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Disturbances in the metabolism of endogenous metals (Zn and Cu) in nickel-exposed rats
ENVIRONMENTAL
RESEARCH
27, 216-221 (19821
Disturbances in the Metabolism of Endogenous (Zn and Cu) in Nickel-Exposed Rats
Metals
JADWICACHMIELNICKA,JADWICA A. SZYMA~~SKA, AND JOLANTATYFA
Received February 17, 1981 The effect of nickel chloride on tissue concentrations of zinc and copper was studied in female rats. Animals were subjected to repeated exposure to 5 mg Niikg. Whole-body retention of zinc increased about 30%. and retention of copper did not change. Increase of the zinc content was observed in liver, but in kidneys, lungs, and brain zinc content decreased. It was also noted that the level of metallothionein was higher in nickel-exposed rat liver than in control rat liver. Concentration of metallothionein was correlated with the metal contents t Ni, Cu, Znl.
INTRODUCTION
Nickel deficiency in food brings about alterations in hepatic functions leading in turn to decreased oxygen uptake and augmented fat accumulation. Nielsen et al. (1974) and Schnegg and Kirchgessner (1976) noted that nickel deficiency in the rat results in a decrease of endogenous iron, zinc, and copper in the liver, kidneys, and spleen. On the other hand, Schroeder and Nason (1974) demonstrated an increase of the zinc level in all organs examined but the liver, as well as an increase of the copper level in the spleen after administration of nickel in the food. Nickel damages the kidneys in the rat (Sunderman, 1977). It is accumulated with the highest efficiency in this organ and in blood plasma (KabaIa-Pendias and Pendias, 1979). However, more recent studies of Ling and Leach (1979) did not reveal any effect of nickel on the distribution of obligatory metals. This study was aimed at reexamining the effect of nickel on the whole-body distribution of the endogenous metals copper and zinc in the rat and the influence of nickel on the level of metallothionein in rat kidneys and liver. MATERIAL AND METHODS
Female Wistar rats weighing 180-200 g were used in the experiments. The animals were divided into three groups: I. Control group (six animals), II. animals subjected to repeated exposure (seven doses, subcutaneously, every other day) to nickel chloride (5 mg Niikg, ten animals), III. animals exposed as those of group II but receiving NiSO, labeled with 63Ni. Rats exposed to nickel chloride were sacrificed 24 hr after the last dose. The levels of copper, zinc, and metallothionein were estimated in tissues of rats of groups I and II. Nickel was determined in tissues of rats of group III. 216 0013-9351/82/010216-06$02.00/O Copyright All rights
0 1982 by Academic Press, Inc. of reproduction in any form reserved.
METABOLISM
OF
ENDOGENOUS
217
METALS
Whole tissues (kidneys, liver, lungs, spleen, brain, blood, heart, bowels, muscles, and skin) were mineralized with concentrated sulfuric (reagent grade, POCH) and perchloric (reagent grade, Hopkins and Williams) acid. Copper and zinc were estimated in the mineralizates by atomic absorption spectroscopy (Pye Unicam SP-192). Metallothionein concentrations in the rat liver and kidneys were determined radiochemically according to ielazowski and Piotrowski (1977a). Using the mercury-binding assay, ielazowski and Piotrowski (1977b), Piotrowski et al. (1978), and ielazowski et al. (1978, 1980) determined the metallothionein concentration in mammalian tissues. The nickel content of tissues was estimated radiochemically by measurements of radiation emitted by 63Ni. The ‘j3Ni isotope in the form of ‘j3NiS0, was obtained from the Institute of Nuclear Research in Swierk. The measurements were performed in scintillation counters USB-2 and ssu-70. RESULTS
After seven subcutaneous injections of nickel sulfate (dose of 5 mg Ni/kg) the whole-body zinc pool in the rat increased by 30% as compared with that in the control group (Table 1). In the kidneys, lungs, and brain a statistically significant decrease of the level of zinc was noted. Only in the liver was the level of zinc 2.5fold higher as compared with that in the control group. Copper concentrations found in tissues of control and nickel-exposed animals are shown in Table 2. Smaller changes were observed in concentrations of copper than in those of zinc. Only in the spleen was the level of copper in nickel-exposed rats higher than that in the control group in a statistically significant manner (Table 2). The whole-body retention of copper also did not change. Percentage contribuTABLE DISTRIBUTION
OF ZINC FOLLOWING (MEANS FROM
1
ADMINISTRATION OF SEVEN SEVEN TO TEN RATS AND SD)
7 x 5 mg Niikg
Control
/a znig tissue
Organ Kidneys Liver Heart Lungs Spleen Brain Blood Intestines Muscles Skin
+ bones
54.1
t 9.9
17.3
-+ 1.3
26.5 30.7 19.3
t 8.3 t 5.7 + 1.7
15.9 7.4
i- 1.2
38.3 31.9
f 11.0
37.9
-t 5.0
pg Zniorgan
2 4.3
Total Significantly
from
control
animals
pg Zniorgan
18.3 43.4
+ 3.8:: k 4.9,.
