Department of Environmental Medicine, University of Rochester School of Medicine and Dentistry, 575 Elmwood Ave., Rochester, New York 14642
Received April 14, 2000; accepted July 12, 2000
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ABSTRACT |
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Key Words: 2,3,7,8-tetrachlorodibenzo-p-dioxin; mouse; bone marrow; B lymphopoiesis; time-course; dose response.
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INTRODUCTION |
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Administration of TCDD to rodents has been shown to produce a decreased immune functional response, resulting in increased susceptibility to tumor-cell growth, and to both bacterial and viral infections (Beebe et al., 1995; House et al., 1990
; Kerkvliet, 1995
; Pohjanvirta and Tuomisto, 1994
). Some of these effects have been attributed to suppression of the T-lymphocyte response (Clark et al., 1983
; House, et al., 1990
). The most frequently observed gross response to TCDD immunotoxicity is the induction of thymic hypoplasia, which occurs in a wide range of mammalian species (Pohjanvirta and Tuomisto, 1994
). Although the precise mechanism for this depletion of cortical thymocytes is not completely understood, recent research points to AHR-dependent changes in the hematopoietic compartment as being primarily responsible (Staples et al., 1998
). Another particularly sensitive immunotoxic effect attributed to TCDD is suppression of the primary antibody response to sheep red blood cells (SRBC). This response requires the presence of antigen-presenting cells (e.g., macrophages), regulatory T lymphocytes (e.g., CD4+ cells), and antibody-producing B lymphocytes. Evidence suggests that the TCDD-induced disruption of the SRBC response is attributable to a defect in the T lymphocyte response (Kerkvliet and Brauner, 1987
), although the exact primary cell target has yet to be determined.
Whereas the majority of studies assessing the immunotoxicity of TCDD have focused on T lymphocytes, several reports have shown that the B lymphocyte also is a target. Early work by Vecchi et al. (1980) indicated that acute treatment with TCDD depressed the primary B-cell response in C57BL/6 mice. Subsequent studies indicated that the degree of suppression correlated with the presence of the more sensitive allele of the AHR in these cells (Blank et al., 1987; Luster et al., 1985
; Tucker et al., 1986
). Other investigations have assessed B-cell toxicity elicited by TCDD (reviewed in Kerkvliet, 1995); however, the majority of these studies have focused on the impact of TCDD on the functionality of mature B cells, with little work addressing possible effects on development and maturation. Research by our group supports the hypothesis that TCDD affects early B-cell development. These studies demonstrated that TCDD reduced the levels of mRNA for lymphocyte stem cell-specific enzymes terminal deoxynucleotidyl transferase (TdT) and recombinase-activation gene-1 (RAG-1) in murine bone marrow (Fine et al., 1990
; Frazier et al., 1994a
,b
; Silverstone et al., 1994
). Although these studies focused on prothymocyte activity (Fine, et al., 1990
), the majority of TdT+/RAG+ bone marrow cells are of the B-cell lineage. Thus, it is plausible that TCDD also alters B-cell development.
Recently we demonstrated that a single dose of TCDD produced a decrease in less mature bone marrow B lymphocytes in male C57BL/6 mice at 10 days following treatment (Thurmond et al., 2000). To begin to identify the primary target cell(s) affected, we wanted to further assess the time- and dose-dependence of this B-cell change. Here we show that single-dose administration of TCDD produces temporal- and dose-related changes in the mature B-cell subpopulation. These data further suggest that the exposure to relatively low concentrations of TCDD affect the B cell-maturation process.
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MATERIALS AND METHODS |
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Animals
Male, four- to five-week-old C57BL/6J mice were obtained from Jackson Laboratory (Bar Harbor, ME) and kept in accordance with the University of Rochester, University Committee on Animal Resources and the American Association for Laboratory Animal Science guidelines. Animals were housed 3 or 4 per cage, given food (5001 Rodent Diet; Purina Mills, MO) and water ad libitum, and maintained on a 12-h light/dark schedule. All mice were acclimated in house for one week prior to treatment.
Treatment Protocol
Time course.
Five- to 6-week-old mice were divided into vehicle-treated and TCDD-treated groups containing at least 4 animals per group. Treated animals received 30 µg/kg body weight (bw) TCDD in olive oil, ip. This dose has been demonstrated in our laboratories to produce thymic atrophy in as little as 3 days and to produce decreases in bone marrow levels of both TdT and RAG-1 (Silverstone et al., 1994). Vehicle control animals received a comparable dose of olive oil (0.1 ml/20 g bw). Animals were administered either vehicle or TCDD at day zero and were euthanized on days 1, 2, 3, 6, 9, and 31. By 31 days, we had previously observed thymus weights of TCDD-treated animals to have returned to near vehicle-treated levels (Silverstone, et al., 1994
).
Dose response.
