Biomedical subjects

M I Luster

Publications and source records attributed to M I Luster.

At least 145 records · Page 8Linked to original sources

PubMed1986

1-amino-3,7,8-trichlorodibenzo-p-dioxin: a specific antagonist for TCDD-induced myelotoxicity.

It was recently reported that suppression of murine bone marrow hematopoiesis is a very sensitive indicator for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) toxicity (1). We report here that a structural analog of TCDD, 1-NH2-3,7,8-trichlorodibenzo-p-dioxin (NH2-TriCDD), is a specific and effective antagonist for TCDD-induced myelotoxicity and enzyme induction. When administered to mice or added directly into culture at a 100-fold excess, relative to TCDD, NH2-TriCDD completely abrogated the ability of TCDD to inhibit granulocyte-macrophage progenitor cells (CFU-C) formation, an indicator of hematopoiesis. Further, NH2-TriCDD inhibited TCDD-induced activation of cytochrome P1-450 monooxygenase activity. Studies designed to measure specific binding of TCDD to the cytosolic Ah receptor indicated that NH2-TriCDD effectively inhibited binding of TCDD to the receptor by acting as a competitive antagonist (Ki = 0.72 nM).

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PubMed1986

Toxoplasma gondii: decreased resistance to infection in mice due to estrogen.

Exposure to pharmacological concentrations of potent estrogenic compounds, including 17 beta-estradiol, diethylstilbestrol, and alpha-dienestrol, increased the susceptibility of mice to Toxoplasma gondii as measured by brain cyst formation. Compounds with weak estrogenic activity or other hormonal activity, including 5 alpha-dihydrotestosterone, progesterone, and zearalanol, did not alter host resistance to infection. The ability of estrogens to alter susceptibility was inhibited by the estrogen antagonist, tamoxifen. The restoration of ovariectomized mice with normal physiological concentrations of estrogen had no effect on subsequent infection with T. gondii. These results indicate that pharmacological, but not physiological, levels of estrogen selectively alter host resistance to T. gondii, possibly through hormonal events.

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PubMed1986

Immunotoxicity studies in mice exposed to methyl isocyanate.

The effects of methyl isocyanate (MIC) on systemic immunity were evaluated in female B6C3F1 mice exposed via inhalation to 0, 1, or 3 ppm for 6 hr per day on four consecutive days. Humoral immunity, measured as the antibody response to sheep erythrocytes, and natural killer cell activity were not affected by MIC. Furthermore, resistance to the infectious agents Listeria monocytogenes, mouse malaria parasite, and influenza virus, or to B16F10 transplantable tumor cells, was not compromised by MIC exposure. Although lymphoproliferative responses to mitogens were not significantly suppressed, the response of splenic lymphocytes to allogeneic leukocytes in a mixed leukocyte response (MLR) was suppressed in a dose-related fashion and differed significantly from the control response at the 3-ppm level. These studies indicate that MIC exposure in mice does not severely alter systemic immunity. The moderate changes detected in immune function may be a secondary consequence of respiratory toxicity which occurred in these animals.

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PubMed1986

Suppression of B cell differentiation by 2,3,7,8-tetrachlorodibenzo-p-dioxin.

Acute exposure of adult mice to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) results in a selective suppression of proliferating cells of the immune system, including hematopoietic stem cells and B cells. Suppression of B cell-mediated or humoral immunity, in turn, results in altered host resistance to the parasite Plasmodium yoelii, a malaria model. Data presented in this study demonstrate a direct effect of TCDD on cultured lymphoctes resulting in a selective inhibition of the differentiation of B cells into antibody-secreting cells. A structure-activity study suggested that this inhibition was mediated by the Ah receptor. As previously defined by receptor binding studies in hepatic cytosol, active congeners were inhibitory, whereas inactive congeners were without effect. Using lymphocytes from congenic mice which differ only at the Ah locus, it was determined that the Ahbb-derived cells were inhibited by TCDD in vitro, whereas the Ahdd-derived cells were not. B cell differentiation thus provides a valuable model for understanding TCDD toxicity as well as the role of the Ah receptor in growth and differentiation.

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PubMed1986

Alterations in bone marrow cell cycle kinetics by diphenylhydantoin and folate deficiency are restored by thymic peptides.

