RESUMO
The myelotoxicity of five endocrine active chemicals was evaluated in F1 generation of Sprague-Dawley rats following developmental and adult exposures at three concentration levels. Rats were exposed to genistein (GEN: 25, 250 and 1250 ppm), nonylphenol (NPH: 25, 500 and 2000 ppm), methoxychlor (MXC: 10, 100 and 1000 ppm), vinclozolin (VCZ: 10, 150 and 750 ppm) and ethinyl estradiol (EE2: 5, 25 and 200 ppb) gestationally and lactationally through dams from day 7 of gestation and through feed after weaning on postnatal day (PND) 22 to PND 64. The parameters examined included the number of recovered bone marrow cells, DNA synthesis, and colony forming units (CFU) in the presence of granulocyte macrophage-colony stimulating factor (GM-CSF), macrophage colony-stimulating factor (M-CSF) and erythropoietin. Except for the EE2, the concentrations of other individual chemicals in the diet were in an approximate range that allowed for a comparison to be made in terms of myelotoxic potency. Decreases in the DNA synthesis, CFU-GM and CFU-M seemed to be the common findings among the alterations induced by these compounds. Using the numbers of alterations induced by each chemical in the parameters examined as criteria for comparison, the order of myelotoxic potency in F(1) males was: GEN>MXC>NPH>VCZ; the order in females: GEN>NPH>VCZ. Additionally, some of the functional changes induced by these compounds were gender-specific or dimorphic. Overall, the results demonstrated that developmental and adult exposures of F1 rats to these endocrine active chemicals at the concentrations tested had varied degrees of myelotoxicity with GEN being the most potent. Furthermore, the sex-specific effects of these chemicals in F1 male and female rats suggest that there may be interactions between these compounds and sex hormone in modulating these responses.
Assuntos
Células da Medula Óssea/efeitos dos fármacos , Etinilestradiol/toxicidade , Genisteína/toxicidade , Metoxicloro/toxicidade , Oxazóis/toxicidade , Fenóis/toxicidade , Efeitos Tardios da Exposição Pré-Natal , Animais , Células da Medula Óssea/citologia , Células da Medula Óssea/metabolismo , Contagem de Células , DNA/metabolismo , Eritropoetina/metabolismo , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Fator Estimulador de Colônias de Macrófagos/metabolismo , Masculino , Gravidez , Ratos , Ratos Sprague-DawleyRESUMO
Atrazine (ATZ) is used throughout North America to control annual broadleaf weeds and grasses in various crops including; corn, sorghum, and sugar cane. Unfortunately, contamination of surface and ground water has occurred as a result of ATZ's chemical and physical properties, and its widespread use throughout the U.S. Midwest. A study of ATZ's immunomodulatory properties was conducted using female B6C3F1 mice and a panel of immune assays and host resistance models designed to evaluate cell-mediated and antibody-mediated immunity. Mice were administered ATZ by gavage (0, 24, 250, and 500 mg/kg/day) for 14 days then evaluated for immune responsiveness. ATZ treatment significantly increased the number of splenic CD8+ T cells, cytotoxic T cell and mixed leukocyte responses, and dose-dependently reduced host resistance to B16F10 melanoma. Thymus and spleen weights, total spleen cell numbers and fixed macrophage function was also reduced in mice that were exposed to ATZ. These results demonstrate that oral ATZ exposure is sufficient to alter cell-mediated immune function and disease resistance in female B6C3F1 mice.
