* Department of Pharmacology and Toxicology, Center for Toxicology, The University of Arizona, P.O. Box 210207, Tucson, Arizona 85721-0207;
National Cancer Institute at the National Institute of Environmental Health, Research Triangle Park, North Carolina 27709;
Center for Devices and Radiological Health, Food and Drug Administration, Rockville, Maryland
Received July 9, 2001; accepted October 3, 2001
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ABSTRACT |
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Key Words: cadmium; liver; Sprague-Dawley; Fischer344; heat shock protein 72; metallothionein; Kupffer cell; endothelial cell.
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INTRODUCTION |
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Kupffer cells (KC) are known to contribute to the hepatotoxicity of a variety of chemicals, including Cd. When KC are selectively destroyed or inhibited, the hepatotoxicity of Cd is dramatically reduced (Sauer et al., 1997, Yamano et al., 1998
). KC are known to release a variety of cytotoxic mediators that can directly damage hepatocytes. These include reactive oxygen species, nitric oxide, and cytotoxic proteins. In addition, KC can release chemokines that promote the infiltration of other inflammatory cells to the liver (Laskin et al., 1986
). These, in turn, release a variety of cytotoxic agents that promote the progression of liver injury. For example, infiltrating neutrophils can release large amounts of reactive oxygen species, which can result in oxidative stress and lipid peroxidation (Manca et al., 1991
). The release of tumor necrosis factor
(TNF-
) and interleukin-8 has been associated with Cd-induced liver injury in mice (Kayama et al., 1995
; Nolan and Shaikh, 1986
). Collectively, these data suggest that the hepatic injury from acute Cd exposure occurs as a result of cytotoxic mediators released by KC and other inflammatory cells (Rikans and Yamano, 2000
).
Although Cd may injure hepatocytes directly, there is a growing body of evidence that ischemia may also contribute to Cd-induced liver injury (Liu et al., 1992). This ischemia may result from direct effects of Cd on hepatic EC. The extrusion of these damaged cells into the sinusoidal space alters hepatic microcirculation. The resulting hypoxia can further exacerbate hepatic injury (Rikans and Yamano, 2000
).
Cd can upregulate the expression of a number of genes that produce products that can detoxify Cd and/or repair Cd induced lesions. For example, a critical determining factor in Cd-induced liver injury is the hepatic concentration of metallothionein (MT). The synthesis of this low molecular weight metal-binding protein is induced by Cd exposure. MT forms a complex with Cd and reduces its free concentration within the cell, thus reducing the hepatotoxic potential of Cd. As the binding capacity of MT becomes saturated, the increased availability of unbound Cd initiates a series of events that result in cell injury or death (Chan and Cherian, 1992; Coyle et al., 2000
; Goering and Klaassen, 1984
). Severe hepatic injury results from activation of the cellular immune system with subsequent infiltration of inflammatory cells (Dudley et al., 1982
). The induction of MT by Cd appears to be mediated in part by TNF-
. (Grimble and Bremner, 1989
) Furthermore, Cd has been shown to activate genes that encode for a group of proteins referred to as stress or heat shock proteins (hsps). Stress proteins are synthesized in response to a wide variety of physical and chemical insults, including inorganic chemicals such as Cd, arsenic, zinc, lead, and copper (Nover, 1991
; Schlesinger et al., 1982
). Their upregulation following certain external stimuli results in resistance to subsequent cellular injury (Nover, 1991
). The synthesis of hsp72 has been reported to precede hepatic necrosis induced by Cd (Goering et al., 1993
). The timing and extent of synthesis of hsps following exposure to Cd may influence the extent of Cd-induced liver injury.
Male Fischer 344 (F344) rats are generally more sensitive to chemically induced liver injury than male Sprague-Dawley (SD) rats. To date, these strain comparisons have been made using organic chemicals that require bioactivation to elicit toxicity (e.g., carbon tetrachloride, 1,2-dichlorobenzene, and acetaminophen). Exposure to these agents results in hepatocellular necrosis that is clearly more severe in the F344 rat compared with the SD rat (Newton et al., 1983; Steup et al., 1991
; Stine et al., 1991
). To date, comparison of the sensitivity of the male F344 and male SD rats to inorganic xenobiotics has not been reported. Therefore, the object of these experiments was to determine the relative sensitivities of male F344 and male SD rats to Cd-induced hepatotoxicity and the expression of molecules known to reduce Cd toxicity, e.g., MT and hsps.