20.9 65.3
20.2 15.7 16.9
-+ 14.7 2 8.02 1.7
8.5
+ 4.1-'
13.9 IO.8
102.7 1105.0
4.8 47.6
f 1.4 2 8.3
I 116.2
4400.0 1123.0
39.6 2 12.5
6339.5
34.7
1254.6
7095.5
different
/a za tissue
78.9 154.5
19.7 25.5
f 4.3
DOSES OF NICKEL
(P = 0.01).
+ 22.7
28.6 391.8 15.0 37.3
64.8
9272.5
218
CHMIELNICKA,
SZYMAP;ISKA, TABLE
DISTRIBUUON
OF COPPER
FOLLOWING
(MEANS
FROM
AND
2
ADMINIVRATION
OF SEVEN
TO TEN RATS
SEVEN
TYFA
Control PLg Cuk tissue
Organ Kidneys Liver Heart Spleen Brain Lungs Blood Intestines Muscles Skin
14.6 4.0 5.0 1.3 3.5 2.2 1.8 0.5 0.8 0.7
+ bones
li Significantly
different
from
2 + IT t + -t + 5 k 2
OF NICKEL
7 x 5 mg Niikg /a Cuk tissue
/*g Cuiorgan
4.2 1.6 0.3 0.2 0.3 0.6 0.5 0.3 0.2 0.7
21.6 31.8 4.1 I.5 5.6 4.6 22.7 13.2 104.4 26.2
control
DOSES
SD)
AND
animals
18.4 5.2 5.8 I .9 4.2 1.6 1.1 0.4 0.3 1.2
L! t t 2 2 c _t 2 + c
pg Cu/organ
6.4 I.0 0.4 0.3:,: 0.8 0.5 0.5 0.2 0.3 1.5
28.2 47.6 4.4 1.6 6.2 4.0 15.0 8.8 55.5 42.3
(P = 0.01).
tion of tissues to the binding of copper and zinc in control and nickel-exposed rats is shown in Table 3. The most sign&ant changes were observed in the kidneys, liver, spleen, brain, and lungs with respect to the binding of zinc, and in the kidneys, liver, blood, skin, and muscles with respect to the binding of copper. In tissues whose contributions to the binding of copper and zinc changed more considerably, the concentration of nickel was estimated (Table 4). The highest amounts of nickel were found in liver and blood. In addition, metallothionein was assayed in the liver and kidneys of animals of groups I and II. (Table 5). The level of metallothionein in the liver was significantly higher as compared with that in control animals and correlated with the metal content (Fig. 1). TABLE DISTRIBUTION
or-
COPPER
WHOLE-BODY
Control
Kidneys Liver Heart Spleen Brain Lungs Blood Intestines Muscles Skin
1.1 2.2 0.3 0.3 0.4 0.9 1.5 15.6 62.0 15.8
Nor<,.
+ bones
Percentage
calculated
according
3
ZINC
EXPRESSED
RETENTION Zinc
Organ
AND
OF THESE
AS PERCENTAGE
Copper
(O/c I
7 x 5 mg Niikg
Control
0.3 4.2 0.2 0.1 0.1 0.4 0.7 12.0 68.5 13.5 to metal
contents
OF
METALS
9.2 13.5 1.7 0.6 2.4 2.0 3.6 5.6 44.3 11.1 expressed
in &organ.
