Cadmium and immunologically-mediated homeostasis of anatomical barrier tissues.

Cadmium (Cd) is a toxic heavy metal that when absorbed into the body causes nephrotoxicity and effects in other tissues.Anatomical barrier tissues are tissues that prevent the entry of pathogens and include skin, mucus membranes and the immune system. The adverse effects of Cd-induced immune cell's activity are the most extensively studied in the kidneys and the liver. There are though fewer data relating the effect of this metal on the other tissues, particularly in those in which cells of the immune system form local circuits of tissue defense, maintaining immune-mediated homeostasis. In this work, data on the direct and indirect effects of Cd on anatomical barrier tissue of inner and outer body surfaces (the lungs, gut, reproductive organs, and skin) were summarized.

Acute exposure to cadmium induces prolonged neutrophilia along with delayed induction of granulocyte colony-stimulating factor in the livers of mice.

Acute exposure to cadmium (Cd), a toxic heavy metal, causes systemic inflammation characterized by neutrophilia. To elucidate the mechanism of neutrophilia induced by Cd, we investigated the induction of granulocyte colony-stimulating factor (G-CSF), which regulates neutrophil production, in mice with acute Cd toxicity, and compared it with mice injected with lipopolysaccharide (LPS) as an inducer of general inflammatory responses. We injected BALB/c mice with Cd at 2.5 mg/kg i.p. or LPS at 0.5 mg/kg i.p. and sampled the peripheral blood and organs at time points up to 24 h. In Cd-treated mice, the peripheral neutrophil count increased steadily up to 24 h, whereas LPS-treated mice showed a more rapid increase with a peak at 12 h. The serum G-CSF level increased gradually to reach a plateau at 12-18 h in Cd-treated mice, but LPS-treated mice showed a marked increase, reaching a peak at 2-3 h. A gradual elevation of G-CSF mRNA expression up to 24 h was detected by real-time PCR in the livers of Cd-treated mice, but in LPS-treated mice its highest expression was observed in the liver with a rapid increase at 2 h. By in situ hybridization using G-CSF RNA probes, hepatic Kupffer cells were identified as G-CSF-producing cells in the liver. These results indicated that Cd has a characteristic effect of delayed induction of G-CSF in the liver, causing systemic inflammation accompanied by prolonged neutrophilia.

Effect of cadmium-polluted water on plasma levels of tumor necrosis factor-α, interleukin-6 and oxidative status biomarkers in rats: protective effect of curcumin.

UNLABELLED: The present study was designed to investigate the effect of CdCl2-polluted drinking water (40 mg CdCl2/L) on the level of TNF-α and IL-6, as well as oxidative status biomarkers in plasma of rats. The possible protective effect of oral administration of curcumin (50 mg/kg body weight/day) was assessed. Results illustrated that Cd exposure significantly elevated the plasma levels of TNF-α and IL-6 (p<0.001) as compared to normal rats. Also, Cd administration resulted in a significant elevation in the lipid peroxidation and markedly reduction in the activities of SOD and catalase as well as the level of glutathione and total antioxidant capacity in plasma. The co-treatment of Cd with curcumin significantly reduced the levels of TNF-α and IL-6 and ameliorated the alteration in oxidative status biomarkers induced by Cd. Negative correlation between IL-6 or TNF-α was and the plasma activities of catalase, SOD and the level of total antioxidant capacity were found in rats exposed to Cd. CONCLUSION: Cadmium toxicity induced the release of TNF-α and IL-6 which is associated with systemic oxidative stress. This may be involved in the mechanism of the Cd toxicity. On the other hand, the findings suggest the curative action of curcumin against Cd toxicity.

Prenatal cadmium exposure produces persistent changes to thymus and spleen cell phenotypic repertoire as well as the acquired immune response.