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MATERIALS AND METHODS |
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Treatments.
Cadmium, as CdCl2, was diluted in saline and administered iv via the tail vein (1 ml/kg). In dose-response studies, CdCl2 (1.5, 3.0, and 4.5 mg/kg) was administered to SD and F344 rats and livers were removed at 24 h post dose. In time-course studies, livers were removed at 1.548 h after CdCl2 (3 mg/kg). To determine how KC may affect Cd hepatotoxicity, male F344 and SD rats were pretreated with 10 mg/kg gadolinium chloride (GdCl3, Aldrich Chemical Co., Milwaukee, WI), an inhibitor of KC activity (Husztik et al., 1980). GdCl3 was dissolved in acidified saline and administered by tail vein injection. Twenty-four hours after GdCl3 treatment, animals received a single injection of CdCl2 (3 mg/kg, iv) via the tail vein.
Sample preparation.
At the appropriate time after CdCl2 administration, the rats were euthanized by inhalation of CO2. Blood was collected from the inferior vena cava into glass test tubes containing heparin for measurement of alanine aminotransferase activity (Sigma diagnostic kit procedure No. 59-UV). After collection of blood, a portion of the central lobe of the liver was resected, trimmed, and placed in 10% buffered formalin. Tissues were imbedded in paraffin, and sections (10 µm) were cut, transferred to slides, and stained with hematoxylin and eosin (H&E) for light microscopic examination. An adjacent section of liver was removed and placed in 0.1M cocadylate buffer containing 3% glutaraldehyde for electron microscopy. After fixation, sections were dehydrated in a series of ethanol rinses, cleared with propylene oxide, and embedded in epon. These sections were then evaluated using a Phillips CM-12 transmission electron microscope. Scanning electron microscopy was performed on a Phillips XL30 after the specimens were critical point dried, fractured, and gold coated. Remaining hepatic tissues were snap-frozen in liquid nitrogen and stored at 70°C until analyzed for Cd, MT, and hsp72.
Determination of Cd and MT in liver.
At 3, 6, 12, 24, and 36 h after administration of CdCl2 (3 mg/kg) hepatic Cd and MT were determined by atomic absorption spectroscopy. For Cd analyses, liver tissue (200 mg) was digested overnight in concentrated nitric acid. The solutions were then filtered with a 0.45-µm syringe tip filter and transferred to a flask containing 5 ml distilled deionized (DD) H20. The Cd content of the samples was determined on a Perkin Elmer (model AAnalyst 100) atomic spectrophotometer at 228.8 nm with a Cd lamp. Standards of Cd obtained from Fisher Scientific (Rockville, MD) were prepared in the concentration range of 025 µg/l. Concentrations of MT were determined simultaneously in the remaining tissue using the atomic absorption spectrophotometric Cd-hemoglobin assay. This assay detects bound Cd and assumes that 7 atoms of Cd are bound to each molecule of MT, as described by Eaton and Toal (1982). The rate of MT accumulation was determined using area under curve calculations.
Determination of hsp72 in the livers.
Immunological detection of hsp72 was performed as described by Goering et al. (1992). Briefly, equivalent amounts of protein (10 µg) were diluted with 10 mM Tris-HCl, then applied to polyacrylamide gels (12.5% homogenous polyacrylamide). Prestained molecular weight standards were run concurrently on each gel. After electrophoretic separation, proteins were transferred to nitrocellulose membranes and blocked in Tris blocking solution containing 4% nonfat dry milk. The blots were washed two times in DD H2O for 5 min and incubated for 1215 h with a mouse IgG monoclonal antibody (StressGen, Victoria, BC, Canada) specific for hsp72. Following incubation with the primary antibody, the immunoblots were washed and incubated with goat antimouse IgG conjugated with alkaline phosphatase (Bio-Rad Laboratories, Richmond, CA). After a washing period with deionized H2O, bands were visualized by incubation in a solution of nitroblue tetrazolium/5-bromo-4chloro-3-indolyl, a substrate for alkaline phosphates (Bio-Rad Labs, Richmond, CA).
Cytotoxicity of CdCl2 in primary cultured hepatocytes.
Hepatocytes were isolated from F344 or SD rats using the two-step in situ liver perfusion with collagenase B (Boehringer Mannheim, Mannheim, Germany) as described by McQueen (1989), and plated in Falcon six-well plates (Falcon, Franklin Lakes, New Jersey) at 0.5 x 106 cells/well. Cells were allowed to adhere for 2 h in the presence of 10% bovine calf serum (Hyclone, Logan, Utah), after which the media was replaced with Williams media E (WME; Life Technologies, Grand Island, New York) without bovine calf serum. CdCl2 dissolved in sterile deionized H2O, was added to the monolayers for a final concentration of 03 µM. After 3, 6, 12, or 18 h, the medium was removed, and cells were lysed with 0.5% triton x 100/phosphate buffer (pH 7.4) (Sigma Chemical Company). Cytotoxicity was assessed by the leakage of lactate dehydrogenase (LDH) activity into the media using Sigma Number (Procedure No. 228-UV). LDH activity was expressed as percentage of total activity released (LDH in media ÷ total LDH (media + cellular) x 100).
Statistical analysis.
The data are expressed as mean ± SEM. To compare F344 and SD rats, the data were analyzed using two-way analysis of variance followed by Bonferroni's post hoc test. Differences were considered significant if p < 0.05. All statistical analyses were performed using SigmaStat Statistical Software for Windows, Version 1.0 (Jandel Scientific, San Rafael, CA). Calculations of hepatic levels of MT assumed 7 atoms of Cd per molecule of MT and are expressed as rate of accumulation over 48 h test period (using area under curve calculations).
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RESULTS |
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DISCUSSION |
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Interestingly, when hepatocytes obtained from the livers of F344 or SD rats were incubated with various concentrations of CdCl2, no apparent differences were observed in Cd-induced cytotoxicity. After 18 h of incubation, the LC50 for Cd was similar for F344 and SD rat hepatocytes. Cytotoxicity curves were essentially superimposed throughout the 18-h incubations. One explanation for this lack of correlation between Cd-induced liver injury and its in vitro cytotoxicity is that other cell types play a critical role in Cd-induced liver injury. For example, both hepatic sinusoidal EC and KC have been implicated in Cd-induced liver injury (Rikans and Yamano, 2000).
Indeed, damage to hepatic EC of F344 and SD rats was observed within 3 h after Cd (3 mg/kg CdCl2) administration. For F344 rats, there was extensive destruction of fenestrations on the lumenal surface of EC. In contrast, damage to the EC of SD rat livers was much less extensive. Rikans and Yamano (2000) suggested that EC might be the first cellular targets for Cd-induced hepatocellular injury. Once damaged, the injured EC obstruct the capillary lumen and produce local ischemia. This local ischemia may then initiate a number of molecular and cellular events, which results in hepatocellular injury. Differences in sensitivity of the livers of F344 and SD rats to Cd may relate to the initial damage to the EC, which in turn could predispose the F344 rat to subsequent liver injury. Liu et al (1992) reported large differences in Cd-induced liver injury between C3H/HeJ (Cd-sensitive) and DBAj2 (Cd-resistant) mice. This in vivo difference correlated well with the sensitivity of EC incubated in vitro with Cd. EC of C3H/HeJ mice were more sensitive to Cd than those of DBA/2J mice. No differences in sensitivity of hepatocytes from these two mouse strains were observed when they were incubated in vitro with Cd.
In addition to EC, KC are known to play a role in the progression of liver injury caused by a variety of chemicals including Cd (Decker, 1990; Laskin et al., 1986
; McKim et al., 1992
; Sauer et al., 1997
; Sipes et al., 1989
). When KC were inhibited by pretreatment of rats with GdCl3, Cd-induced liver injury was dramatically reduced. This inhibition was apparent in both strains of rats, but more dramatic in F344 rats. Therefore, activation of KC plays a critical role in the development of Cd-induced hepatocellular injury. Whether Cd activates KC directly or indirectly is not known. Incubation of a murine macrophage cell line (RAW 264.7) with soluble or insoluble Cd results in activation of these cells (Goering et al., 2000
), suggesting that Cd can activate KC directly. KC can also be activated indirectly. For example, hepatocytes treated in vitro with ethanol release factors that stimulate production of interleukin-8 (CINC) by KC (Maher, 1995
). Furthermore, Cd has been reported to stimulate the production of cytokines from isolated hepatocytes (Dong et al., 1998
). These cytokines can, in turn, upregulate the activity of KC and promote their involvement in Cd-induced liver injury. Understanding direct and/or indirect mechanisms by which KC are activated during Cd intoxication may reveal the critical events that explain the differences in Cd-induced hepatotoxicity between these two rat strains.