(%) 7 x 5 mg Niikg 13.2 22.3 ‘.I 0.7 1.9 1.9 7.0 4. I 26.0 19.8
METABOLISM
OF
ENDOGENOUS TABLE
OF ‘isNi FOI.LOWING
DISTRIBUTION
Organ
pg Niig
Kidneys Liver Spleen Brain Lungs Blood !Votz.
4
ADMINISTRATION 5 mg Niikg
tissue
OF SEVEN
DOSES
OI- NICKEL,
EACH
Percentage administered
pg Niiorgan
5.4 7.9 8.1 6.2 4.0 4.5
Administered
219
METALS
8.0 68.0 7.5 9.7 5.3 64.3
of dose
0.09 0.78 0.09 0.11 0.06 0.74
dose 8.75 mg Ni = IOO?.
DISCUSSION
The present study demonstrates significant changes in the metabolism of zinc and only slight changes in the metabolism of copper due to nickel. However, our data differ from those obtained by Schroeder and Nason (1974). These differences are probably caused by different types of exposure. These authors employed microgram amounts of nickel in a prolonged exposure. To our best knowledge there are no data in the literature on alterations in the concentrations of endogenous metals by higher doses of nickel. Disturbances in the metabolism of zinc and copper induced by administration of heavy metals have been observed already for such metals as Bi, Hg, Cd, Sn, and Au (Julsham et al., 1977; Nordberg, 1978; Piotrowski et al., 1979; Stonard and Webb, 1976; Szymanska and ielazowski, 1979; Chmielnicka et al., 1981; Szymanska et al., 1981). The above-mentioned reports demonstrated a two- to sixfold increase of the copper concentration in the kidneys. On the other hand, two- to threefold increases of the zinc content were noted in the rat liver after administration of bismuth and tin (Szymanska et al., 1981: Chmielnicka et al., 1981). In all these experiments the concentrations of Hg, Bi, and Cd were in the range of more than 10 pg/g kidneys, the concentration of bismuth (cumulated in the liver) was 1 pg/g liver and that of tin was 0.03 pg/g liver and 0.2 pg/g kidneys. In our studies the concentrations of nickel were up to 5.4 pg Nilg kidneys and 7.9 j&g liver. Repeated exposure to nickel resulted in a statistically significant increase of the content of metallothionein in the liver. These changes were observed at a nickel concentration of 7.9 &g tissue and at a 2.5fold elevation of zinc in this organ. TABLE THE LEVEL
0~
Kind
MErALLol-HIoNEiN
AND KIDNEYS (mg/g TISSUE)
of exposure
Control Ni. 7 x 5 mg Niikg Significantly
different
from
control
5
IN LIVER
animals
OF CowRot.
AND
EXPOSED
Liver
Kidney
0.08 0.28,:
0.16 0.38
(P = 0.01).
RATS
220
CHMIELNICKA,
0’
”
0.1
SZYMANSKA,
a
0.2
0.3
”
0.4
05
06
Metals, Fmole metal/c FIG. 1. Dependence of the levels of metallothionein + copper (- --), and zinc + copper + nickel (-.
AND
4
0.7
TYFA
“*
0.8
0.9
tissue
in liver on the concentration
of zinc (---),
zinc
-).
Stimulation of the metallothionein level by nickel was described previously by Piotrowski and Szymanska (1976) as well as Suzuki and Yoshikawa (1976), but these authors did not determine the concentrations of nickel or copper and zinc in the liver. In the results obtained here the correlation between the concentrations of metallothionein and of the metals studied in the tissue seems noteworthy (Fig. 1). However, the question of the nickel-induced metallothionein binding of these metals (i.e., copper, zinc, or nickel) needs further investigation. Although several groups of human populations are exposed to nickel no published reports on interactions between nickel and essential elements in humans are available at present. However, the effect of nickel on copper and zinc metabolism may have public health implications. ACKNOWLEDGMENT The paper Sciences.