We have previously shown that the anticonvulsant drug, diphenylhydantoin (DPH), causes impaired humoral immunity and host resistance in subchronically treated mice as a consequence of myelotoxicity. The bone marrow is a primary and sensitive target for this drug, which causes a selective loss of stem cells in S phase. The present report describes the restoration of stem cell kinetics by thymosin in both drug-treated and folate-deficient mice. Thymosin and the thymic peptide, FTS (facteur thymique serique), were also able to protect the progenitor stem cell, CFU-GM, from DPH inhibition in vitro, indicating a direct effect of both drug and thymic factors on stem cells. Although the mechanism of this protection is not yet understood, the observation may have important implications concerning immunotherapy of DPH-treated epileptics, who are at increased risk of infectious diseases and malignancies.

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PubMed1985

Acute myelotoxic responses in mice exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).

Blood cells are derived from a multitiered system of progenitor stem cells that lose their capacity for proliferation and self-renewal as they continue along pathways of differentiation. Since these hematopoietic events can be readily monitored in vivo and in vitro in the mouse, we have utilized this system to examine altered cellular differentiation associated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) toxicity. Progenitor cells were suppressed following acute exposure of mice to TCDD at doses as low as 1.0 micrograms/kg body wt. In vitro studies demonstrated that myelotoxicity occurs by a direct inhibition of proliferating stem cells. Genetic studies indicated that the myelotoxic responses to TCDD, both in vivo and in vitro, segregate with the Ah locus. In addition, the in vitro myelotoxicity of various polyhalogenated aromatic hydrocarbon congeners correlated with their previously reported ability to induce hepatic microsomal enzyme activity and to bind to an intracellular receptor for TCDD. TCDD was also found to bind specifically to bone marrow cells from Ah-responsive, but not nonresponsive mice, indicating that bone marrow cells possess a specific receptor for TCDD. These data indicate that the myelotoxic response to TCDD is regulated by the Ah receptor present in the target tissue and demonstrates the utility of this system for examining the cellular and molecular events associated with the toxicity of polyhalogenated aromatic hydrocarbons, the prototype for which is TCDD.

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PubMed1985

Correlation of murine susceptibility to tumor, parasite and bacterial challenge with altered cell-mediated immunity following systemic exposure to the tumor promoter phorbol myristate acetate.

Phorbol myristate acetate (PMA), the most potent of the tumor promoting phorbol diesters, modulates function in several immunoresponsive cells following in vitro exposure. Since suppression of cellular mechanisms capable of limiting tumors and infections can adversely affect health, these experiments were designed to evaluate relevant components of cell-mediated immunity (CMI) following in vivo PMA exposure, and to determine the biological significance of any alterations utilizing assays of host resistance. Adult, female B6C3F1 mice were administered 0.2, 2.0, 20.0 or 40.0 micrograms PMA/g body weight subcutaneously over a two-week period. Mechanisms of cell-mediated host resistance were assessed by quantitating natural killer (NK), cytotoxic T-lymphocyte (CTL) and macrophage-mediated lysis of radiolabelled tumor target cells, and macrophage-induced cytostasis in tumor cell populations. Macrophages from PMA-treated mice were cytostatic to tumor cells, inhibiting up to 90% of growth in cultured tumor cells, but were not tumoricidal. Furthermore, pyran-elicited (primed) macrophages, which are activated to fully cytotoxic states by in vitro exposure to lipopolysaccharide, were inhibited in tumoricidal activation by in vivo PMA exposure. The induction of responsive but not cytotoxic macrophages by in vivo PMA exposure is consistent with the enhanced resistance to Listeria bacterial challenge, and increased susceptibility to B16F10 tumor and Trichinella parasitic challenges observed in these mice. Furthermore, previous reports of decreased in vitro NK activity following in vivo PMA exposure and present observations of correlative decreases of in vivo NK activity (55% decrease in mice exposed to 20 micrograms PMA/g) suggest an important role for NK activity in limiting in vivo B16F10 melanoma growth. CTL effector function was less susceptible to PMA-induced suppression than NK function at similar dosages, further supporting a predominant role of macrophages and NK cells or possibly other effector functions in the resistance to Listeria, Trichinella, or B16F10 challenge. Nevertheless, significant suppressive effects of PMA on CTL function at higher dosages cannot be excluded as contributing to altered host resistance to these agents. These studies demonstrate that in vivo exposure to PMA can modify cell-mediated mechanisms of host resistance with coincident alterations in the incidence of infections and tumors.

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PubMed1985

Influence of estrogen on host resistance: increased susceptibility of mice to Listeria monocytogenes correlates with depressed production of interleukin 2.