Others have reported that differences in the susceptibility of rat strains to CD-induced injury relates to constitutive levels and/or induction of MT (Klaassen et al., 1999; Theocharis et al., 1994
). For example, the male Wistar rat is more sensitive to Cd-mediated hepatocellular necrosis than Quinster or Lewis rats. When levels of hepatic MT were compared following treatment with Cd, it was shown that low MT levels contributed to the greater hepatic injury in the Wistar rat (Theocharis et al., 1994
). The present study indicates that, generally speaking, SD rats treated with Cd produced a higher maximal level of MT at an apparently faster rate than in the F344 rat. However, at many time points after Cd exposure, MT levels were not significantly different. The enhanced induction of MT may have played some role in reduced sensitivity in SD rats, although this is clearly not the only factor. In this regard, MT is generally thought to be produced in hepatocytes (Din and Frazier, 1985
, McKim et al. 1992
) and it is clear from the present study that EC and KC are important for Cd injury. Therefore, although some differences in production of MT in response to Cd in SD and F344 rats could play a role in strain-related sensitivity, this does not appear to be the main factor.
Our data demonstrated that pharmacokinetic differences in the uptake of Cd by the liver do not account for the differences in susceptibility to Cd-induced liver injury between SD and F344 rats. The hepatic accumulation of Cd was similar in both strains. The possibility exists that the cellular distribution of Cd in the liver could be different on a per-cell basis. EC are known to accumulate more Cd than hepatocytes and KC (Caperna and Failla, 1984; McKim et al., 1992
). Therefore, EC of F344 rats may accumulate more Cd than EC of SD rats. Determining total hepatic Cd concentrations may mask these differences, and uptake of Cd by different cell types in subsequent experiments could address this issue.
Although the detoxification of Cd is due primarily to enhanced MT synthesis, other proteins known as heat shock or stress proteins may contribute to cytoprotection (Goering et al., 1993). Inducible hsps have been associated with cytoprotection against a variety of toxic insults (Nover, 1991
; Welch, 1987
, 1992
). Hsps confer cytoprotection through proteinprotein interactions that preserve the conformational integrity of proteins. Such interactions can stabilize damaged proteins and promote repair and refolding (Welch, 1987
, 1992
). Therefore, the earlier synthesis of hsps might contribute to the ability of the liver to repair early stages of Cd-dependent injury. Induction of hsp72 protein was observed in the livers of F344 and SD rats. However, this induction was apparent 3 h earlier in the livers of SD rats. Therefore, the SD rat responds to Cd with an earlier induction of known hepatoprotective factors such as MT and hsps. These factors may minimize the degree of injury and mitigate its progression. Indeed, at the ultrastructural level, hepatocytes of F344 and SD rats treated with Cd had evidence of injury as early as 3 h after administration of CdCl2. Hepatocytes of both F344 and SD rats displayed abnormal vesicles at this time point. These vesicles were not detected 24 h after administration of Cd to the SD rat but were still present in the F344 rats. The SD rat apparently had mechanisms that repair these early lesions and/or prevented further progression of hepatocellular injury.
Collectively, the delayed expression of hsp72, and possibly MT, may contribute to the increased sensitivity of the F344 to Cd-induced liver injury. The livers of F344 rat appear to respond less efficiently to the induction of these protective responses. Because hepatoprotective measures are expressed earlier in livers of SD rats, the initial injury is minimized and the subsequent inflammatory cascade is blunted.
The initiation and progression of Cd-induced hepatocellular injury involves multiple cell types. EC are the first liver cells that come into contact with free Cd and are clearly involved in the early stages of Cd-induced liver injury. In the current study, the endothelial cells of the F344 were damaged more extensively than the EC of the SD rats. Once damaged, these cells obstruct the hepatic microcirculation, which leads to localized ischemia. This occlusion of hepatic inflow could lead to hypoxic conditions that promote hepatocellular necrosis. The liver responds to these conditions by synthesizing repair proteins. In fact, hsp72 has been shown to be produced early after total hepatic inflow occlusion (Dai et al., 1998). The earlier synthesis of MT and hsp72 may contribute to the decreased sensitivity of the SD rat to Cd-induced hepatotoxicity, but at least with regard to MT, this does not appear to be a primary factor. The hepatocytes and EC respond to hepatocellular injury by releasing chemokines and cytokines that result in inflammation orchestrated in part by KC.
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ACKNOWLEDGMENTS |
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NOTES |
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