was supported
by Grant
536iVI
from
the Division
of Medical
Sciences,
Polish
Academy
of
REFERENCES Chmielnicka, J., Szymanska, J. A., and Sniec, J. (1981). Distribution of tin in the rat and disturbances in the metabolism of zinc and copper due to repeated exposure to SnCl,. Arch. 7’mid. 47, 263 - 268. Julsham, K.. Utne, F., and Brackkan. 0. R. (1977). Interactions of cadmium, zinc and iron in different organs and tissues of the rat. Actu PI7~1.177~1~.0/. To.ric~o/. 41, 515-524. Kaba)a-Pendias, A., and Pendias, H. (1979). “Pierwiastki Sladowe w Srodowisku biologicznym.” Wydawnictwo Geologiczne, Warsaw. Ling, J. R., and Leach. R. M. (1979). Studies on nickel metabolism interaction with other mineral elements. Metabolism and nutrition. Porrltrv Sci. 58, 591-596. Nielsen. F. H., Ollerich, D. A., Fosmire, G. J., and Sandstead, H. H. (1974). Nickel deficiency in chicks and rats. AJIWII. Exp. Mrd. Bid. 48, 389-403. Nordberg, G. F. ( 1978). Factors influencing metabolism and toxicity of metals: A consensus report by the task group on metal interaction. Et71iron. Hedfh Perspecf. 25, 3. Piotrowski, J. K., and Szymanska, 5. A. (1976). Influence of certain metals on the level of metallothionein-like proteins in the liver and kidneys of rats. J. Tu.~ico/. Environ. Health. 1, 991- 1002.
METABOLISM
OF
ENDOGENOUS
METALS
221
Piotrowski, J. K., Zelazowski, A. J., Pasek. W., and Eagiewski, A. (1978). Binding of cadmium in human kidneys. Brorrr. Clreur. Toxicof. 11, 323-328. Piotrowski, J. K.. Szymanska, J. A., Mogilnicka, E. M., and Zelazowski. A. J. (1979). Renal metal binding proteins. Experic~/7tirr. Suppl. 34, 363 -37 1. Schnegg, A., and Kirchgessner, M. (1976). Zur Interaction van Nickel mit Eisen, Kupfer und Zink. Arch. Tic,rc~r,7rrc~hrr,t7~ 26, 543 -549. Schroeder, H. A., and Nason, A. P. (1974). Interactions of trace metals in rat tissues. Cadmium and nickel with zinc, chromium, copper. manganese. J. N~ltr. 104, 167-178. Stonard. M. D., and Webb, M. (1976). Influence of dietary cadium on the distribution of the essential metals copper, zinc and iron in tissues of the rat. C‘lrerrr. Biol. Ir7fc,rc7ct. 15. 349. Sunderman. F. W. ( 1977). A review of the metabolism and toxicology of nickel. Aft/r. C/i/r. Lrth. SC;. 7, 3777398. Suzuki. Y., and Yoshikawa. H. (1976). Induction of hepatic zinc-binding proteins of rats by various metals. 11711. Hrtrlth 14, 25 -3 1, Szymanska. J. A., and Zelazowski, A. J. (1979). Effect of cadium. mercury, and bismuth on the copper content in rat tissues. /371~irou. Rev. 19, 17-l ~ 126. Szymanska. J. A., Zelazowski, A. J., and Kawiorski, S. (1981). Some aspects of bismuth metabolism. C/i/7. To.ricol., in press. Zelazowski, A. J., and Piotrowski, J. K. (1977a). A modified procedure for determination of metallothionein-like proteins in animal tissues. Actrt Biodtiw. Pd. 24, 97- 103. Zelazowski, A. J.. and Piotrowski, J. K. (1977b). The levels of metallothionein-like proteins in animal tissues. E.rpeviet7titr 33, 1624- 1625. Zelazowski. A. J., Piotrowski, J. K., Mogilnicka, E. M.. Szymariska, J. A., and Kaszper. B. W. (1978). The preparation of metallothionein from equine venal cortex as a standard protein for analytical purposes. Bro/rr. Chrrt7. T~.kd. 11, 5 I-57. Zelazowski, A. J.. Szymanska, J. A., and Witas. K. (1980). Purification of low molecular weight metal binding proteins by polyacrylamide gel electrophoresis. Prep. Biocl7rv7. 10, 4955.505.
RESEARCH
27, 216-221 (19821
Disturbances in the Metabolism of Endogenous (Zn and Cu) in Nickel-Exposed Rats
Metals
JADWICACHMIELNICKA,JADWICA A. SZYMA~~SKA, AND JOLANTATYFA
Received February 17, 1981 The effect of nickel chloride on tissue concentrations of zinc and copper was studied in female rats. Animals were subjected to repeated exposure to 5 mg Niikg. Whole-body retention of zinc increased about 30%. and retention of copper did not change. Increase of the zinc content was observed in liver, but in kidneys, lungs, and brain zinc content decreased. It was also noted that the level of metallothionein was higher in nickel-exposed rat liver than in control rat liver. Concentration of metallothionein was correlated with the metal contents t Ni, Cu, Znl.
INTRODUCTION
Nickel deficiency in food brings about alterations in hepatic functions leading in turn to decreased oxygen uptake and augmented fat accumulation. Nielsen et al. (1974) and Schnegg and Kirchgessner (1976) noted that nickel deficiency in the rat results in a decrease of endogenous iron, zinc, and copper in the liver, kidneys, and spleen. On the other hand, Schroeder and Nason (1974) demonstrated an increase of the zinc level in all organs examined but the liver, as well as an increase of the copper level in the spleen after administration of nickel in the food. Nickel damages the kidneys in the rat (Sunderman, 1977). It is accumulated with the highest efficiency in this organ and in blood plasma (KabaIa-Pendias and Pendias, 1979). However, more recent studies of Ling and Leach (1979) did not reveal any effect of nickel on the distribution of obligatory metals. This study was aimed at reexamining the effect of nickel on the whole-body distribution of the endogenous metals copper and zinc in the rat and the influence of nickel on the level of metallothionein in rat kidneys and liver. MATERIAL AND METHODS
Female Wistar rats weighing 180-200 g were used in the experiments. The animals were divided into three groups: I. Control group (six animals), II. animals subjected to repeated exposure (seven doses, subcutaneously, every other day) to nickel chloride (5 mg Niikg, ten animals), III. animals exposed as those of group II but receiving NiSO, labeled with 63Ni. Rats exposed to nickel chloride were sacrificed 24 hr after the last dose. The levels of copper, zinc, and metallothionein were estimated in tissues of rats of groups I and II. Nickel was determined in tissues of rats of group III. 216 0013-9351/82/010216-06$02.00/O Copyright All rights
0 1982 by Academic Press, Inc. of reproduction in any form reserved.
METABOLISM
OF
ENDOGENOUS
217
METALS
Whole tissues (kidneys, liver, lungs, spleen, brain, blood, heart, bowels, muscles, and skin) were mineralized with concentrated sulfuric (reagent grade, POCH) and perchloric (reagent grade, Hopkins and Williams) acid. Copper and zinc were estimated in the mineralizates by atomic absorption spectroscopy (Pye Unicam SP-192). Metallothionein concentrations in the rat liver and kidneys were determined radiochemically according to ielazowski and Piotrowski (1977a). Using the mercury-binding assay, ielazowski and Piotrowski (1977b), Piotrowski et al. (1978), and ielazowski et al. (1978, 1980) determined the metallothionein concentration in mammalian tissues. The nickel content of tissues was estimated radiochemically by measurements of radiation emitted by 63Ni. The ‘j3Ni isotope in the form of ‘j3NiS0, was obtained from the Institute of Nuclear Research in Swierk. The measurements were performed in scintillation counters USB-2 and ssu-70. RESULTS
After seven subcutaneous injections of nickel sulfate (dose of 5 mg Ni/kg) the whole-body zinc pool in the rat increased by 30% as compared with that in the control group (Table 1). In the kidneys, lungs, and brain a statistically significant decrease of the level of zinc was noted. Only in the liver was the level of zinc 2.5fold higher as compared with that in the control group. Copper concentrations found in tissues of control and nickel-exposed animals are shown in Table 2. Smaller changes were observed in concentrations of copper than in those of zinc. Only in the spleen was the level of copper in nickel-exposed rats higher than that in the control group in a statistically significant manner (Table 2). The whole-body retention of copper also did not change. Percentage contribuTABLE DISTRIBUTION
OF ZINC FOLLOWING (MEANS FROM
1
ADMINISTRATION OF SEVEN SEVEN TO TEN RATS AND SD)
7 x 5 mg Niikg
Control
/a znig tissue
Organ Kidneys Liver Heart Lungs Spleen Brain Blood Intestines Muscles Skin
+ bones
54.1
t 9.9
17.3
-+ 1.3
26.5 30.7 19.3
t 8.3 t 5.7 + 1.7
15.9 7.4
i- 1.2
38.3 31.9
f 11.0
37.9
-t 5.0
pg Zniorgan
2 4.3
Total Significantly
from
control
animals
pg Zniorgan
18.3 43.4
+ 3.8:: k 4.9,.