Assuntos
Atrazina/administração & dosagem , Atrazina/toxicidade , Melanoma Experimental/imunologia , Administração Oral , Animais , Cruzamentos Genéticos , Relação Dose-Resposta a Droga , Feminino , Imunidade Celular/efeitos dos fármacos , Imunidade Inata/efeitos dos fármacos , Leucócitos/efeitos dos fármacos , Leucócitos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Baço/efeitos dos fármacos , Baço/imunologiaRESUMO
Methoxychlor, a chlorinated hydrocarbon pesticide, is a persistent environmental contaminant that has been identified in human reproductive tissues. Methoxychlor has been shown to be estrogenic in both in vivo and in vitro studies. As an endocrine disrupter, it may have the potential to adversely affect endocrine, reproductive, and immune systems in animals. The present study evaluated methoxychlor's immunotoxic potential in F0 (dams) and F1 generations of Sprague Dawley rats exposed to an isoflavone-free diet containing methoxychlor at concentrations of 10, 100, and 1000 ppm. In dams, exposure to methoxychlor from gestation day 7 to postpartum day 51 (65 days total exposure) produced a significant increase in the NK activity (1000 ppm) and the percentages of T cells (1000 ppm), helper T cells (1000 ppm) and macrophages (100 and 1000 ppm). In contrast, a decrease in the numbers of splenocytes and B cells was observed at the 100 and 1000 ppm concentrations. In F1 males, exposure to methoxychlor gestationally, lactationally and through feed from postnatal day 22-64 (78 days total exposure) produced an increase in the spleen IgM antibody-forming cell response to sheep red blood cells (100 and 1000 ppm) and the activity of NK cells (1000 ppm). However, there was a decrease in the terminal body weight (1000 ppm), spleen weight (1000 ppm), thymus weight (100 and 1000 ppm), and the numbers of splenocytes (1000 ppm), B cells (100 and 1000 ppm), cytotoxic T cells (1000 ppm) and NK cells (100 and 1000 ppm). In F1 females, exposure to methoxychlor produced a decrease in the terminal body weight (1000 ppm) and the percentages of cytotoxic T cells (10, 100 and 1000 ppm). These results demonstrate that developmental and adult dietary exposure to methoxychlor modulates immune responses in Sprague Dawley rats. Immunological changes were more pronounced in the F1 generation male rats that were exposed during gestation and postpartum, when compared to the F0 and F1 generation females. Increases in antibody-forming cell response and NK cell activity, and altered spleen cell subpopulation numbers were observed in the F1 generation male rats, without similar changes to the F1 generation females.
Assuntos
Células Produtoras de Anticorpos/efeitos dos fármacos , Inseticidas/toxicidade , Linfócitos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Metoxicloro/toxicidade , Animais , Animais Recém-Nascidos , Células Produtoras de Anticorpos/imunologia , Dieta , Feminino , Imunoglobulina M/imunologia , Fatores Imunológicos/toxicidade , Contagem de Linfócitos , Linfócitos/imunologia , Macrófagos/imunologia , Masculino , Fenótipo , Gravidez , Ratos , Ratos Sprague-Dawley , Fatores Sexuais , Baço/citologia , Baço/imunologiaRESUMO
Nonylphenol (NP) has been identified at low levels in surface waters throughout North America. This industrial chemical is primarily used for the production of certain non-ionic surfactants, and has been reported to have weak estrogen-like activity. As estrogen has immunoregulatory properties and is crucial for normal fetal development, it was hypothesized that adult and developmental exposures to NP had the potential to adversely affect the immune system. Furthermore, developmental exposure to NP might also produce differential immunomodulation in F(1) male and female rats. Thus, a two-generation feeding study was conducted to evaluate the potential for NP to modulate certain immune parameters. Pregnant female Sprague-Dawley rats were exposed to NP (0, 25, 500, and 2000 ppm) in their feed for 65 days, beginning 7 days into gestation. The F(1) generation male and female offspring were exposed in utero at the respective treatment levels, commencing the 7th day of gestation, and continuing through to 64 days of age. Changes in splenic antibody-forming cell response, natural killer cell activity, and leukocyte numbers were used to evaluate NP immunotoxicity. The results from the present study indicate that dietary exposure to NP can increase splenic natural killer (NK) cell activity and splenocyte subpopulation numbers in the F(1) generation rats, without similar changes to the F(0) generation. The immunological changes that were observed in the F(1) generation also appeared to be gender-specific.