Cadmium (Cd) is a common environmental contaminant. Adult exposure to Cd alters the immune system, however, there are limited studies on the effects of prenatal exposure to Cd. Pregnant C57Bl/6 mice were exposed to an environmentally relevant dose of CdCl(2) (10 ppm) and the effects on the immune system of the offspring were assessed at 20 weeks of age. Prenatal Cd exposure caused an increase in the percent of CD4(-)CD8(-)CD44(+)CD25(-) (DN1) thymocytes in both sexes and a decrease in the percent of CD4(-)CD8(-)CD44(-)CD25(+) (DN3) thymocytes in females. Females had an increase in the percent of splenic CD4(+) T cells, CD8(+) T cells, and CD45R/B220(+) B cells and a decrease in the percent of NK cells and granulocytes (Gr-1(+)). Males had an increase in the percent of splenic CD4(+) T cells and CD45R/B220(+) B cells and a decrease in the percent of CD8(+) T cells, NK cells, and granulocytes. The percentage of neutrophils and myeloid-derived suppressor cells were reduced in both sexes. The percent of splenic nTreg cells was decreased in all Cd-exposed offspring. Cd-exposed offspring were immunized with a streptococcal vaccine and the antibody response was determined. PC-specific serum antibody titers were decreased in Cd exposed female offspring but increased in the males. PspA-specific serum IgG titers were increased in both females and males compared to control animals. Females had a decrease in PspA-specific serum IgM antibody titers. Females and males had a decrease in the number of splenic anti-PspA antibody-secreting cells when standardized to the number of B cells. These findings demonstrate that very low levels of Cd exposure during gestation can result in long term sex-specific alterations on the immune system of the offspring.

Chronic overexposure to cadmium fumes associated with IgA mesangial glomerulonephritis.

BACKGROUND: Cadmium is a metal used in the zinc, copper and steel industries, and in the manufacture of electric batteries and solar cells. Acute cadmium poisoning is characterized by irritation of the respiratory tract, while in chronic poisoning the main target organ is the renal tubule. AIMS: We report a patient with chronic work overexposure to cadmium, who presented a IgA mesangial glomerulonephritis with no respiratory or renal tubule involvement. Case report A 39-year-old patient was referred to our hospital for evaluation of a glomerular nephropathy. For the past 12 years he had worked as a welder, using cadmium electrodes. The patient had no respiratory symptoms and the chest X-ray was normal. Tests showed a proteinuria of 2 g in 24 h with microhaematuria [150 red blood cells/high power field (rbc/hpf)], with preservation of the renal function (creatinine clearance of 137 ml/min). The concentrations of cadmium in blood and urine were 45 micro g/l and 25 micro g/g creatinine, and an environmental study showed that levels of cadmium in the workplace were 52 micro g/m(3). A renal biopsy showed an IgA mesangial glomerulonephritis. The patient ceased to work with cadmium, and 1 year later cadmium levels had decreased and renal function was found to be stable. CONCLUSIONS: IgA mesangial glomerulonephritis is a disease of unknown aetiology which has been associated with other diseases. Chronic overexposure to cadmium may contribute to the development of this nephrophathy.

Influence of cadmium and zinc on the mice resistance to Listeria monocytogenes infection.