20.9 65.3
20.2 15.7 16.9
-+ 14.7 2 8.02 1.7
8.5
+ 4.1-'
13.9 IO.8
102.7 1105.0
4.8 47.6
f 1.4 2 8.3
I 116.2
4400.0 1123.0
39.6 2 12.5
6339.5
34.7
1254.6
7095.5
different
/a za tissue
78.9 154.5
19.7 25.5
f 4.3
DOSES OF NICKEL
(P = 0.01).
+ 22.7
28.6 391.8 15.0 37.3
64.8
9272.5
218
CHMIELNICKA,
SZYMAP;ISKA, TABLE
DISTRIBUUON
OF COPPER
FOLLOWING
(MEANS
FROM
AND
2
ADMINIVRATION
OF SEVEN
TO TEN RATS
SEVEN
TYFA
Control PLg Cuk tissue
Organ Kidneys Liver Heart Spleen Brain Lungs Blood Intestines Muscles Skin
14.6 4.0 5.0 1.3 3.5 2.2 1.8 0.5 0.8 0.7
+ bones
li Significantly
different
from
2 + IT t + -t + 5 k 2
OF NICKEL
7 x 5 mg Niikg /a Cuk tissue
/*g Cuiorgan
4.2 1.6 0.3 0.2 0.3 0.6 0.5 0.3 0.2 0.7
21.6 31.8 4.1 I.5 5.6 4.6 22.7 13.2 104.4 26.2
control
DOSES
SD)
AND
animals
18.4 5.2 5.8 I .9 4.2 1.6 1.1 0.4 0.3 1.2
L! t t 2 2 c _t 2 + c
pg Cu/organ
6.4 I.0 0.4 0.3:,: 0.8 0.5 0.5 0.2 0.3 1.5
28.2 47.6 4.4 1.6 6.2 4.0 15.0 8.8 55.5 42.3
(P = 0.01).
tion of tissues to the binding of copper and zinc in control and nickel-exposed rats is shown in Table 3. The most sign&ant changes were observed in the kidneys, liver, spleen, brain, and lungs with respect to the binding of zinc, and in the kidneys, liver, blood, skin, and muscles with respect to the binding of copper. In tissues whose contributions to the binding of copper and zinc changed more considerably, the concentration of nickel was estimated (Table 4). The highest amounts of nickel were found in liver and blood. In addition, metallothionein was assayed in the liver and kidneys of animals of groups I and II. (Table 5). The level of metallothionein in the liver was significantly higher as compared with that in control animals and correlated with the metal content (Fig. 1). TABLE DISTRIBUTION
or-
COPPER
WHOLE-BODY
Control
Kidneys Liver Heart Spleen Brain Lungs Blood Intestines Muscles Skin
1.1 2.2 0.3 0.3 0.4 0.9 1.5 15.6 62.0 15.8
Nor<,.
+ bones
Percentage
calculated
according
3
ZINC
EXPRESSED
RETENTION Zinc
Organ
AND
OF THESE
AS PERCENTAGE
Copper
(O/c I
7 x 5 mg Niikg
Control
0.3 4.2 0.2 0.1 0.1 0.4 0.7 12.0 68.5 13.5 to metal
contents
OF
METALS
9.2 13.5 1.7 0.6 2.4 2.0 3.6 5.6 44.3 11.1 expressed
in &organ.