Assuntos
Células Matadoras Naturais/efeitos dos fármacos , Leucócitos/efeitos dos fármacos , Fenóis/farmacologia , Baço/citologia , Animais , Animais Recém-Nascidos , Células Produtoras de Anticorpos/efeitos dos fármacos , Células Produtoras de Anticorpos/imunologia , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Peso Corporal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Contagem de Leucócitos , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Masculino , Tamanho do Órgão/efeitos dos fármacos , Gravidez , Ratos , Ratos Sprague-Dawley , Ovinos/imunologia , Baço/efeitos dos fármacos , Baço/imunologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologiaRESUMO
Previously, we have reported that thalidomide (Thd) treatment can modulate the immune responses in female B6C3F1 mice. The present study was designed to evaluate whether or not these immunomodulatory responses were of sufficient magnitude to alter host resistances in a number of pathogen and tumor models. B6C3F1 mice were treated intraperitoneally with Thd (30-150 mg/kg) for 14 or 28 days, then inoculated with either Plasmodium yeolii, PYB6 fibrosarcoma tumor cells, B16F10 melanoma tumor cells, Listeria monocytogenes, or Streptococcus pneumoniae. Significant dose-dependent protection against B16F10 and L. monocytogenes was observed in mice that were treated with Thd. Furthermore, time course study using bacterial colony-forming units per spleen and liver as the endpoints indicated that the protective effect of Thd on host resistance to L. monocytogenes was time-dependent. In contrast, Thd treatment did not affect host resistance to P. yeolii, S. pneumoniae and PYB6 tumor. Additionally, the effect of Thd on the phagocytic function of the mononuclear phagocyte system (MPS) was evaluated following intravenous injection of 51Cr-labeled sRBCs. The overall phagocytic activity of MPS was not significantly altered by Thd treatment. In conclusion, these results demonstrate that Thd immunomodulation altered host resistance to B16F10 and L. monocytogenes; and selective modulation of Thd on the immune system may be responsible for the pathogen or tumor-specific effect of this compound.
Assuntos
Adjuvantes Imunológicos/uso terapêutico , Infecções Bacterianas/prevenção & controle , Imunidade Inata/efeitos dos fármacos , Neoplasias Experimentais/prevenção & controle , Talidomida/uso terapêutico , Adjuvantes Imunológicos/administração & dosagem , Animais , Infecções Bacterianas/imunologia , Infecções Bacterianas/microbiologia , Relação Dose-Resposta a Droga , Feminino , Injeções Intraperitoneais , Fígado/efeitos dos fármacos , Fígado/imunologia , Fígado/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos , Neoplasias Experimentais/imunologia , Fagocitose/efeitos dos fármacos , Fagocitose/imunologia , Talidomida/administração & dosagemRESUMO
The potential effects of the phytoestrogen genistein (GEN) on the immune system were evaluated in both F(0) (dams) and F(1) generations of Sprague-Dawley rats exposed to a soy-free diet containing low (L: 25 ppm), middle (M: 250 ppm), and high (H: 1250 ppm) levels of GEN. In dams, exposure to GEN from Gestation Day 7 to Postpartum Day 51 (totally 65 days) produced a significant increase in NK cell activity (M and H), while a decrease in the percentage of helper T cells (H). In F(1) males, exposure to GEN gestationally, lactationally, and through feed from Postnatal Days 22 to 64 (total 78 days) produced an increase in the relative weights (% body) of spleen (L and H) and thymus (L). Furthermore, exposure to GEN increased the number of splenic B cells (H), T cells (L, M, and H), and T-cell subsets (L, M, and H). Although GEN decreased the percentages of splenic NK cells (L, M, and H), no effect on the activity of NK cells was observed. In F(1) females, exposure to GEN produced a decrease in terminal body weight (H), with an increase in the relative weight of spleen (L, M, and H). Exposure to GEN also increased the number of splenic B cells (L), macrophages (L and M), T cells (H), helper T cells (L and H), and cytotoxic T cells (M and H). Additionally, exposure to GEN increased the percentages of T cells (M and H), helper T cells (H), and cytotoxic T cells (M and H). Moreover, the spleen IgM antibody-forming cell response to sheep red blood cells was enhanced (H), although the percentages of B cells were decreased (M and H). No effect on the activity of NK cells was observed; however, the percentages of splenic NK cells were decreased by GEN (L and H). In conclusion, these results demonstrate that exposure to GEN can modulate the immune responses in Sprague-Dawley rats. Furthermore, the sexual dimorphic effects of GEN in F(1) male and female rats suggest that there may be interactions between GEN and the responses modulated by sex hormones.
