No contribution of GSTM1 and GSTT1 null genotypes to the risk of neutropenia due to benzene exposure in Southeastern Brazil

Exposure to benzene has been associated with haematological diseases such as neutropenia (NEB) and acute myeloid leukaemia (AML). We tested whether the null genotypes of the GSTM1 and GSTT1 genes, involved in benzene inactivation, altered the risk for NEB in southeastern Brazil. Genomic DNA from 55 NEB patients and 330 controls was analysed by multiplex-polymerase chain reaction. The frequency of the GSTM1, GSTT1 and combined null genotypes was similar in patients and controls (GSTM1, 27.3% vs. 38.8%, p = 0.16; GSTT1, 25.5% vs. 19.7%, p = 0.24; GSTM1/GSTT1, 12.7% vs. 6.7%, p = 0.26; respectively). The distribution of genotype classes in NEB patients was similar to normal controls, suggesting that GSTM1 and GSTT1 null genotypes make no specific contribution to the risk of NEB. As the GSTM1 and GSTT1 null genotypes were previously associated with increased risk for AML in Brazil and elsewhere, we hypothesise that different thresholds of chemical exposure relative to distinct GSTM1 and GSTT1 genotypes may determine whether AML or NEB manifests in benzene exposed individuals from southeastern Brazil. Although indicative, our results still require support by prospective and large scale epidemiological studies, with rigorous assessment of daily chemical exposures and control of the possible contribution of other polymorphic genes involved in benzene metabolism

HEMATOPOIETIC EFFECTS IN MICE EXPOSED TO DELTAMETHRIN AND HYDROCORTISONE

The effects of deltamethrin on bone marrow and spleen progenitor cell responsiveness to granulocyte and macrophage colony-stimulating factors were evaluated. Deltamethrin was tested in parallel with hydrocortisone to further investigate some similarity in the in vivo effects of both compounds observed in previous studies in our laboratory. In vivo effects were studied after the subcutaneous administration in mice of three 5 mg/kg injections of deltamethrin and a single 30 mg/kg injection of hydrocortisone to Balb/c mice. Soft agar colony formation, marrow and spleen cell counts body, spleen and thymus weights were determined. Data obtained in vivo indicate that deltamethrin and hydrocortisone reversibly increase the formation of granulocyte and macrophage colonies in the marrow, but not in the spleen. No changes were observed in total and differential cell counts in the marrow and spleen and spleen weights. Treatment with both compounds, however, resulted in a dramatic reduction in thymus weights. Assays for endotoxin demonstrate that these effects were not due to the liberation of endotoxin. In vitro addition of 10(-5), 10(-6) and 10(-7) M deltamethrin and hydrocortisone to marrow cultures from untreated mice resulted in different effects from those observed in vivo. Hydrocortisone increased granulocyte and reduced macrophage colonies, whereas deltamethrin was without in vitro effects. It is suggested that deltamethrin effects are due to an indirect action on the hypothalamic - pituitary axis leading to increased corticosteroid levels. The importance of biotransformation mechanisms is also emphasized.15330130

The effect of a Titanocene Dichloride derivative, TiIV(C5H5)(2) NCS2, on the haematopoietic response of Ehrlich tumour-bearing mice

The effects of the [Ti IV (C5H5)(2) NCS2] metallocene (BCDT), a Titanocene Dichloride derivative, on the growth and differentiation of granulocyte-macrophage progenitor cells [colony-forming unit-granulocyte-macrophage (CFU-GM)] and bone marrow cellularity in normal and Ehrlich ascites tumour-bearing mice were studied. As expected for the Ehrlich ascites tumour-model, concomitant myelosuppression, increased number of spleen CFU-GM and changes in bone marrow cellularity were observed. The treatment of Ehrlich ascites tumour-bearing mice with BCDT (10-30 mg/kg/day) produced a dose-dependent increase in myelopoiesis, a reduction in splenic colonies and a restoration in the total and differential marrow cell counts. We also observed an increase in CFU-GM number when bone marrow cells obtained from normal mice were incubated in vitro with serum from normal mice treated with BCDT. In addition, BCDT prolonged, in a dose-dependent manner, the survival of mice inoculated with Ehrlich ascites tumour. Although it has been previously reported that substitutions in the two halides of the titanocene do not interfere with antitumoural effect, our results with BCDT demonstrated a reduction in antitumour efficacy when compared to previous results with the original titanocene produced in our laboratory. (C) 2002 Published by Elsevier Science B.V.43941699354

Measurement of the respiratory burst and chemotaxis in polymorphonuclear leukocytes from anti-ChE insecticides-exposed workers

Neutrophil function in 32 workers occupationally exposed to anti-ChE insecticides, as measured by chemotaxis through the leading front method and nitroblue tetrazolium dye reduction, was investigated and compared to those of age- and sex-matched controls. The cholinesterase (ChE) activity was normal in all the workers studied, although decrease of chemotaxis and of nitroblue tetrazolium reduction was observed in the exposed population. These results suggest that the identified functional changes in polymorphonuclear neutrophils might be an early indicator of anti-ChE insecticides toxicity, even in those individuals with no impairment in the ChE activity.21362163

The effect of lead on the bone marrow stem cells of mice infected with Listeria monocytogenes