UNLABELLED: The objective of this study was to examine the effect of chronic exposure to cadmium and zinc on the mice resistance to experimental Listeria monocytogenes infection. MATERIALS AND METHODS: At the day beginning of experiment outbred mice were injected with suspension of bacteria and 8 weeks were given the following oral intake treatment: control group (n=28) deionized drinking water, Cd- group (n=37) water containing CdCl2 10 mg/l and Cd+Zn- group (n=33) water containing CdCl2 10 mg/l and ZnSO4 100 mg/l. The delayed type hypersensitivity was evaluated by the inflammatory response during so-called "foot" test. Listerial proteins solution was injected under plantare of lower aponeurosis of rear foot of experimental animals. Survival of L. monocytogenes in organs of experimental animals was evaluated by the presence of bacteria colonies after 30 days incubation of livers homogenates in broth medium at +4 degrees C and inoculation on CASO-agar. Kidneys, liver and spleen were used for metals analysis. Differences were significant if the P value was below 0.05. RESULTS: Chronic exposure to Cd or to Cd with Zn for 8 weeks caused influence on survival of mice: Cd- and Cd+Zn groups mice died more rapidly than control group ones. Bacterial growth in organs was observed for all groups until fourth week. From sixth-week, control and Cd+Zn- group's mice more rapidly eliminated bacteria from organs, demonstrating that Zn- treated mice were more resistant to listerial infection than Cd- intoxicated ones. On the other hand, mice from Cd+Zn- group had significantly decreased spleen index (up to 74%, p<0.01) as compared to control group. Chronic poisoning of mice with low doses cadmium and zinc during infection significantly affected (p<0.05) their growth rate from fourth week in both experimental groups. Cadmium and zinc insignificantly decreased the delayed type hypersensitivity response to L. monocytogenes allergens in Cd+Zn- group of mice, and no differences were observed in Cd- group, as compared with control group. CONCLUSIONS: 1. Cadmium-exposed mice are more susceptible to Listeria monocytogenes and to other opportunistic infections than not intoxicated mice. 2. Zinc significantly reduces the negative effect of cadmium on the antimicrobial defense of mice. 3. Cadmium and zinc no significantly decrease the delayed type hypersensitivity response to L. monocytogenes allergens as compared with control.

New aspects of murine coxsackie B3 myocarditis--focus on heavy metals.

The magnitude of inflammatory lesions in the hearts of coxsackie B3 (CB3)-virus infected mice can be affected by the potentially toxic heavy metals cadmium (Cd), nickel (Ni) and methyl mercury (MeHg). The infection is associated with a changed distribution, such as Cd accumulation in the spleen and kidneys. New target organs for Ni during the infection were the heart, pancreas and lungs in which inflammatory lesions were present. This increased uptake was correlated with the disturbed function of immune cells and an increased inflammatory reaction. Ni and MeHg appeared to have a direct effect on immune cells that resulted in changed natural killer cell activity and decreased mobilization of macrophages, CD4+ and CD8+ cells into the inflammatory lesions. Although MeHg increased spleen T cell activity and gamma-interferon (IFN-gamma) levels, the inflammatory lesions in the heart increased. Another detrimental effect of MeHg treatment was evident by an increased calcium and decreased zinc content in the inflamed heart, which may partly explain the more severe inflammatory lesion. The host's response, CB3 infection, changed the distribution of each metal in a specific way, a fact which may subsequently result in altered target organ toxicity and resistance to the infection.

The effect of concurrent lead and cadmium exposure on the cell-mediated immune response in goats.

Cell-mediated immune response was monitored by cutaneous hypersensitivity reaction (CHR) to 2-4 dinitrochlorobenzene in goats given lead or cadmium alone or in combination. Twenty goats were divided into 4 groups of 5 animals each. Group A served as control whereas Groups B, C and D were given po doses of 50 mg lead acetate/kg body weight, 10 mg cadmium chloride/kg body weight or 50 mg lead acetate/kg body weight + 10 mg cadmium chloride/kg body weight, respectively, for 42 d. Primary sensitization was done on day 27 followed by a challenge dose after 14 d. Elicitation of CHR, as measured by average increase in skin thickness, was suppressed significantly in goats of all dosed groups. Suppression was more in the cadmium-dosed than in the lead or lead + cadmium dosed goats. Histopathology demonstrated reduced intensity of cellular reactions in the cadmium and lead + cadmium-dosed animals.

Strain differences in cadmium-mediated suppression of lymphocyte proliferation in mice.