Assuntos
Anticarcinógenos/farmacologia , Linfócitos B/efeitos dos fármacos , Genisteína/farmacologia , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Baço/imunologia , Animais , Linfócitos B/ultraestrutura , Peso Corporal/efeitos dos fármacos , Feminino , Imunoglobulina M/biossíntese , Imunoglobulina M/imunologia , Células Matadoras Naturais/ultraestrutura , Contagem de Leucócitos , Macrófagos/efeitos dos fármacos , Masculino , Tamanho do Órgão/efeitos dos fármacos , Fenótipo , Gravidez , Ratos , Ratos Sprague-Dawley , Linfócitos T/efeitos dos fármacosRESUMO
The isoflavone genistein (GE) and methoxychlor (MXC) have been shown to be estrogenic in both in vitro and in vivo experimental systems. The objective of the present study was to evaluate the effects of GE and MXC on the immune system in adult and developing rats and the potential interaction between these compounds in their immunomodulatory actions. Timely pregnant Sprague-Dawley rats were exposed to GE (300 or 800 ppm), MXC (800 ppm), or their combinations in feed starting on day 1 of gestation. The offspring were exposed to these chemicals gestationally and lactationally. Immunological evaluation was performed on postnatal day 22. In F0 females, exposure to GE had no effect on the percentages of thymocyte subsets, but caused a significant decrease in the absolute thymus weight at the 800-ppm dose level. In the spleen, GE did not affect the activity of natural killer cells but induced changes in the percentages of splenic T lymphocyte subsets. Exposure to MXC produced no effect on the immune parameters examined except for a decrease in the percentage of CD4+CD8- thymocytes. Additionally, minimal interaction between GE and MXC was observed. In F(1) males, both GE and MXC decreased the percentage of CD4+CD8- thymocytes, but only GE increased spleen natural killer cell activity. MXC in combination with 300 ppm-GE, but not separately, produced significant decreases in the absolute weights of thymus and spleen. In F1 females, GE decreased the percentage of CD4+CD8- thymocytes, increased the percentage of CD4+CD8+ thymocytes, and decreased the activity of spleen natural killer cells. In contrast, MXC increased the percentages of spleen natural killer cells and CD8+ T cells. Overall, the results demonstrate that both GE and MXC can modulate the immune system with greater effects observed in developing rats. Moreover, male and female rats have differential responses to these compounds. A lack of interaction between these two estrogenic chemicals in modulating these immune parameters indicates that their effects on the immune system might involve other mechanisms in addition to the estrogen receptors.
Assuntos
Estrogênios não Esteroides/toxicidade , Genisteína/toxicidade , Inseticidas/toxicidade , Células Matadoras Naturais/imunologia , Metoxicloro/toxicidade , Linfócitos T/imunologia , Animais , Peso Corporal/efeitos dos fármacos , Feminino , Citometria de Fluxo , Marcadores Genéticos , Células Matadoras Naturais/efeitos dos fármacos , Subpopulações de Linfócitos/efeitos dos fármacos , Masculino , Troca Materno-Fetal , Tamanho do Órgão/efeitos dos fármacos , Fenótipo , Gravidez , Ratos , Ratos Sprague-Dawley , Baço/citologia , Linfócitos T/efeitos dos fármacosRESUMO
The isoflavone genistein (4,7,4'-trihydroxyisoflavone) is a phytoestrogen found in high levels in soy products that has been associated with decreased incidences of breast and prostate cancers. The potential effects of genistein on the immune system were evaluated in adult female B6C3F1 mice. Groups of mice were exposed to vehicle or genistein by gavage for 28 d. The doses of genistein used were 2, 6 and 20 mg/kg body. Consistent with the chemopreventive effect of genistein, exposure to this compound significantly increased host resistance to B16F10 tumor as reflected by a decrease in the number of lung tumor nodules after tumor cell injection at the middle and high dose levels. Inhibition of B16F10 tumor formation was not due to a direct effect of serum genistein and/or its metabolites on the proliferation of B16F10 tumor cells. When innate and acquired immune responses were evaluated, a dose-related increase of cytotoxic T-cell activity was observed in genistein-treated mice with significant changes observed at the middle and high dose levels. Furthermore, in vitro interleukin (IL)-2-stimulated natural killer (NK) cell activity was significantly enhanced in the high genistein dose group, although the basal NK cell activity was not affected. Although no affect on the mixed lymphocyte responses and anti-CD3 antibody-mediated splenocyte proliferation was observed, exposure to genistein significantly increased basal splenocyte proliferation. Exposure to genistein did not alter the activity of the mononuclear phagocyte system and the cytotoxic/cytostatic function of thioglycollate-recruited peritoneal cells on B16F10 tumor cells. Finally, exposure to genistein did not produce biologically meaningful changes in spleen immunoglobulin (Ig)M and IgG antibody-forming cell responses. In conclusion, genistein enhanced host resistance as evaluated in the B16F10 tumor model, which may be related to the increases in the activities of cytotoxic T cells and NK cells.