We investigated the effects of lead exposure on the growth and differentiation of bone marrow hematopoietic cells, the so called colony-forming cells, in normal and Listeria monocytogenes infected mice (resistant and susceptible strains). We also studied the effects of lead on the serum colony-stimulating activity (CSA), as well as on the survival of the mice after the infection. The doses of lead acetate were 13, 130 and 1300 ppm For 10, 30 and 70 d. At the end of this dosing, mice were infected with Listeria monocytogenes and killed 24, 48 or 72 h after inoculation of the bacteria. A dose-response suppressive effect of lead was observed in both strains in the 3 periods studied. However, in the resistant strain of mice the suppressive effects were overcome 48 h after the administration of the bacteria, whereas in the susceptible mice the suppressive effect of the infection was evident in all 3 time periods. The administration of lead caused no changes in serum hematopoietic growth factors, thus suggesting this metal acts by direct action on the myelopoietic cells. A significant decrease in host resistance, as measured by the mortality rate, was found when both strains of mice were challenged with sub-lethal doses of Listeria monocytogenes. Lethality was determined for a period of 10 d after dosing with 1300 ppm lead for 30 d.38318619

POLYMORPHONUCLEAR PHAGOCYTOSIS AND KILLING IN WORKERS EXPOSED TO INORGANIC MERCURY

The ability of neutrophils to phagocytose- and kill Candida species as well as the splenic phagocytic function were investigated in workers from a mercury-producing plant. In the neutrophil phagocytosis study, two species of Candida were used since in individuals with myeloperoxidase deficiency neutrophils are unable to kill Candida albicans, while Candida pseudotropicalis can be effectively lysed. Phagocytosis of both antigens and splenic phagocytic function were normal in all the workers studied. However, following ingestion of the organisms there was considerable reduction in the ability of neutrophils from exposed workers to kill both species of Candida, and this was not explained by a mild impairment of phagocytosis. After improvement in the hygiene conditions in the factory, a new evaluation was performed, 6 months later, in the same workers and urinary mercury concentrations were determined monthly in each worker. Despite a significant reduction in urinary mercury concentrations, a greater impairment in the ability of neutrophils to kill C. albicans was observed. The killing of C. pseudotropicalis presented no further impairment when compared to the previous evaluation. These results suggest that impairment of the lytic activity of neutrophils from workers with urinary mercury concentrations within the safe level for exposed population is due, at least in part, to some interference with myeloperoxidase activity. In addition, the mercury-NADPH complex, once formed, could limit the utilization of reduced pyridine nucleotides by NADPH-dependent enzymes such as NADPH oxidase, thereby inhibiting the PMN respiratory burst.16121011101

Immunoglobulin E and autoantibodies in mercury-exposed workers.

In this work we have studied the serum immunoglobulin E (IgE) levels and the concentration of anti-DNA and anti-nucleus antibodies in mercury-exposed workers. The study group consisted of 36 workers from a mercury producing plant, with a mean age of 27 years and a mean exposure period to mercury of 19 months. At the time of testing, and for the three previous months, the exposed population had urinary mercury levels below the currently accept limit of 50 ug/g creatinine. Significantly increased IgE levels was found in the mercury-exposed individuals. Moreover, a moderate negative correlation (r = -0.43 P < 0.05) between the length of exposure to mercury and IgE levels was observed. Anti-DNA and anti-nucleus antibodies were not detected in these workers. These results suggest that the humoral immune response is an indicator of cellular changes in workers chronically exposed to mercury, even in those with urinary mercury concentrations within levels considered safe in the occupational area.19338339

beta-1,3-Glucan given orally modulates immunomyelopoietic activity and enhances the resistance of tumour-bearing mice

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)beta-Glucans have been reported to be potent adjuvants in stimulating innate and adaptive immune responses. The aim of the present study was to determine the immunohematopoietic effects of Imunoglucan (HEBRON) following its oral administration to normal and Ehrlich ascites tumour (EAT)-bearing mice. Mice were treated with 250, 500 and 1000mg/kg per day, p.o., Imunoglucan (beta-1,3-glucan extracted from Saccharomyces cerevisae) for 18 consecutive days. Treatment started 10days prior to and ended 8days after tumour inoculation. At 500 and 1000mg/kg per day, Imunoglucan enhanced the life span of EAT-bearing mice and prevented myelosuppression and splenomegaly caused by the tumour by increasing the number of granulocytemacrophage progenitors in the bone marrow and increasing colony-stimulating activity in the serum. At 500mg/kg, Imunoglucan restored the reduced ability of stromal cells to display myeloid progenitors in long-term bone marrow cultures of EAT-bearing mice and upregulated the production of interleukin (IL)-6 and IL-1 alpha by these cells, consistent with a higher number of non-adherent cells. Moreover, 500mg/kg Imunoglucan restored natural killer cell activity in tumour-bearing mice, consistent with the increased production of interferon (IFN)-gamma observed. The results of the present study suggest that Imunoglucan given orally indirectly modulates immune activity and probably disengages tumour-induced suppression by producing a higher reserve of myeloid progenitors in the bone marrow in consequence of biologically active cytokine release (colony-stimulating factors, IL-1 alpha, IL-6 and IFN-gamma).393209217Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq