Mutagenesis, Vol. 15, No. 2, 109-114,
March 2000
© 2000 UK Environmental Mutagen Society/Oxford University Press
Induction of genotoxicity by cadmium chloride inhalation in several organs of CD-1 mice
Departamento de Genética y Toxicología Ambiental, Instituto de Investigaciones Biomédicas and 1 Departamento de Biología Celular y Tisular, Facultad de Medicina, UNAM, AP.70228 Ciudad Universitaria, 04510 México DF and 2 Facultad de Medicina, UASLP, México
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Abstract |
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In recent years, the concentration of metals in the environment has increased significantly. Metal compounds, as a group, are among the best-documented human carcinogens, but the mechanisms by which they act are not completely understood. In the present study a cadmium inhalation model in mice was implemented in order to detect the induction of genotoxic damage as single-strand breaks and alkali-labile sites in several organs (nasal epithelial cells, lung, whole blood, liver, kidney, bone marrow, brain and testicle) using the single cell gel electrophoresis (SCGE) or Comet assay. We found differences among the studied organs after a single and subsequent inhalations: in the organs analyzed we observed that major DNA damage was induced after a single inhalation; in subsequent inhalations there was a tendency to maintain the same magnitude of damage or in some cases it decreased. A correlation between length of exposure, DNA damage and metal tissue concentration was found. These results suggest that cadmium chloride inhalation induces systemic DNA damage; some organs showed less damage than others (liver, brain, etc.) and this finding could be as a consequence of the capacity to remove the damage induced by long periods of exposure, possibly because of the induction of detoxifying mechanisms such as induction of metallothionein.
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Introduction |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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The mechanism by which metals induce carcinogenesis is still unknown, but one possible pathway may involve their interaction with DNA, either directly or indirectly (Hartman and Speit, 1994
). From the results of several hundred short-term tests performed to assess the carcinogenic properties of metal salts on the basis of their mutagenicity, it can be concluded that there is a clear relationship between the carcinogenic potential of a metal compound and its genotoxicity. These assays have also demonstrated that the response obtained depends on the ability of the metal to penetrate the cell and interact with DNA, the chemical species, the physical properties (oxidative state, charge, solubility, crystal form, properties of ligands and complex stereochemistry) and possible interactions with other xenobiotics (Goyer, 1991). However, the relation observed between the carcinogenicity of some metal compounds and their genotoxic potential does not exclude the possibility of additional mechanisms such as the induction of metallothioneins (MT) (Leonard and Bernard, 1993). MT are a family of low molecular weight, inducible proteins rich in sulfhydryl groups, some of which are believed to have evolved to modulate the effects of zinc (Gochfeld, 1997). The induction of MT protects against the toxicity of some metals (such as cadmium), they act as a free radical scavenger protecting against oxidative damage, and they also protect against the toxicity of alkylating anticancer drugs and other electrophiles (Klaasen and Liu, 1998). The MT multigene family is composed of at least four isoforms. MT-I and MT-II exist in all tissues, they are regulated in a coordinate fashion, and appear functionally equivalent. Other members of the MT gene family, however, show different patterns of expression: MT-III is found mainly in the brain and MT-IV in stratified squamous epithelium. MT-III and MT-IV are regulated very differently to MT-I and MT-II and their significance is not yet understood (Klaasen and Liu, 1998). MT-I and MT-II can be easily induced by heavy metals, hormones, inflammation, acute stress and many other chemicals.
