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R D Irons

Publications and source records attributed to R D Irons.

At least 37 records · Page 2Linked to original sources
PubMed1996

Murine thymic lymphoma is associated with a species-specific hematopoietic progenitor cell subpopulation.

Many strains of laboratory mouse are uniquely susceptible to the development of T cell lymphoma/leukemia, either spontaneously or as a result of chemical or radiation exposure. In contrast, T cell leukemias or lymphomas which are relatively uncommon in human populations, are not easily induced by radiation, and are not generally associated with chemotherapy or chemical exposure. Evidence is presented to suggest that differences in the susceptibility to the development of these malignancies is related to subtle but important variations in the regulation of hematopoietic stem cell differentiation between these two species.

Adult↗
PubMed1996

Inorganic lead activates NF-kappa B in primary human CD4+ T lymphocytes.

Inorganic lead (Pb) is a ubiquitous environmental contaminant that produces a variety of effects on humoral and cell mediated immune responses. The underlying molecular mechanism for Pb's complex effects on the immune system remain obscure. Many of Pb's effects on the immune system could be explained through activation of the transcription factor, NF-kappa B. NF-kappa B is critical for T lymphocyte function and is a strong inducer of HIV-LTR activation. We demonstrate that Pb at physiologically relevant concentrations activates NF-kappa B in primary human CD4+ T lymphocytes. Pb-induced activation of NF-kappa B is blocked by antibodies for p65 and p50 subunits but not cRel, indicating that the p65:p50 heterodimer (NF-kappa B) is involved. Functional activation of gene expression by Pb was confirmed using primary CD4+ T cells transfected with an NF-kappa B dependent reporter gene construct. Pb did not activate NF-kappa B in 4 different T cell lines, suggesting that lymphoid cell lines may not be reliable surrogates for the study of transcriptional activation in human T cells. These data suggest that NF-kappa B may be an important molecular mediator of Pb-induced immunotoxicity.

Base Sequence↗
PubMed1996

The effects of benzene and other leukaemogenic agents on haematopoietic stem and progenitor cell differentiation.

A characteristic shared by a diverse group of myelotoxic compounds and leukaemogens is the ability to act synergistically with granulocyte-macrophage colony stimulating factor (GM-CSF) in increasing clonogenic response. Pretreatment of murine or human bone marrow cells with the benzene metabolite, hydroquinone, but not phenol, catechol or trans, trans-muconaldehyde, results in a selective enhancement of GM-CSF but not an interleukin-3 (IL-3)-mediated clonogenic response. Clonal enhancement is preserved and magnified in enriched populations of CD34+ cells (> 95% purity), suggesting an intrinsic effect on haematopoietic progenitor cell (HPC) recruitment rather than a secondary effect involving accessory cytokines. Clonogenic enhancement of murine HPCs is not accompanied by alterations in GM-CSF receptor expression or ligand affinity and appears to be mediated via a p53-independent mechanism. These observations suggest that hydroquinone treatment alters recruitment and differentiation in a primitive subpopulation of CD34+ cells and are consistent with a role for altered stem cell differentiation in the development of chemically induced myelodysplasias.

Animals↗
PubMed1996

The process of leukemogenesis.

Leukemias are monoclonal diseases that arise from cells in the hematopoietic stem and progenitor cell compartment. Consistent with emerging models of carcinogenesis, leukemogenesis is an evolutionary process that involves multiple independent genetic and epigenetic events. Over the last half-century a predominant paradigm has emerged to describe leukemia developing secondary to alkylating drug therapy or exposure to benzene in which progressive dysplastic changes, accompanied by a distinct pattern of clonal cytogenetic abnormalities, give rise to acute myelogenous leukemia. Characterization of these clonal chromosomal aberrations, together with observed alterations in other growth-promoting genes, provides a useful framework for studying chemical leukemogenesis and for use in understanding the origins and development of leukemia in general.

Benzene↗
PubMed1996

Impact of benzene metabolites on differentiation of bone marrow progenitor cells.

Interleukin-3 (IL-3) and granulocyte/macrophage-colony-stimulating factor (GM-CSF) are responsible for maintaining survival and stimulating growth of early dormant hematopoietic progenitor cells (HPC). These cytokines exhibit extensive overlap, with GM-CSF supporting growth and differentiation of myeloid HPC. A characteristic shared by a diverse group of leukemogens is the ability to act synergistically with GM-CSF to increase clonogenic response. Previous studies have revealed that pretreatment of murine HPC with hydroquinone (HQ) but not phenol, catechol, or trans-trans-muconaldehyde results in a selective enhancement of GM-CSF but not IL-3-mediated clonogenic response. Pretreatment of murine bone marrow cells with these agents or their metabolites in vitro results in increased numbers of HPC dividing and forming colonies in response to GM-CSF but not IL-3. The present studies explored the molecular mechanisms associated with altered cytokine response in early HPC in murine bone marrow and extended our initial observations in murine bone marrow to human bone marrow cells. HQ pretreatment of murine HPC did not induce either an up- or a down-regulation of GM-CSF receptors or any change in receptor affinity. CD34+ cells, which represent between 1 and 5% of human bone marrow, contain virtually all clonogenic stem and HPC. Pretreatment of CD34+ cells (approximately 95% purity) with HQ also results in enhanced clonogenic response with GM-CSF but not IL-3. These findings suggest that an early step in chemical leukemogenesis may involve transient alterations in the regulation of cytokine response to GM-CSF.

Animals↗
PubMed1996

An epidemiologic study of early biologic effects of benzene in Chinese workers.

Benzene is a recognized hematotoxin and leukemogen, but its mechanisms of action in humans are still uncertain. To provide insight into these processes, we carried out a cross-sectional study of 44 healthy workers currently exposed to benzene (median 8-hr time-weighted average; 31 ppm), and unexposed controls in Shanghai, China. Here we provide an overview of the study results on peripheral blood cells levels and somatic cell mutation frequency measured by the glycophorin A (GPA) gene loss assay and report on peripheral cytokine levels. All peripheral blood cells levels (i.e., total white blood cells, absolute lymphocyte count, platelets, red blood cells, and hemoglobin) were decreased among exposed workers compared to controls, with the exception of the red blood cell mean corpuscular volume, which was higher among exposed subjects. In contrast, peripheral cytokine levels (interleukin-3, interleukin-6, erythropoietin, granulocyte colony-stimulating factor, tissue necrosis factor-alpha) in a subset of the most highly exposed workers (n = 11) were similar to values in controls (n = 11), suggesting that benzene does not affect these growth factor levels in peripheral blood. The GPA assay measures stem cell or precursor erythroid cell mutations expressed in peripheral red blood cells of MN heterozygous subjects, identifying NN variants, which result from loss of the GPA M allele and duplication of the N allele, and N phi variants, which arise from gene inactivation. The NN (but not N phi) GPA variant cell frequency was elevated in the exposed workers compared with controls (mean +/- SD, 13.9 +/- 8.4 mutants per million cells versus 7.4 +/- 5.2 per million cells, (respectively; p = 0.0002), suggesting that benzene produces gene-duplicating but not gene-inactivating mutations at the GPA locus in bone marrow cells of exposed humans. These findings, combined with ongoing analyses of benzene macromolecular adducts and chromosomal aberrations, will provide an opportunity to comprehensively evaluate a wide range of early biologic effects associated with benzene exposure in humans.

Adult↗
PubMed1996

Reactive oxygen species mediate stem cell factor synergy with granulocyte/macrophage colony-stimulating factor in a subpopulation of primitive murine hematopoietic progenitor cells.

Reactive oxygen species (ROS) have been shown to stimulate proliferation and growth responses in a variety of mammalian cell types and to act as important mediators in many cellular processes, including hematolymphopoiesis. We examined the effect on primitive murine hematopoietic progenitor cells (HPC) of ROS generated by xanthine plus xanthine oxidase (xanthine/XO) and various antioxidants. Pretreatment of murine HPC (C57BL/6) with xanthine/XO produced a dose-dependent enhancement of clonogenic response to granulocyte/macrophage colony-stimulating factor (GM-CSF) but not to interleukin-3 or granulocyte colony-stimulating factor. Stem cell factor (SCF), a potent comitogen for many hematopoietic growth factors, also synergized with GM-CSF. However, the synergistic enhancement of GM-CSF with xanthine/XO and SCF was not additive, indicating that xanthine/XO and SCF may target the same subpopulation of HPC. Support for this conclusion came from experiments demonstrating that 1) mutant mice strains constitutively lacking a SCF-responsive population of HPC [White spotted (W/WV) and Steel (SI/SId)] are unresponsive to xanthine/XO- and SCF-induced enhancement of GM-CSF and 2) 3,4-epoxybutene, which selectively abrogates SCF synergy with GM-CSF, inhibits xanthine/XO-induced enhancement. As xanthine/XO can mimic SCF in this population of HPC, the possibility exists that ROS also play a role in normal SCF-mediated proliferation of these cells. To test this hypothesis, we used the antioxidants N-tert-butyl-alpha-phenylnitrone, exogenous superoxide dismutase, and catalase. Both N-tert-butyl-alpha-phenylnitrone and superoxide dismutase effectively inhibited SCF and xanthine/XO synergism with GM-CSF, whereas catalase had no effect, indicating that the superoxide anion may be involved. Also, none of these compounds affected SCF synergism with other hematopoietic growth factors, such as interleukin-3 or granulocyte colony-stimulating factor, suggesting a population-specific phenomenon. These findings indicate that xanthine/XO mimics SCF in stimulating a subpopulation of murine HPC to proliferate and that SCF synergy with GM-CSF in this population is sensitive to antioxidant inhibition.

Animals↗
PubMed1995

2'3'-Dideoxycytidine-induced thymic lymphoma correlates with species-specific suppression of a subpopulation of primitive hematopoietic progenitor cells in mouse but not rat or human bone marrow.

The nucleoside analogue, 2',3'-dideoxycytidine (ddC), is a potent inhibitor of HIV replication, and AIDS patients receiving ddC experience clinical improvement without significant hematologic toxicity. Repeated ddC administration (1,000 mg/kg per day) for 13 wk produces an increased incidence of thymic lymphoma in B6C3F1 mice. Previous studies reveal a common link between chemically induced and genetically associated models of mouse thymic lymphoma that involves a defect in a subpopulation of primitive hematopoietic progenitor cells. This defect is characterized by suppression of a subpopulation of IL-3-responsive cells and ablation of stem cell factor synergy with GM-CSF. The present study was undertaken to ascertain whether ddC produces the same pattern of bone marrow toxicity in mice, and whether this effect is observed in rat and human bone marrow. ddC exposure in vivo and in vitro produced a select suppression of murine CFU identical to that previously described for other models of mouse thymic lymphoma. In contrast, this selective CFU suppression was not observed in rat and human bone marrow or in CD34+ cells. These studies suggest that the mouse may not be a good predictive model for ddC hematotoxicity in humans and that susceptibility to the development of thymic lymphoma may be unique to the mouse.

Adult↗
PubMed1994

Peroxidase activity in murine and human hematopoietic progenitor cells: potential relevance to benzene-induced toxicity.

Peroxidases may be important in the mechanism of toxicity of a number of compounds including benzene, a chemical that has been associated with bone marrow toxicity and leukemia after chronic exposure. The major peroxidase in bone marrow is myeloperoxidase (MPO), which has been previously thought to be expressed at the promyelocytic stage of differentiation. Hematopoietic progenitor cells are important potential cellular targets of bone marrow toxins and leukemogens. We therefore examined peroxidase activity in both murine and human progenitor cells. Murine progenitor populations were purified as lineage-negative cells (> 99% enriched) and human progenitor populations were purified as CD34+ cells (> 95% enriched). Using conventional biochemical assays for peroxidase activity, murine and human progenitor cells were found to have 30% and 11% of the peroxidase activity of murine and human unpurified marrow, respectively. Peroxidase activity was confirmed in purified murine and human progenitor populations by flow cytometry using a 2,7-dichlorofluorescein assay, adapted to measure peroxidase activity. In addition, two-color flow cytometry of murine whole marrow using phycoerythrin-conjugated antibodies to lineage markers confirmed the peroxidase activity of the murine progenitor cell population. A reverse transcription-polymerase chain reaction assay was developed for MPO mRNA, which was detected in murine progenitor cells. These data show that MPO mRNA is expressed in murine progenitor cells and that both murine and human progenitor cells have marked peroxidase activity. These data may have relevance for studies of hematopoietic cell differentiation and for the examination of mechanisms underlying cell-specific toxicity in bone marrow.

Animals↗
PubMed1993

Chemical suppression of a subpopulation of primitive hematopoietic progenitor cells: 1,3-butadiene produces a hematopoietic defect similar to steel or white spotted mutations in mice.

Chronic exposure of mice to 1,3-butadiene produces a macrocytic-megaloblastic anemia, thymic hypoplasia, and an increased incidence of T-cell lymphoma/leukemia. This is reminiscent of pathologies observed in mice bearing mutations at the W and Sl loci, which are deficient in c-kit and c-kit ligand (CKL), respectively. The influence of 3,4-epoxybutene (EB), the primary metabolite of 1,3-butadiene, on the colony-forming response of hematopoietic progenitor cells (HPCs) from C57BL/6, Sl, and W mice was investigated in order to elucidate the role of altered HPC regulation in the pathogenesis of 1,3-butadiene toxicity. EB pretreatment suppressed interleukin 3 colony formation and abrogated CKL synergism of the granulocyte-macrophage/colony-stimulating factor (GM-CSF) response in C57BL/6 cells, had no effect on colony formation induced by GM-CSF or granulocyte/colony-stimulating factor (G-CSF) alone, and failed to suppress CKL-induced synergism of the G-CSF response. Experiments conducted with cells from Sl and W mice revealed that they lack the same primitive HPC targeted by EB. EB pretreatment in vitro and butadiene exposure in vivo mimic hematopoietic defects seen in W and Sl mice, suggesting that the pleotypic pathologies encountered in these murine models may be largely due to a common defect in primitive HPCs. Susceptibility to EB appears to define a functional subpopulation of primitive HPCs and illustrates that differences observed in the susceptibility of specific cytokine responses to chemical/drug exposure may provide a valuable tool for characterizing functional subpopulations of HPCs.

Animals↗
PubMed1993

Cell proliferation and differentiation in chemical leukemogenesis.

In tissues such as bone marrow with normally high rates of cell division, proliferation is tightly coordinated with cell differentiation. Survival, proliferation and differentiation of early hematopoietic progenitor cells depend on the growth factors, interleukin 3 (IL-3) and/or granulocyte-macrophage colony stimulating factor (GM-CSF) and their synergism with other cytokines. We provide evidence that a characteristic shared by a diverse group of compounds with demonstrated leukemogenic potential is the ability to act synergistically with GM-CSF. This results in an increase in recruitment of a resting population of hematopoietic progenitor cells normally unresponsive to the cytokine and a twofold increase in the size of the proliferating cell population normally regarded to be at risk of transformation in leukemogenesis. These findings support the possibility that transient alterations in hematopoietic progenitor cell differentiation may be an important factor in the early stages of development of leukemia secondary to chemical or drug exposure.

Animals↗
PubMed1993

Carcinogenicity of inhaled benzene in CBA mice.

This study investigated benzene-induced neoplasia in CBA/Ca mice, with special emphasis on hematopoietic tissues. Ten-week-old male CBA/Ca mice were exposed to 300 ppm benzene via inhalation for 6 hr/day, 5 days/week, for 16 weeks and held 18 months after the last exposure. There were 125 benzene-exposed and 125 sham-exposed mice. Malignant lymphoma was a statistically significant cause of early mortality in the benzene-exposed mice. Fourteen benzene-exposed mice developed lymphoma (lymphoblastic, lymphocytic, or mixed) as compared to only 2 sham-exposed mice. Benzene-exposed mice also developed preputial gland squamous cell carcinomas (60% in benzene-exposed vs 0% in sham-exposed) and had an increased incidence of lung adenomas (36% vs 14%). Moderate to marked granulocytic hyperplasia was present in benzene-exposed animals, with a 36% incidence in the bone marrow and 6% in the spleen, as compared to the sham-exposed with 8 and 0%, respectively. Interpretation of the granulocytic response as a direct effect of benzene was complicated by the presence of inflammation in the mice. Although inhaled benzene was clearly carcinogenic in CBA mice, it did not induce granulocytic leukemia.

Administration, Inhalation↗
PubMed1993

Toxicity of 1,3-butadiene to bone marrow mimics haematopoietic defects observed in mice bearing white spotted or steel mutations.

In order to clarify the role of haematopoietic stem and progenitor cells in bone-marrow toxicity induced by 1,3-butadiene, we examined the effects of its primary metabolite, 3,4-epoxybutene, on the cytokine response of these cells from C57B1/6 mice. Pretreatment with epoxybutene in vitro suppressed recombinant interleukin-3-stimulated colony formation in haematopoietic stem and progenitor cells, had no effect on colony formation with recombinant granulocyte/macrophage-colony stimulating factor or recombinant granulocyte-colony stimulating factor alone, and completely blocked the synergism of recombinant c-kit ligand and granulocyte/macrophage colony stimulating factor. Butadiene-induced leukaemogenesis, macrocytic anaemia and thymic atrophy are reminiscent of the conditions observed in mice bearing mutations at the W or Sl loci, which are deficient in the c-kit receptor and c-kit ligand, respectively. Epoxybutene did not suppress colony formation in cells from W/Wv and Sl/Sld mice, consistent with the absence of the population of haematopoietic stem and progenitor cells that is susceptible to butadiene in those genetically deficient strains. These findings indicate that the pathological conditions observed after either exposure to butadiene or W or Sl mutations are due to a functional defect in a subpopulation of primitive haematopoietic stem and progenitor cells that plays a major role in the pathogenesis of both T-cell leukaemia/lymphoma and anaemia in the mouse.

Animals↗
PubMed1992

Synergistic action of the benzene metabolite hydroquinone on myelopoietic stimulating activity of granulocyte/macrophage colony-stimulating factor in vitro.

The effects of in vitro pretreatment with benzene metabolites on colony-forming response of murine bone marrow cells stimulated with recombinant granulocyte/macrophage colony-stimulating factor (rGM-CSF) were examined. Pretreatment with hydroquinone (HQ) at concentrations ranging from picomolar to micromolar for 30 min resulted in a 1.5- to 4.6-fold enhancement in colonies formed in response to rGM-CSF that was due to an increase in granulocyte/macrophage colonies. The synergism equaled or exceeded that reported for the effects of interleukin 1, interleukin 3, or interleukin 6 with GM-CSF. Optimal enhancement was obtained with 1 microM HQ and was largely independent of the concentration of rGM-CSF. Pretreatment with other authentic benzene metabolites, phenol and catechol, and the putative metabolite trans, trans-muconaldehyde did not enhance growth factor response. Coadministration of phenol and HQ did not enhance the maximal rGM-CSF response obtained with HQ alone but shifted the optimal concentration to 100 pM. Synergism between HQ and rGM-CSF was observed with nonadherent bone marrow cells and lineage-depleted bone marrow cells, suggesting an intrinsic effect on recruitment of myeloid progenitor cells not normally responsive to rGM-CSF. Alterations in differentiation in a myeloid progenitor cell population may be of relevance in the pathogenesis of acute myelogenous leukemia secondary to drug or chemical exposure.

Animals↗
PubMed1992

Risk characterization and the extended spaceflight environment.

Recent trends toward prolonged space flights have highlighted concern over potential health hazards for crews occupying a confined habitat for an extended duration mission. Previous spaceflight and remote habitat experiences have identified a large number of compounds that pose potential hazards as space habitat contaminants. A project is underway to prioritize these compounds according to: 1) the degree of potential exposure, 2) known or potential health risks, 3) process- and mission-specific determination of sources of contamination, and 4) preliminary evaluation of mission performance degradations associated with compound contaminant or substitution. An effort is underway to establish a comprehensive database making use of all available national and international data in order to provide a basis from which to evaluate both the impact and the likelihood of long term or transient exposure to these agents. The database will define projected capabilities of Space Station Freedom from early assembly phase through man-tended and permanently-manned capability, previous knowledge of the lunar base environment, and the limited data available from the Viking mission for the Mars environment. This information will then form the basis for mitigation measures including: 1) future process modification or substitution, 2) special provisions for compound containment or use restrictions, 3) re-evaluation of current exposure standards, and 4) reprioritization of information needs (e.g., toxicology, effects on human performance, or re-evaluation of alternative-process mission requirements).

Ecological Systems, Closed↗
PubMed1990

Studies on the mechanism of 1,3-butadiene-induced leukemogenesis: the potential role of endogenous murine leukemia virus.

Previous studies have revealed marked differences in the incidence of leukemia between rats and mice exposed to 1,3-butadiene that do not appear to be readily explained on the basis of pharmacokinetics or metabolism. Chronic exposure to 1,3-butadiene results in a high incidence of thymic lymphoma in B6C3F1 mice that is not observed in Sprague-Dawley rats. Studies at the Chemical Industry Institute of Toxicology have focused on evaluating the potential of endogenous ecotropic retroviral background to influence susceptibility to 1,3-butadiene leukemogenesis. These studies have compared the pathogenesis and incidence of thymic lymphoma between B6C3F1 and NIH Swiss mice. Proviral ecotropic sequences are truncated in the NIH Swiss mouse, and the virus is not expressed. Chronic exposure to 1,3-butadiene (1250 ppm) for up to 1 year resulted in a fourfold difference in the incidence of thymic lymphoma between B6C3F1 and NIH Swiss mice. These results provide presumptive evidence for retrovirus involvement since NIH Swiss mice lack ecotropic viruses and appear to be relatively resistant to induction of lymphoma by 1,3-butadiene. Other explanations appear to be less likely in light of the fact that target organ toxicity has been determined to be virtually identical between the two strains during the preleukemic phase of 1,3-butadiene exposure.

Animals↗
PubMed1989

Susceptibility to 1,3-butadiene-induced leukemogenesis correlates with endogenous ecotropic retroviral background in the mouse.

Previous studies have revealed marked differences in the pattern of carcinogenesis between rats and mice exposed to 1,3-butadiene (BD) that do not appear to be readily explained on the basis of pharmacokinetics or metabolism. Chronic exposure of B6C3F1 mice to BD produces a high incidence of thymic lymphoma (TL) that is not observed in rats. The potential of the endogenous ecotropic retroviral background to influence susceptibility to BD leukemogenesis was examined by comparing the incidence of TL between B6C3F1 and NIH swiss mice. Proviral ecotropic sequences are truncated in the NIH Swiss mouse, and the virus is not expressed. Chronic exposure to BD (1250 ppm) for up to 1 year resulted in a fourfold difference in the incidence of TL between B6C3F1 (57%) and NIH Swiss (14%) mice. These results provide presumptive evidence for retrovirus involvement since NIH Swiss mice lack ecotropic viruses and appear to be relatively resistant to induction of lymphoma by BD.

Animals↗