Mice given pharmacological levels of the synthetic estrogen diethylstilbestrol demonstrated a marked increase in susceptibility to infection with Listeria monocytogenes. Experiments were performed in an effort to determine the mechanism(s) by which estrogen treatment increases the susceptibility of mice to L. monocytogenes infection. Estrogen exposure depressed the in vivo proliferative response of splenic lymphocytes to L. monocytogenes, which correlated with the decreased in vitro response of these cells to phytohemagglutinin. Interleukin 2 (IL 2) production by splenic lymphocytes from estrogen-treated mice was decreased, although these cells were capable of proliferating normally in response to exogenous IL 2. Interleukin 1 production by peritoneal macrophages was not depressed by estrogen exposure. The number of bacteria observed in the spleens of estrogen-exposed mice challenged with L. monocytogenes was reduced by IL 2 administration. Thus, estrogens may decrease host resistance to L. monocytogenes by inhibiting IL 2 production and the subsequent proliferation of antigen-sensitized T lymphocytes required for recovery.

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PubMed1985

Immunosuppressive effects of benzidine in mice: evidence of alterations in arachidonic acid metabolism.

Benzidine (4,4'-diaminobiphenyl), a known human bladder carcinogen used in the synthesis of dyes, was immunosuppressive in mice after subchronic exposure. Suppression, particularly of cell-mediated immunity, occurred at dose levels previously found to be subtumorigenic in mice, as evidenced by suppressed lymphoproliferative and delayed hypersensitivity responses. In addition, benzidine exposure was found to decrease host resistance, including resistance to the growth of transplantable tumor cells and infection with Listeria. These data suggest that the development of neoplastic disease may be facilitated by the ability of benzidine to alter the immune response. The mechanism(s) responsible for immunosuppression by benzidine, however, is probably not the same as that responsible for its direct carcinogenicity. The addition of benzidine in vitro to mitogen-activated lymphocytes mimicked the suppression of lymphocyte responsiveness in vivo. In vitro studies suggested that alterations in metabolites of the arachidonic acid/lipoxygenase pathway were responsible for the immune alterations. Benzidine and the lipoxygenase inhibitor NDGA inhibited arachidonic acid metabolism and the mitogen response in lymphocytes, whereas the cyclooxygenase inhibitor indomethacin was ineffective. Addition of 8brcGMP partially restored benzidine-suppressed responses, whereas arachidonic acid potentiated the suppression. These data are consistent with the hypothesis that alterations in lymphocyte functions may occur as a result of quantitative changes or depletion of conversion products in the arachidonate/lipoxygenase pathway induced by the addition of compounds that serve as co-oxidative substrates for hydroperoxidases, the prototype being benzidine.

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PubMed1985

Alteration of bone marrow cell cycle kinetics by diphenylhydantoin: relationship to folate utilization and immune function.

Female B6C3F1 mice were administered the anticonvulsant drug diphenylhydantoin (DPH) for 1 to 4 weeks by gavage at doses of 25 to 200 mg/kg. None of the dosing regimens caused toxicological manifestations other than hepatomegaly. Evaluation of the immune status of the drug-treated mice revealed no alteration of cellular immunity, measured by delayed hypersensitivity response and lymphocyte responsiveness to mitogens or allogeneic leukocytes. Humoral immunity, as measured by serum immunoglobulin quantitation and plaque-forming cell response to sheep erythrocytes, was depressed by DPH at 100 mg/kg after 2 weeks, as was host resistance to infection with the parasite Plasmodium yoelii. The bone marrow was the most sensitive target organ with loss of the multipotent stem cell colony-forming unit-spleen occurring within 1 week at a dose of 50 mg/kg. The colony-forming unit-spleen suppression was the result of a selective loss of stem cells in S phase. Committed granulocyte macrophage progenitor cells, colony-forming unit-granulocyte macrophage, were also inhibited by DPH in vivo, as well as in vitro at concentrations as low as 0.2 microM. Bone marrow cells from DPH-treated mice were folate deficient, as determined by the inability of these cells to convert deoxyuridine to thymidine. However, these mice had normal serum folate levels, even after 4 weeks of treatment. Folic acid protected bone marrow stem cells after both in vivo and in vitro treatment with DPH. It is suggested that DPH inhibits folate utilization or metabolism at the cellular level, selectively affecting bone marrow stem cells and resulting in altered stem cell kinetics. This lesion ultimately results in altered humoral immunity and impaired host resistance.

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PubMed1984

Bone marrow alterations induced in mice with inhalation of chrysotile asbestos.

The effect of chrysotile asbestos exposure on bone marrow and immune parameters was examined in mice at 2, 12, and 26 weeks following a 3-day inhalation exposure. Ultrastructural examination revealed that the fibers were deposited primarily at alveolar duct bifurcations within the centriacinar region of the lung. Histological pulmonary changes were minimal, but by 26 weeks early asbestosis characterized by clusters of macrophages and minimal fibrosis were present in the centriacinar region of the lung. Lymphoproliferative responses, antibody levels, and number of plaque forming cells were not significantly altered in exposed mice. Pulmonary macrophages, but not peritoneal macrophages, showed evidence of activation in the chrysotile-exposed mice at 26 weeks following exposure. The most striking change was the depression of the number of bone marrow pluripotent stem cells (CFU-S) and marrow granulocyte macrophage progenitors (CFU-GM) which were lower at all three postexposure examinations. It is felt that the depression of bone marrow progenitors in asbestos-exposed mice may have relevance to the leukopenia reported in workers with occupational history of asbestos exposure.

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PubMed1984

Myelotoxicity and macrophage alteration in mice exposed to ochratoxin A.

Six- to seven-week-old female B6C3F1 mice were administered a total of 0, 20, 40, or 80 mg/kg of ochratoxin A (OCT A) ip on alternate days over an 8-day period. Twenty-four hours following the final dose, histopathology, bone marrow, and macrophage parameters were assayed. There was a dramatic dose related decrease in thymic mass with the mean thymus weight of the high dose animals being only 33% of controls. Histologic evidence of nephrotoxicity was minimal and restricted to the inner cortex. Myelotoxicity was present as evidenced by bone marrow hypocellularity, decreased marrow pluripotent stem cells (CFU-S), granulocyte-macrophage progenitors (CFU-GMs), and decreased 59Fe uptake in marrows and spleens of exposed mice. Peritoneal macrophages from sc as well as ip injected mice demonstrated increased phagocytic capacities and increased capacity to inhibit tumor cell growth. These alterations in bone marrow cells and macrophages suggest myelotoxicity is an additional potential hazard of OCT A exposure.

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PubMed1984

Mechanisms of estrogen-induced myelotoxicity: evidence of thymic regulation.

Mice exposed to pharmacological levels of steroidal and nonsteroidal estrogens including alpha-dienestrol, 17 beta-estradiol, and diethylstilbestrol demonstrate bone marrow hypocellularity, and decreased numbers of pluipotent hemopoietic stem cells. Hormones with little estrogenic activity including testosterone and progesterone failed to induce myelotoxicity as did nonestrogenic metabolites of DES. Myelotoxicity associated with estrogen exposure is regulated by a complex bimodal mechanism. One of these mechanisms is mediated through the thymus since surgical thymectomy abolished the ability of estrogens to suppress CFU proliferation. Furthermore, supernatants of thymic epithelial cells cultured in the presence of estradiol were capable of inhibiting CFU-GM colony formation. Specific myelotoxic events can also be disassociated chemically by testing weakly estrogenic compounds such as zearalanol which shows different sensitivity on cytoxic and antiproliferative events. Myelotoxicity is not mediated indirectly through the ovary or adrenal gland. That the initial events in estrogen-induced myelotoxicity may be mediated through a receptor mechanism was suggested by the ability of antiestrogens to induce antagonism when administered prior to estradiol and the presence of estrogen binding components in lymphoreticular tissues including the thymus and bone marrow. These studies suggest that reduced CFU kinetics observed following estrogen exposure is, in part, due to alterations in regulatory factors produced by thymic epithelial cells in response to a specific estrogen stimulus. Estrogens may also influence bone marrow functions through non-thymic mechanisms at higher dose levels.

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PubMed1984

Altered host resistance to Trichinella spiralis infection following subchronic exposure to diethylstilbestrol.

The effects of subchronic exposure to diethylstilbestrol on the host response to infection with Trichinella spiralis were examined in adult B6C3F1 mice. Expulsion of adult Trichinella from the small bowel, intestinal inflammation and delayed hypersensitivity responses to Trichinella antigens in artificially sensitized mice were investigated. Administration of 8 micrograms/g of diethylstilbestrol for five consecutive days beginning on days -5,0, +3 or +8 of infection inhibited adult worm expulsion and tissue reactions in the small intestine. Expulsion of adult parasites was also delayed in mice given 0.2 microgram/g of diethylstilbestrol for the first five days of infection. When the chemical was given during a primary infection, mice failed to expel a second infection as rapidly as untreated controls or previously infected mice exposed during a second infection. These findings indicate that diethylstilbestrol exposure altered the immune responses that mediate expulsion of adult worms from the gut, especially when exposure occurred during the inductive phase of host immunity. These results also suggest that use of diethyl-stilbestrol as a weight-gain promoter may lead to increased parasite burdens. While diethylstilbestrol-exposed mice retained adult worms longer than controls, no significant increase was found in numbers of encysted muscle-phase larvae, contrary to the usual findings in animals maintaining adult worm burdens for extended periods. The possibility that macrophages activated by diethylstilbestrol treatment had a role in limiting larvae encystment in the host musculature is discussed.