Assuntos
Anticarcinógenos/farmacologia , Genisteína/farmacologia , Imunidade Inata/efeitos dos fármacos , Imunidade/efeitos dos fármacos , Melanoma Experimental/prevenção & controle , Animais , Linfócitos T CD8-Positivos/imunologia , Divisão Celular , Feminino , Interferon gama/farmacologia , Lipopolissacarídeos/farmacologia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/prevenção & controle , Teste de Cultura Mista de Linfócitos , Macrófagos Peritoneais/imunologia , Melanoma Experimental/imunologia , Melanoma Experimental/patologia , Camundongos , Transplante de Neoplasias , Linfócitos T Citotóxicos/imunologia , Células Tumorais CultivadasRESUMO
Bromate is one of the water disinfection by-products (DBPs) produced during the process of ozonation. The purpose of this study was to evaluate the immunotoxic potential of sodium bromate (SB) in female B6C3F1 mice. SB was administered in the drinking water for 28 days at doses of 80-800 mg/l. There was no difference in drinking water consumption between the animals exposed to SB and the tap water controls. Exposure to SB did not produce any signs of overt toxicity. Furthermore, no significant differences were observed in body weight, body weight gain, or the weights of thymus, liver, kidneys or lungs. No gross pathological lesions were observed in SB-treated animals. However, animals exposed to SB had a significant increase in absolute (28%) and relative (26%) spleen weights. The erythrocyte count, hemoglobin, hematocrit, mean corpuscular volume (MCV), platelet count, total leukocyte count, and counts of differential leukocytes were unaffected by SB. A dose-related increase in reticulocytes was observed following exposure to SB with the greatest increase (78%) observed at the highest dose level. Overall, there were no changes in the absolute number of total T cells, CD4+CD8- T cells, CD4-CD8+ T cells, natural killer (NK) cells and macrophages. Exposure to SB did not affect the percentage of B cells, although a slight increase in absolute number of B cells at the dose of 600 mg/l was observed. There was no alteration in IgM antibody-forming cell (AFC) response, mixed leukocyte reaction (MLR) and NK cell activity after exposure to SB. When the activity of peritoneal macrophages, unstimulated or stimulated with IFN-gamma and LPS, was evaluated using the cytotoxic/cytostatic assay of B16F10 tumor cells, the suppressive effect of macrophages on the proliferation of B16F10 tumor cells was decreased after exposure to SB. In conclusion, SB, when administered in the drinking water at doses from 80 mg/l to 800 mg/l, produced minimal toxicological and immunotoxic effects in female B6C3F1 mice.
Assuntos
Bromatos/toxicidade , Desinfecção , Compostos de Sódio/toxicidade , Água/administração & dosagem , Animais , Contagem de Células Sanguíneas , Peso Corporal/efeitos dos fármacos , Feminino , Hematócrito , Rim/efeitos dos fármacos , Contagem de Leucócitos , Fígado/efeitos dos fármacos , Teste de Cultura Mista de Linfócitos , Camundongos , Nível de Efeito Adverso não Observado , Tamanho do Órgão/efeitos dos fármacos , Ozônio , Baço/citologia , Baço/efeitos dos fármacos , Timo/efeitos dos fármacosRESUMO
BACKGROUND: Although the Murine Local Lymph Node Assay (LLNA) is efficient in identifying chemicals with sensitizing potential, there is increasing need for alternative end points. Cinnamaldehyde (CIN) was chosen for evaluation based on its moderate potency and extensive use in fragrance materials. OBJECTIVES: The purpose of the present studies is to incorporate some alternative end points, such as phenotypic analysis and cytokine production, into a modified LLNA/irritancy assay (IA) to evaluate the sensitization of female B6C3F1 mice to CIN. METHODS: Several nontraditional end points, including the analysis of lymphocyte subpopulations, B7 costimulatory molecule and cytokine messenger RNA (mRNA) expression, and intracellular interferon-gamma (IFN-gamma) levels, were incorporated into a modified murine local lymph node (LLNA)/irritancy assay (IA) to evaluate the sensitization of female B6C3F1 mice to cinnamaldehyde (CIN). RESULTS: The alternate end points used in these studies support the classification of CIN as a moderately potent sensitizer. Dermal treatment with CIN resulted in an increase in the percentage of B cells in the auricular lymph nodes (ALNs) and expression of the costimulatory molecule, B7-2, on B cells. Lymph node cells also showed increased transforming growth factor-beta1, migration-inhibition factor, and mild increases in IFN-gamma and interleukin-2 cytokine mRNA expression. Although the increase in IFN-gamma mRNA expression did not translate into increased intracellular IFN-gamma levels, the absolute number of T cells producing IFN-gamma in the ALNs increased. Conversely, the MEST did not classify CIN as a contact allergen. CONCLUSION: The nontraditional end points used in the LLNA/IA were not as sensitive as the traditional radioisotope method used to assess cell proliferation. However, they may help identify compounds inappropriately classified as sensitizers or nonsensitizers by the LLNA and MEST.
