and ethanol are mainly caused by the action of Cd, although a modifying effect of ethanol is also seen. The modifying influence of ethanol on the body status of Fe may result from its direct action on the one hand and indirect effects via the changes in Cd body turnover on the other.

In the present paper, we have presented Cd concentrations only in chosen tissues of rats exposed to Cd, ethanol or both. The effect of ethanol on Cd turnover in the same experimental model has been reported and discussed in detail in a separate paper (Brzóska et al., 2002Go). We have noted that the whole Cd pool in internal organs of rats in the Cd + ethanol group was at the same level as in those receiving Cd alone, in spite of its lower intake. If the modifying effect of ethanol was absent, then the concentrations and content of Cd in animals co-exposed should have been lower than in those exposed to Cd alone. Thus, our results give evidence that ethanol influences Cd turnover (increases gastrointestinal absorption and retention of the absorbed metal), making the organism more susceptible to its accumulation.

Due to lower Cd and ethanol intake after co-exposure, than during their separate administration, we cannot correctly interpret the interactive effect of Cd and ethanol regarding Fe body status. We may speculate that, when intake of Cd and ethanol in co-exposed rats is the same as in those receiving both substances separately, disorders in Fe body status will be more serious after co-exposure. However, the observations of the present study suggest that Cd and ethanol may have a significant toxicological interaction with respect to Fe metabolism. Further studies are required to better elucidate Cd and ethanol interference with Fe metabolism and the health consequences of these interactions.


    FOOTNOTES
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
* Author to whom correspondence should be addressed. Back


    REFERENCES
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
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