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PubMed1984

A screening assay for the tetrachlorodibenzo-p-dioxin receptor using the [125I]iodovaleramide derivative of trichlorodibenzo-p-dioxin as the binding ligand.

A relatively simple assay method for the putative cytosolic 'receptor' that binds 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds is described. The assay is based on specific binding of [125I]dioxin to cytosol 'receptor' protein. Saturation is ensured by competition experiments in which unlabeled TCDD and other competitors displace the radiolabeled ligand from specific binding sites. This assay has been applied to estimation of levels of 'receptor' in cytosol.

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PubMed1984

Influence of steroidal and nonsteroidal sex hormones on host resistance in mice: increased susceptibility to Listeria monocytogenes after exposure to estrogenic hormones.

Subchronic exposure to pharmacological levels of estrogenic compounds, including 17 beta-estradiol, diethylstilbestrol, and alpha-dienestrol, significantly increased the mortality of B6C3F1 female mice after Listeria infection. Compounds with little estrogenic activity, including 5 alpha-dihydrotestosterone, progesterone, zearalenol, and corticosterone, did not alter Listeria-related mortality. Estrogen-induced alterations in resistance were inhibited by both adult thymectomy and the estrogen antagonist tamoxifen. Estrogen exposure depressed the accumulation of monocytes and lymphocytes at infective foci. Significantly elevated numbers of bacteria were observed in infective foci of estrogen-treated mice later in the infection when bacteria were nearly eliminated from untreated animals. These results indicate that estrogen-induced suppression of Listeria immunity is partially mediated by the thymus, probably through receptor events which may ultimately suppress the activation of T cell-dependent defense mechanisms. This may be partially reflected by the inability of estrogen-exposed mice to eliminate Listeria cells or to accumulate mononuclear effector cells at infective foci at the same rate as controls.

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PubMed1984

Estrogen immunosuppression is regulated through estrogenic responses in the thymus.

Previous studies have clearly established that physiologic and pharmacologic levels of estrogens modulate immunologic responses that result in simultaneous activation of the reticuloendothelial system and depression of cell-mediated immunity. The mechanisms of estrogen immunoregulation were examined in adult female mice administered pharmacologic levels of exogenous estrogens. Evaluation of steroidal and nonsteroidal compounds with varying degrees of estrogenicity (i.e., uterotrophic activity) provided evidence that their immunotoxicity, for the most part, correlates with estrogenicity. The mechanisms responsible for these effects appear to be complex, mediated through a direct chemical interaction with lymphoid target cells, as well as with nonlymphoid tissue, resulting in the release of soluble immunoregulatory factors. The latter phenomenon was examined in detail and it appears to constitute a regulatory factor(s) produced by thymic epithelium in response to an estrogen stimulus. This response is not only estrogen specific but may involve specific binding to estrogen receptors or receptor-like structures present in cytosol preparations from thymic epithelial cells.

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PubMed1983

Immunological and biochemical responses in mice treated with mercuric chloride.

Adult B6C3F1 male mice were given water containing 3, 15, and 75 ppm mercury (as mercuric chloride) for 7 weeks. There were dose-related increases in blood and kidney mercury levels but only the former showed a time-dependent change. Mercury was not detected in any of the lymphoid organs except for the spleen. There was no mortality and only minimal histological changes occurred in kidneys of dosed mice. Nonspecific toxicity occurred at the 75 ppm dose level, consisting of small differences in body and organ weights, hematological changes, and general enzyme inhibition in the bone marrow and spleen. However, there were specific immunotoxic and biochemical alterations in lymphoid organs of mice treated at the lower doses of mercury. The immunological defects were consistent with altered T-cell function as evidenced by decreases in both T-cell mitogen and mixed leukocyte responses. There was a particular association between the T-cell defects and inhibition of thymic pyruvate kinase, the rate-limiting enzyme for glycolysis. The differences in the pattern of enzyme responses among lymphoid organs implied that two mechanisms of mercury toxicity were operative--one at high concentrations that caused physicochemical enzyme inhibition and another at low concentrations that caused indirect enzyme inhibition.

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