Cadmium is a modern environmental contaminant that is toxic and carcinogenic (Sunderman, 1978; Leonard et al., 1984; Goyer, 1991). Industrial exposure, food and cigarette smoking are the major sources of the body burden of cadmium (Leonard et al., 1984). Cadmium avidly binds to polythiol groups in proteins such as metallothionein as well as zinc sites in metalloenzymes and transcriptional factors (Vallee and Ulmer, 1972; Vallee and Galdes, 1984; Freedman et al., 1988; Makowski et al., 1991). Cadmium compounds are inactive or weakly active in gene mutation (Costa et al., 1981; Leonard et al., 1984; Klein et al., 1991) and other genotoxicity assays (Beyersmann et al., 1994; Rojas et al., 1999). Therefore, epigenetic mechanisms probably play a significant role in the carcinogenicity of cadmium, although the mechanisms are not well understood. Cadmium has been considered carcinogenic in laboratory animals (Sunderman, 1978; Leonard et al., 1984; Goyer, 1991; IARC, 1993). Rats exposed to aerosols containing CdCl2 produced an increase of 50% in the incidence of lung tumors (Takenaka et al., 1983). A single s.c. injection of 40 µmol/kg CdCl2 in rats produced a high incidence of Leydig cell adenomas in the testicle, prostatic neoplasia and sarcomas at the site of injection (Waalkes et al., 1988). Oral administration of CdCl2 to rats also potentially induced tumors in the prostate, testicle and hematopoietic system (Waalkes and Rehm, 1992).
Long-term exposure to low levels of Cd2+ produced transformed muntjac cells with normal karyotypes. Chronic exposure studies in rats with several different Cd compounds (i.e. CdSO4, CdO dust, CdO fumes, CdS and CdCl2) showed induction of a carcinogenic pulmonary response to these inhaled Cd compounds (Glaser et al., 1990; Oberdöster et al., 1994).
In contrast to these unequivocal findings in rats, Heinrich et al. (1989) did not observe a significant pulmonary carcinogenic response in chronic inhalation studies in mice and hamster, using the same Cd compounds and exposure concentrations. The evidence that Cd is a pulmonary carcinogen in humans has been termed limited by the International Agency for Research on Cancer (IARC, 1987) based on a number of epidemiological studies that did not uniformly show a significant correlation between Cd inhalation exposure and lung cancer; this issue is still controversial (Thun et al., 1985; Doll, 1992). The results of experimental animal and epidemiological studies suggest that the pulmonary tumorigenic potency of inhaled Cd compounds is quite different in different mammalian species. An important question arises about the best appropriate animal model for extrapolation to humans. A basic knowledge of the mechanisms involved in various species for the different responses would also contribute greatly to our understanding of the human carcinogenic process. Since inhalation is one of the main routes of environmental Cd exposure, this route is evaluated, along with induction of genotoxic effects in several CD-1 mouse organs (nasal epithelial cells, lung, whole blood, liver, kidney, bone marrow, brain and testis) after inhalation of 0.08 µg/cc cadmium chloride (CdCl2), using the alkaline single cell gel electrophoresis (SCGE) assay. The SCGE assay is a sensitive procedure to quantify DNA damage [primarily single-strand breaks (SSB) and alkali-labile sites] in mammalian cells in vitro and in vivo (Singh et al., 1988). One of the advantages of the simultaneous assessment of DNA damage in many organs from the same animal is, as reported here, the comparison of their responses under identical treatment conditions at the same time and with the same physiological status.
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Materials and methods |
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Chemical reagents
Normal agarose, low melting point agarose (LMPA), ethidium bromide, Tris, Na2EDTA, dimethyl sulfoxide, Triton X-100 and RPMI-1640 medium were obtained from Sigma Chemical Co. (St Louis, Mo), NaOH from Merck and NaCl from Baxter.
Animals
CD-1 male mice (from the Medical School Vivarium, UNAM, Mexico), 45 days old and weighing 30–35 g, were housed in hanging plastic cages under controlled lighting conditions (12 h light/12 h dark regime) relative humidity (50 ± 5%) and temperature (17 ± 2°C) and fed Purina Rat Chow and water ad libitum.
Groups
Twenty-four males were allotted randomly to four exposure groups of six animals each (four exposed and two controls). Group 1, single inhalation (acute treatment); group 2, two weeks of exposure, three inhalations; group 3, three weeks of exposure, five inhalations; group 4, four weeks of treatment, seven inhalations.
Treatments
Inhalations were performed in an acrylic box (50x30x20.98 cm), connected to an ultra-nebulizer (Ultra-Neb 99; DeVilbis) with a flux of 10 l/min. The exposure protocol and cadmium chloride concentrations were according to Fortoul et al. (1999). Briefly, 16 animals, four from each group, were placed in an acrylic box and the cadmium chloride (0.08 µg/cc) inhalations were performed for 60 min, twice a week (Monday and Wednesday). The control animals (eight) inhaled deionized water for the same time. After inhalation the animals were returned to their respective cages.
Sampling
Groups of six animals (four exposed and two controls) were killed by cervical dislocation every week, 24 h after the last inhalation. Immediately, whole blood was obtained by intracardiac puncture with a preheparinized syringe and the brain, lung, nasal septum, liver, kidney, femur and testicle were removed. The organs were placed in cold saline solution (0.9% NaCl) until cell suspensions were prepared.
Cell suspensions
All organs, other than the nasal septum and femur, were washed twice with cold saline solution and placed in cold RPMI-1640 medium and minced with the help of cold scissors into 1 mm3 pieces. Then the cell suspensions were kept at 4°C until a sediment was observed. The nasal septum was placed in 1 ml of cold saline solution, shaken in the solution with tweezers and then discarded. For bone marrow cells, 1 ml of cold saline solution was used to gently wash the femur medullar cavity to detach the cells and resuspend them. The viability of the cell suspension was determined using the trypan blue exclusion technique.
SCGE assay
An appropriate number of cells was obtained in 30 µl of cell suspension and mixed with 75 µl of 0.5% LMPA. Cells and LMPA at 0.36% final concentration were loaded onto a microscope slide prelayered with 200 µl of 0.5% normal melting point agarose. The SCGE assay was performed as described by Tice et al. (1992). Briefly, after lysis at 4°C for at least 1 h [2.5 M NaCl, 100 mM EDTA, 10 mM Tris, pH 10, 10% DMSO, 1% fresh Triton X-100), slides were placed in a horizontal electrophoresis chamber with running buffer solution (300 mM NaOH, 1 mM Na2EDTA, pH 13). The slides remained for 10 min in the electrophoresis buffer to allow the DNA to unwind. Electrophoresis was performed for 10 min at 0.8 V/cm, and all technical steps were conducted using very dim indirect light. After electrophoresis, the slides were gently removed and rinsed with neutralization buffer (0.4 M Tris, pH 7.5) at room temperature (15 min). The slides were dehydrated with absolute ethanol (15 min), after which they were air dried. Ethidium bromide (75 µl of a 20 µg/ml solution) was added to each slide and a coverslip was placed on the gel. Individual cells were visualized at 200x magnification on an Olympus BX-60 microscope with fluorescence attachments (excitation filter 515–560 nm and barrier filter 590 nm) and the extent of migration (tail length value) was measured with a scaled eyepiece. To evaluate DNA migration 100 cells/tissue/animal were scored for each condition.
Measurement of cadmium
As an exposure marker, cadmium concentration was measured in three different organs (lung, liver and kidney) after each treatment by atomic absorption spectrophotometry. Cadmium analyses were performed using a Perkin-Elmer 2380 atomic absorption spectrophotometer. Tissue samples of lung, kidney and liver were placed in acid-washed glass test tubes and solubilized with a mixture of nitric and perchloric acids for al least 5 h. Cadmium was quantified by the graphite furnace method. As an internal quality control, we analyzed blind random samples of reference material (SRM 1577b bovine liver) obtained from the National Institute of Standards and Technology. For cadmium, recoveries were 104%.
Statistical analysis
All the statistical analysis were performed with GraphPAD InStat software v.1.14. The Mann–Whitney U test was used to determine statistical differences between groups of animals for each organ (Kirk, 1999).
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Results |
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The viability, using the classical trypan blue exclusion technique, of the cell suspensions was >80% in all organs immediately after death. DNA damage as SSB and alkali-labile sites induced by cadmium chloride inhalation was analyzed in several mouse organs with respect to times of exposure.
Different organs displayed different sensitivities after one exposure. The distribution of damage from high to low susceptibility was: brain > bone marrow > nasal cells > lung > leukocytes > testicle> liver > kidney (Figure 1). An analysis of genotoxicity throughout the treatment showed accumulation of DNA damage in the majority of the organs studied.
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Testicle and nasal epithelial cells
There was an increase in DNA migration after the first exposure and the damage remained at the same value through the exposure time. A dose–damage response was not evident in the testicle (Figure 2A
). However, in nasal cells (Figure 2B) a tendency for increased induction of DNA damage with time of exposure could be observed. However, there were no statistical differences at the end of the treatment with respect to controls, possibly due to the high standard deviation observed and the heterogeneous response.
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Lung and bone marrow
After nasal epithelial cells, the lung is the second organ in contact with cadmium chloride. The sensitivity of the lung (Figure 3A
) and bone marrow (Figure 3B) is higher than other organs, such as liver, kidney, nasal cells, testicle and leukocytes. The greatest induction of DNA damage was observed after the first exposure and remained constant until the last inhalation, after 4 weeks.
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Liver and kidney
These organs showed a slight increase in DNA damage after the first exposure, which increased a little until week 3 of treatment, while a remarkable increase in DNA damage in the last week was apparent for both organs (Figure 4A and B
, respectively).
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Leukocytes and brain
After the first exposure both organs showed an increase in DNA damage. Brain (Figure 5B
) showed the greatest susceptibility to cadmium chloride exposure. DNA migration remained constant until week 3 of treatment, although in the last week of exposure in leukocytes, but not in brain, a remarkable increase in induction of DNA damage was evident (Figure 5A).
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After each inhalation the metal concentration was determined in lung, liver and kidney throughout the exposure time (Table I
), employing atomic absorption spectrophotometry. Figure 6 shows the correlation between cadmium concentration in the three different organs and the time of exposure. In all organs a good correlation between time and metal concentration was found; in lung the r value was 0.98, for liver r = 0.98 and for kidney r = 0.97.
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The correlation between DNA damage, measured as tail length, induced by cadmium inhalation and the accumulation of metal in lung, liver and kidney is shown in Figure 7
, when applying the equation: 
, where m is the slope of the curve (biological effect), x is the cadmium concentration and b is the basal value of DNA migration (µm). It is possible to calculate that 1.0 µg of Cd induced an increase in DNA migration of 0.69 µm. The proposed formula for lung is:
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Discussion |
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The potential of metals to cause toxicity has traditionally been regarded as a function of dose and potency of the metal itself. Over the last 10 years it has become clear that several metals undergo biotransformation in mammalian tissues and that metabolism may have important implications in their toxicity and on its health impact (Manzo et al., 1992
). Since the effects of metals are related to their concentration at specific target sites, metabolic data are also important in interpreting toxicological findings. The aim of this work was to determine the different susceptibilities of several mouse organs to cadmium chloride inhalation (0.08 µg/cc). Different DNA migration distances in target organs were observed. For a single inhalation, the brain was the most susceptible organ, while after 4 weeks exposure the liver showed the highest DNA damage. Several modulating effects were present when genotoxicity induced by the treatment in each organ was analyzed.
Nasal epithelial cells are the first epithelial tissue in contact with the metal, however, a significant genotoxic effect was not evident until the last week of treatment (Figure 2b
); this could be due to the size of the particles, which was less than 0.5 µm, or another explanation could be the high metallothionein concentration observed in several epithelia (Foulkes, 1991).
The second organ in contact is the lung, the size of the metal particle having the capacity to reach the alveoli (Wanner, 1993). This could be reflected in the induction of DNA damage (Figure 3a). In this respect, Oberdöster et al. (1994) reported a high susceptibility to cadmium inhalation in mouse lung. Likewise, mice exhibited a marked and sustained pulmonary inflammatory and proliferative response after Cd exposure in his model. Furthermore, as a consequence of the inflammatory response there was an increase in free radicals, which have the capacity to induce DNA strand breaks. However, considering the magnitude of DNA damage in our results it is possible that the lung has the capacity to prevent some of the damage by induction of metallothionein. Oberdöster et al. (1994) showed that pro-inflammatory cytokines, such as TNF-
and IL-1, induce MT synthesis. This could explain the induction of DNA migration of median magnitude.
After absorption via the pulmonary or gastrointestinal routes Cd is transported in the plasma, initially bound to albumin and other large proteins (Foulkes, 1994). This reflects high levels of metal–tissue interaction and could explain the high levels of damage found in leukocytes after the first exposure and accumulation of damage throughout the treatment (Figure 5a). In kidney induction of DNA damage was observed at week 2. This is in agreement with Foulkes (1991), who reported that the nephrotoxic action of some heavy metals becomes apparent only after a significant delay following their administration.
Cadmium as the chloride salt is immediately bound to plasma proteins and subsequently accumulates, primarily in liver and in other tissues; these processes do not exclude the possibility that cadmium accumulation after some time was a factor in the induction of DNA damage observed in kidney (Foulkes, 1994).
In liver a slight dose–response curve during the first three weeks was observed (Figure 4a), maybe because metallothionein was induced after the first inhalation (Foulkes, 1994), but subsequent exposure to cadmium saturated the capacity for detoxification by this mechanism (Klaassen and Liu, 1998); this could explain the increase in DNA damage observed in the last week.
In the testicle the induction of damage observed was not severe but was statistically significant. There are several reports of reprotoxic effects of cadmium administered by the i.p. route (Gebhart and Rossman, 1991); the response observed in this study could be due to the route of exposure, since inhalation implicates metal absorption by the lung.
The bone marrow was the organ with the highest susceptibility to cadmium, as it showed one of the highest inductions of DNA damage through all the weeks of exposure. Bone marrow tissue could be more sensitive to cadmium chloride due to the high level of proliferation, as this metal interferes with a number of enzymes involved in DNA repair and replication (Hartwig, 1994, 1995). On the other hand, although induction of metallothionein in bone marrow had been reported (Tamura and Ohya, 1995; Klaassen and Liu, 1998), in our work, after the first exposure an equilibrium between the cadmium and metalliothionein concentrations seems to be reached. This could explain why we did not observe a dose-related response in this tissue.
Brain cells also showed a high response to cadmium, similar to bone marrow, but in the case of the brain the probable mechanism could be an interaction with calcium and not direct, as in other tissues (Nordberg and Nordberg, 1988; Smith et al., 1994).
In general we could detect different susceptibilities to cadmium chloride inhalation in several organs of CD-1 mice, measured as SSB, alkali-labile sites and delayed repair sites.
The SCGE assay was a sensitive method to detect DNA damage in several mouse organs (Sasaki et al., 1997). Results obtained in this study using this assay correlated with the cadmium concentration in the lung, liver and kidney, which could be related to the levels of metallothionein.
Based on the fact that in this study the lung was the organ with the highest cadmium concentration throughout the treatment, the correlation between DNA damage and cadmium concentration was lower (r = 0.59), because the level of DNA migration was low, probably due to induction of MT, principally MT-I and MT-II, which can be easily induced by heavy metals (Cd), hormones, inflammation, acute stress and chemicals (Klaasen and Liu, 1998), and protects against metal toxicity. In these functions, MTs act as free radical scavengers, protecting against oxidative damage (Hartwig, 1995). On the other hand, our liver and kidney data with respect to the correlation between DNA damage and cadmium concentration agree with Klaasen and Liu (1998), who reported that tolerance to Cd toxicity is apparently attributable to MT protection against Cd-induced acute toxicity. However, due to the fact that the induction of MT is saturable, its inhibition is possible. In this context it is important to consider that MTs are expressed in an inducible manner in essentially every tissue, providing evidence that MTs play a role in both the extracellular (homeostatic) and intracellular control of zinc and copper metabolism (Karin et al., 1985). The induction of genotoxicity by environmental agents is a very important aspect of modern environmental research since the most recent molecular cancer genetics and cytogenetics data have provided strong evidence that genotoxic events can be the initial step of the malignant process, and metals could be the first step.
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Acknowledgments |
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Thanks are due to M.C. López, M. Sordo, I. Sánchez and I. López for their technical support. This study was partially supported by CONACyT project 3180P-M. M.V. was the recipient of a fellowship from DGEP and CONACyT.
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Notes |
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3 To whom correspondence should be addressed. Tel: +52 5 622 3366; Fax: +52 5 622 3365; Email: emilior{at}servidor.unam.mx
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References |
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Received on June 23, 1999; accepted on October 21, 1999.
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