Assuntos
Acroleína/análogos & derivados , Acroleína/farmacologia , Alérgenos/farmacologia , Dermatite Alérgica de Contato/diagnóstico , Subpopulações de Linfócitos/efeitos dos fármacos , Titulação por Diluição de Reatividade a Testes Cutâneos/normas , Animais , Antígenos CD/efeitos dos fármacos , Antígeno B7-2 , Citocinas/efeitos dos fármacos , Orelha Externa , Feminino , Interferon gama/efeitos dos fármacos , Linfonodos/efeitos dos fármacos , Glicoproteínas de Membrana/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos , Valor Preditivo dos Testes , RNA Mensageiro/efeitos dos fármacosRESUMO
There is growing evidence that heavy metals, in general, and mercurial compounds, in particular, are toxic to the human immune system. In this regard, we have previously shown that both inorganic and organic mercurials are potent human T-cell apoptogens; moreover, mitochondria appear to be a target organelle for the induction of cell death. To ascertain whether both mercury species utilize the same molecular pathway to trigger the apoptotic cascade, cells were treated with MeHgCl or HgCl2 and mitochondrial activity was examined. We show that both mercury species affect mitochondrial activity by inducing the development of a membrane permeability transition. This state is characterized by a decline in both the transmembrane potential and the intracellular pH, as well as the generation of reactive oxygen species. We also determined that mercury exposure results in a decline in the T-cell GSH content. Since mitochondrial dysfunction and the development of a permeability transition may result in the release of cytochrome c, a factor that promotes apoptosis, we assessed the abilities of both species of mercury to induce the translocation of cytochrome c from mitochondria to the cytosol. We noted that MeHgCl caused a significant increase in cytosolic cytochrome c. Surprisingly, however, HgCl2 did not alter the level of cytosolic cytochrome c. We next determined whether the mercurials could alter the level of the anti-apoptotic protein Bcl-2. Our results demonstrate that HgCl2 induces a significant elevation in the Bcl-2 content of T-cells; in contrast, T-cells treated with MeHgCl did not exhibit altered levels of this anti-apoptotic protein. Regardless of whether cytochrome c is released from the mitochondria, both mercurial species were capable of activating the caspase cascade, as evident by cleavage of poly (ADP-ribose) polymerase. Thus, our study shows that, whereas each of the mercury species shares common features in the apoptotic process, profound differences exist in a number of key steps in the pathway. The significance of these differences is discussed.