Strain differences were investigated on the proliferative responses of splenic lymphocytes obtained from C3H/He, BALB/c, and DBA/2 mice that were treated with cadmium (Cd) for 5 days (0.5 or 1.0 mg Cd/kg/day, sc), and the results were compared with those of in vitro treatment of spleen cells with Cd. Following in vivo treatment, splenocytes from the C3H strain were significantly more susceptible to suppressive effects of Cd exposure on all indices for proliferative responses to mitogens (concanavalin A, phytohemagglutinin, and lipopolysaccharide) and allogeneic lymphocytes, while those from DBA and BALB strains were fairly resistant. Among the three strains, the highest Cd concentrations in plasma and spleen were obtained in the C3H strain with the lowest hepatic concentration of Cd. On the other hand, the Cd exposure hardly affected the splenic concentration of zinc in the C3H strain in contrast to its decrease in the others. When spleen cells obtained from normal mice were treated in vitro with Cd, the C3H strain was more resistant to the suppressive effect of Cd than the other strains. These results indicate that the mouse strain variations in Cd-mediated suppression of lymphocyte proliferation are not based on intrinsic lymphocyte sensitivities, but likely are due to differences in the metabolism of Cd, which is under genetic control.

Immunopathology of chronic cadmium administration in mice.

Young male mice were given drinking water containing 50 ppm cadmium (Cd) for 3 weeks, and were killed 0, 3 and 6 weeks after the cessation of treatment. At 0 weeks, suppression in the number of splenic plaque-forming cells in response to sheep red blood cell immunization was noted 5 days after antigen injection, but not 7 days after injection. Plasma IgG concentration and thymic factor activity were unaffected at 0 weeks. The number of circulating lymphocytes tended to be less in the Cd-treated mice at all times. Cd treatment had no effect upon liver and kidney weights, and upon the weights and the lymphocyte contents of the thymus and spleen at any of the observation times. Employing immunofluorescence with anti-mouse IgG and C3, no evidence of an autoimmune response was found in the kidney of the treated mice at 0 and 3 weeks. Mitochondrial abnormalities in the renal proximal tubule cells were noted at 0 weeks in the Cd-treated mice. The Cd concentrations of the liver and kidneys remained high at all observation times. The results suggest that a modest dose of Cd produces some depression of the immune system, and the biological half-life of Cd is long.

Evaluation of host resistance and immune function in cadmium-exposed mice.

Adult female B6C3F1 mice received distilled water only or water containing 10, 50, or 250 ppm of cadmium chloride (CdCl2) for 90 days. Body weights were measured weekly. On selected days during exposure and on Day 91, Cd tissue concentrations were measured along with changes in primary antibody responses. On Day 91 mice also received a primary challenge with various infectious agents. T- and B-cell mitogenesis, natural killer (NK) cell function, delayed type hypersensitivity (DTH) as well as macrophage bactericidal activity, and phagocytosis were measured. There was no change in body weight gain, organ weights, or in humoral immunity during treatment even though cadmium had accumulated in significant quantities in the tissues. Compared with controls, exposure to cadmium had no statistically significant effect on mortality and mean survival time following primary or secondary challenge with any of the infectious agents. However, there was a dose-related, increased susceptibility to Herpes simplex type 2 virus. T- and B-lymphocyte proliferation was significantly reduced, and macrophage phagocytosis was significantly increased following cadmium exposure. NK cell activity was augmented, but not significantly. Macrophage bactericidal activity and DTH were not significantly altered.

Effect of dietary chronic cadmium exposure on cell-mediated immune response in rhesus monkey (Macaca mulatta).

Rhesus monkeys (Macaca mulatta) were daily exposed orally to cadmium (Cd) at 5 mg/kg body wt in diet for a period of 2 and 6 months. Significant amount of Cd accumulated in liver, kidney and spleen after its exposure to monkeys. Cell mediated immune response was assessed by the responsiveness of peripheral blood lymphocytes (PBL) to phytohemagglutinin (PHA), concanavalin A (Con A) and pokeweed mitogen (PWM). Even after 6 months of exposure, Cd increased DNA synthesis, although not significantly, in unstimulated and mitogen stimulated lymphocytes. Stimulation Index (SI), however, decreased largely due to increased unstimulated [( 3H]thymidine incorporation) observed after Cd exposure. It, therefore, indicates that Cd is not immunosuppressive in primates, phylogenetically closer to humans.