(%) 7 x 5 mg Niikg 13.2 22.3 ‘.I 0.7 1.9 1.9 7.0 4. I 26.0 19.8
METABOLISM
OF
ENDOGENOUS TABLE
OF ‘isNi FOI.LOWING
DISTRIBUTION
Organ
pg Niig
Kidneys Liver Spleen Brain Lungs Blood !Votz.
4
ADMINISTRATION 5 mg Niikg
tissue
OF SEVEN
DOSES
OI- NICKEL,
EACH
Percentage administered
pg Niiorgan
5.4 7.9 8.1 6.2 4.0 4.5
Administered
219
METALS
8.0 68.0 7.5 9.7 5.3 64.3
of dose
0.09 0.78 0.09 0.11 0.06 0.74
dose 8.75 mg Ni = IOO?.
DISCUSSION
The present study demonstrates significant changes in the metabolism of zinc and only slight changes in the metabolism of copper due to nickel. However, our data differ from those obtained by Schroeder and Nason (1974). These differences are probably caused by different types of exposure. These authors employed microgram amounts of nickel in a prolonged exposure. To our best knowledge there are no data in the literature on alterations in the concentrations of endogenous metals by higher doses of nickel. Disturbances in the metabolism of zinc and copper induced by administration of heavy metals have been observed already for such metals as Bi, Hg, Cd, Sn, and Au (Julsham et al., 1977; Nordberg, 1978; Piotrowski et al., 1979; Stonard and Webb, 1976; Szymanska and ielazowski, 1979; Chmielnicka et al., 1981; Szymanska et al., 1981). The above-mentioned reports demonstrated a two- to sixfold increase of the copper concentration in the kidneys. On the other hand, two- to threefold increases of the zinc content were noted in the rat liver after administration of bismuth and tin (Szymanska et al., 1981: Chmielnicka et al., 1981). In all these experiments the concentrations of Hg, Bi, and Cd were in the range of more than 10 pg/g kidneys, the concentration of bismuth (cumulated in the liver) was 1 pg/g liver and that of tin was 0.03 pg/g liver and 0.2 pg/g kidneys. In our studies the concentrations of nickel were up to 5.4 pg Nilg kidneys and 7.9 j&g liver. Repeated exposure to nickel resulted in a statistically significant increase of the content of metallothionein in the liver. These changes were observed at a nickel concentration of 7.9 &g tissue and at a 2.5fold elevation of zinc in this organ. TABLE THE LEVEL
0~
Kind
MErALLol-HIoNEiN
AND KIDNEYS (mg/g TISSUE)
of exposure
Control Ni. 7 x 5 mg Niikg Significantly
different
from
control
5
IN LIVER
animals
OF CowRot.
AND
EXPOSED
Liver
Kidney
0.08 0.28,:
0.16 0.38
(P = 0.01).
RATS
220
CHMIELNICKA,
0’
”
0.1
SZYMANSKA,
a
0.2
0.3
”
0.4
05
06
Metals, Fmole metal/c FIG. 1. Dependence of the levels of metallothionein + copper (- --), and zinc + copper + nickel (-.
AND
4
0.7
TYFA
“*
0.8
0.9
tissue
in liver on the concentration
of zinc (---),
zinc
-).
Stimulation of the metallothionein level by nickel was described previously by Piotrowski and Szymanska (1976) as well as Suzuki and Yoshikawa (1976), but these authors did not determine the concentrations of nickel or copper and zinc in the liver. In the results obtained here the correlation between the concentrations of metallothionein and of the metals studied in the tissue seems noteworthy (Fig. 1). However, the question of the nickel-induced metallothionein binding of these metals (i.e., copper, zinc, or nickel) needs further investigation. Although several groups of human populations are exposed to nickel no published reports on interactions between nickel and essential elements in humans are available at present. However, the effect of nickel on copper and zinc metabolism may have public health implications. ACKNOWLEDGMENT The paper Sciences.
was supported
by Grant
536iVI
from
the Division
of Medical
Sciences,
Polish
Academy
of
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