Assuntos
Apoptose/efeitos dos fármacos , Imunotoxinas/toxicidade , Cloreto de Mercúrio/toxicidade , Compostos de Metilmercúrio/toxicidade , Linfócitos T/efeitos dos fármacos , Adulto , Linhagem Celular/efeitos dos fármacos , Grupo dos Citocromos c/efeitos dos fármacos , Fragmentação do DNA , Feminino , Citometria de Fluxo , Glutationa/análise , Humanos , Marcação In Situ das Extremidades Cortadas , Masculino , Potenciais da Membrana/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/fisiologia , Proteínas Proto-Oncogênicas c-bcl-2/efeitos dos fármacosRESUMO
The immunotoxic potential of glycidol was evaluated in female B6C3F1 mice using a battery of functional assays and three host resistance models. Glycidol was administered to the animals by oral gavage as a solution in sterile distilled water daily for 14 days at doses of 25, 125 and 250 mg/kg. In tier I, we observed that glycidol exposure produced a dose-related decrease in splenocyte IgM antibody-forming cell response to sheep red blood cells (sRBC); the spleen natural killer (NK) cell activity was also decreased. A decrease in B cell proliferative responses to anti-IgM F(ab')2 and/or interleukin-4 (IL-4) was observed while the splenocyte proliferative responses to T cell mitogen ConA and B cell mitogen LPS were not affected. The splenocyte proliferative response to allogeneic cells as evaluated in the mixed leukocyte reaction (MLR) to DBA/2 spleen cells was not affected. In tier II, we found that exposure to glycidol decreased the number and percentage of B cells and the absolute number of CD4+ T cells in the spleen while the number of total T cells, CD8+ T cells and CD4+CD8+ T cells was not affected. The cytotoxic T lymphocyte (CTL) response to mitomycin C-treated P815 mastocytoma was not affected; the cytotoxic activity of peritoneal macrophages was not suppressed. Moreover, the host resistance to Listeria monocytogenes was not affected although a slight increase in host resistance to Streptococcus pneumoniae was observed. However, exposure to glycidol decreased host resistance to the B16F10 melanoma tumor model with the maximal tumor formation in lung observed in the high dose group. Overall, these dada support the finding that glycidol is an immunosuppressive agent in female B6C3F1 mice.
Assuntos
Células Produtoras de Anticorpos/efeitos dos fármacos , Carcinógenos/toxicidade , Compostos de Epóxi/toxicidade , Imunoglobulina M/imunologia , Imunossupressores/toxicidade , Células Matadoras Naturais/efeitos dos fármacos , Propanóis/toxicidade , Baço/efeitos dos fármacos , Animais , Formação de Anticorpos/efeitos dos fármacos , Linfócitos B/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Carcinógenos/administração & dosagem , Relação Dose-Resposta a Droga , Compostos de Epóxi/administração & dosagem , Feminino , Sistema Imunitário/efeitos dos fármacos , Imunidade/efeitos dos fármacos , Imunidade Celular , Imunossupressores/administração & dosagem , Intubação Gastrointestinal , Ativação Linfocitária/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos , Tamanho do Órgão/efeitos dos fármacos , Propanóis/administração & dosagem , Baço/patologia , Testes de ToxicidadeRESUMO
OBJECTIVE: To investigate the clinical result and influence factors of prognosis after repair of ruptured Achilles tendon with operative treatment. METHODS: From 1961 to 1994, 62 cases with ruptured Achilles tendon were treated operatively. Among them, "8"-shaped suture was used in 8 cases, aponeurosis flap repair in 30 cases, transfer repair of tendon of peroneus longus muscle in 2 cases, reverse "V-Y" shaped tendon plastic operation in 10 cases, and mattress suture of opposite ends in 12 cases. RESULTS: Followed up 3 to 33 years, there was excellent in 40 cases, better in 13 cases, moderate in 6 cases, poor in 3 cases, 85.5% in excellent rate. Postoperative infection and re-rupture were occurred in 6 cases respectively. CONCLUSION: Different operative procedures are adopted to achieve better long-term clinical result according to the injury types.
Assuntos
Tendão do Calcâneo/lesões , Tendão do Calcâneo/cirurgia , Retalhos Cirúrgicos , Adolescente , Adulto , Idoso , Criança , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Procedimentos de Cirurgia Plástica , RupturaRESUMO
The objective of our study was to define the mechanism by which MeHgCl induces human T-cell apoptosis. We asked the question: does mercury disrupt the Deltapsim and induce a mitochondrial permeability transition state? Using two fluorescent reagents, JC-1 and DiOC6(3), we demonstrated that MeHgCl exposure resulted in a decrease in the Deltapsim. Since a decline in Deltapsim can disturb the pHi, we employed SNARF-1 to assess pHi; results indicate that mercury treatment reduced the pHi from 7.0 to 6.5. Consistent with these observations, we noted that uncoupled electron transfer reactions generated ROS, while cardiolipin, a mitochondrial phospholipid, was oxidized. In concert with the biochemical changes, there was a decrease in overall dimension of the mitochondria of mercury-treated cells and a loss in cristae architecture. The toxicant also depleted the thiol reserves of the cell and promoted translocation of cytochrome c from the mitochondria to the cytosol. Furthermore, when T cells were thiol-depleted, there was increased susceptibility to MeHgCl-induced apoptosis. Finally, we established a temporal relationship between the decline in Deltapsim, generation of ROS, and depletion of thiol reserves. The earliest detectable event was at the level of the mitochondrion; in the presence of MeHgCl there was a profound reduction in mitochondrial Deltapsim and a decline in GSH levels within 1 h. Subsequently, a further decrease in thiol reserves was linked to the generation of ROS. We propose that the target organelle for MeHgCl is the mitochondrion and that induction of oxidative stress leads to activation of death-signaling pathways.