Impaired resistance to Listeria monocytogenes in mice chronically exposed to cadmium.

It is shown in this work that resistance to Listeria monocytogenes is greatly impaired in C57BL/6 mice chronically exposed to cadmium (Cd) chloride. Animals received 0.5 mg/kg Cd by an intraperitoneal route three times a week during a 4-week period and were then infected with L. monocytogenes. Susceptibility to this pathogenic bacteria was not due to a defect of the specific immune response, since mice developed normal levels of anti-Listeria T cell-mediated immunity and did not show any impairment of macrophage activation. In fact, bacterial growth in organs was rapid in Cd-exposed mice during the early phase of infection, suggesting an impairment of non-specific defence mechanisms. Experimental data indicate that the susceptibility to L. monocytogenes might be due to a defect of macrophage recruitment in sites of infection during the early phase of the host response.

Modified distribution of lymphocyte subpopulation in blood and spleen from mice exposed to cadmium.

The effect of cadmium (Cd) on the lymphocyte subpopulation in peripheral blood and spleen was studied in ICR mice given a daily subcutaneous injection of 0.5 and 1.0 mg Cd/kg body weight for 5 days or mice fed with the drinking water containing 3, 30 and 300 ppm Cd for 10 weeks. The reduction of blood B lymphocytes observed in Cd-injected mice was accompanied by the increase of the number of splenic B lymphocytes. On the other hand in Cd-fed mice the reduction of blood T lymphocytes was found and associated with the increase of the number of splenic T lymphocytes. These findings suggest that circulating lymphocytes may redistribute differentially in lymphoid organs responded to the Cd exposure.

An immunological study on patients with chronic cadmium disease.

Parameters of humoral and cellular immunity were investigated in patients with chronic cadmium (Cd) disease and compared to values in an age matched control group. In the patient group, there was a slight reduction in WBC although T and B lymphocyte ratios were normal. RBC counts were significantly reduced (P less than 0.05). No significant differences in serum immunoglobulin (Ig) concentrations were found. Blood Cd was significantly raised (P less than 0.001) and urine Cd was elevated. In lymphocyte transformation tests, responses to Staphylococcus aureus, PHA and PPD were not impaired and no evidence of Cd hypersensitivity was found. Responses in PHA and ADCC cytotoxicity tests were normal and nitro-blue tetrazolium (NBT) reduction was only slightly decreased in the patient group. beta 2-Microglobulin (beta 2M) was significantly raised in serum (P less than 0.001) and urine (P less than 0.001) of patients. Patient 3 day lymphocyte cultures produced significantly more beta 2M than cultures from the control group (P less than 0.01). beta 2M was increased in lymphocyte cultures, from patient and control groups, containing PHA (P less than 0.01), low Cd concentrations (P less than 0.01) or PPD. The results indicate that chronic Cd disease is not associated with significant alterations in immunological parameters in vitro. The high beta 2M levels associated with this disease may not result entirely from kidney damage but may in part be due to an increase in the release of beta 2M from cells, induced by Cd.

Acute effects of cadmium on delayed-type hypersensitivity in mice.

A single exposure of mice to cadmium resulted in suppression of the induction of primary delayed-type hypersensitivity (DTH) responses as well as memory T-cell and suppressor T-cell activities, augmenting and inhibiting DTH respectively. Furthermore, cadmium suppressed the expression of already established DTH, in immune mice, even though DTH-effector T cells in the spleen of immune mice were not affected by cadmium injection. Such suppressive effects were demonstrated when cadmium was administered within 2 days before immunization or elicitation for DTH. Cadmium caused also within 2 days in mice thymic involution and splenomegaly. These results indicate that cadmium inhibits not only the generation of certain populations of T lymphocytes for DTH but also some mechanisms in the host involved in the expression of DTH.