Assuntos
Apoptose/efeitos dos fármacos , Compostos de Metilmercúrio/toxicidade , Mitocôndrias/efeitos dos fármacos , Linfócitos T/efeitos dos fármacos , Adulto , Células Cultivadas , Glutationa/análise , Humanos , Concentração de Íons de Hidrogênio , Potenciais da Membrana/efeitos dos fármacos , Mitocôndrias/metabolismo , Oxirredução , Espécies Reativas de Oxigênio/metabolismo , Linfócitos T/metabolismo , Linfócitos T/ultraestruturaRESUMO
Pasteurella haemolytica leukotoxin (LKT) is a member of the RTX family of pore-forming toxins that kill bovine immune cells. Several studies have suggested that RTX toxins kill target cells by the induction of apoptosis. In the present study, BL3 bovine leukaemia cells were exposed to LKT and assessed by molecular and flow cytometric techniques that measure different aspects of apoptotic cell death. The intoxicated cells demonstrated morphological, light scatter and Hoechst 33258 staining characteristics consistent with cells undergoing apoptosis. The cells also exhibited internucleosomal DNA fragmentation and poly (ADP-ribose) polymerase (PARP) cleavage, both indicators of apoptosis. LKT-treated cells bound annexin-V-FITC indicating that phosphatidylserine groups were translocated from the inner to the outer leaflet of the cell membrane. The effect of LKT on cells was dose dependent and inhibitable by incubation with anti-LKT monoclonal antibody. Finally, an early step for induction of apoptosis appears to be the binding of LKT to a beta2 integrin since pre-incubating cells with anti-beta2 integrin antibodies inhibited LKT-induced apoptosis. This study provides new insights into understanding the pathogenesis of bovine pasteurellosis and could lead to the development of both preventative and therapeutic strategies for disease management.
Assuntos
Apoptose , Toxinas Bacterianas/toxicidade , Exotoxinas/toxicidade , Mannheimia haemolytica/química , Animais , Anticorpos Monoclonais/farmacologia , Especificidade de Anticorpos , Apoptose/efeitos dos fármacos , Toxinas Bacterianas/antagonistas & inibidores , Toxinas Bacterianas/metabolismo , Western Blotting , Antígenos CD18/metabolismo , Bovinos , Membrana Celular/efeitos dos fármacos , DNA/efeitos dos fármacos , DNA/genética , Fragmentação do DNA , Exotoxinas/antagonistas & inibidores , Exotoxinas/metabolismo , Citometria de Fluxo , Microscopia Eletrônica , Poli(ADP-Ribose) Polimerases/efeitos dos fármacos , Células Tumorais Cultivadas/efeitos dos fármacosRESUMO
It has been shown that lead (Pb) potentiates lipopolysaccharide (LPS) lethality in animals by increasing the secretion and uptake or reactivity of tumor necrosis factor-alpha (TNF-alpha). Herein we report that PbCl2 increased TNF-alpha secretion from LPS-treated human peripheral blood mononuclear cells (PBMC) in a concentration- and time-dependent manner. PbCl2 also increased total cellular TNF-alpha levels but had no effect on the steady-state levels of TNF-alpha mRNA. PbCl2 decreased membrane-associated TNF-alpha (mTNF-alpha) on LPS-treated monocytes, whereas PbCl2 increased TNF-alpha receptor (TNF-R) p55 surface expression, and had no effect on TNF-R p75 surface expression by LPS-treated monocytes. Overall, the results suggest that PbCl2 increases TNF-alpha expression by posttranscriptional mechanisms in human PBMC, and enhances the reactivity and uptake of TNF-alpha by increasing the surface expression of TNF-R p55.