Animals, treatment groups, and route of dosing were as stated above. The doses of TCDD used were: 0.3, 3, 6, 9, 15, and 30 µg/kg bw. Animals were administered either vehicle or TCDD on day zero and were euthanized on day 2 (a time point at which significant changes in B-lymphocyte subpopulations were seen at the 30 µg/kg bw-TCDD dose). The day 2 sample point was chosen also to permit assessment of dose-related alterations in the hematopoietic progenitor cells, which have been shown to be significantly affected by TCDD (Murante and Gasiewicz, 2000).
Antibodies
The following monoclonal antibodies were used at predetermined saturating levels for detection of B lymphocytes: fluorescein isothiocyanate (FITC)-conjugated anti-mouse CD45R/B220 (clone RA3-6B2, rat IgG2a, ) (B220), phycoerythrin (PE)-conjugated anti-mouse CD24 (heat stable antigen) (clone M1/69, rat (DA) IgG2b,
), biotin-conjugated anti-AA4.1 (clone AA4.1), and biotin-conjugated anti-mouse IgM (clone R6-60.2, rat IgG2a). All antibodies were obtained from PharMingen (San Diego, CA), with the exception of the anti-mouse PE-AA4.1, which was obtained from Dr. Ihor Lemischka (MBI, La Jolla, CA) via Rochelle Diamond (CIT, Pasadena, CA) and Chromaprobe, Inc. (Mountain View, CA).
Bone Marrow Cell Isolation
Mice were euthanized by CO2 asphyxiation. Femurs and tibiae were removed and the marrow cavities flushed with 10 ml of Hank's Minimum Essential Medium (GIBCO/BRL, Grand Island, NY) (HMEM) containing 5% fetal bovine serum and Penicillin-Streptomycin (P/S/; 100U/ml penicillin, 0.1 mg/ml streptomycin; GIBCO/BRL). The marrow cells were placed in suspension by successive passage through 22- and 25-gauge needles and filtered through 80-micron nylon mesh (TETKO Inc., Briarcliff Manor, NY) to remove any remaining debris. The filtered cells were then pelleted by centrifugation at 300 x g for 6 min. The pellet was resuspended in 1 ml of lysis buffer (0.17 M NH4Cl, 10 mM KHCO3, 1 mM EDTA, pH 7.4) for 4 min to remove red blood cells. The cells were then washed once, repelleted, and the pellet resuspended in HMEM, to a volume of 5 ml, for cell counting. The cell yield was enumerated by diluting the cells and counting at least 2 samples for each cell preparation with a Neubauer hemocytometer. Cell viability was determined to be > 90% by trypan-blue dye (0.08%) exclusion.
Cell Staining and Flow Cytometric Analysis
Freshly isolated bone marrow cells from each mouse were pelleted by centrifugation and washed in Hank's Balanced Salts Solution with Ca2+ and Mg2+ (GIBCO/BRL), containing 0.2% bovine serum albumin (BSA) (HBSS-0.2%BSA). Following the wash, each pellet was resuspended in HBSS-0.2%BSA to a concentration of 1 x 107 cells/ml. Aliquots of 1 x 106 cells were then pre-blocked on ice for 15 min with anti-FcIII/IIR (clone 2.4G2, Rat IgG2b) (Fc Block; PharMingen) to reduce nonspecific binding. The cells were next incubated in the primary antibodies (anti-mouse FITC-CD45R/B220 plus anti-mouse biotin-IgM, and anti-mouse FITC-CD45R/B220 plus anti-mouse PE-CD24 plus anti-mouse biotin-AA4.1) for 30 min on ice. Following this procedure, the cells were washed twice in HBSS-0.2% BSA and the cells receiving the biotinylated antibodies were incubated in Streptavidin-Cy-Chrome® (PharMingen) for 30 min on ice. Negative and positive control cell tubes containing unstained cells, primary antibodies alone, isotype antibodies alone, and Streptavidin-Cy-Chrome alone were run simultaneously. After completion of staining, the cells were washed twice in HBSS-0.2%BSA and fixed in 1% paraformaldehyde (in Dulbecco's Phosphate Buffered Saline; GIBCO/BRL). Fixed cells were stored at 4°C and all samples were analyzed within 3 days.
Data on the fixed bone marrow cells were acquired on a Becton Dickinson (BD) FACSCAN® flow cytometer (Mountain View, CA) with BD LYSYS II® software, and were analyzed using BD CellQuest® software (version 3.1). Fifty thousand events were acquired and analyzed for each sample (Fig. 1, left panel), and B220-positive cells within this gate were analyzed. Figure 1
(right panel) is a representative dot plot from a vehicle-treated animal showing the bone marrow B-lymphocyte subpopulations within the viable cell gate, using 2-color staining with B220 and IgM antibodies. Three subpopulations of B lymphocytes are evident: B220lo/IgM, B220lo/IgM+, and B220hi/IgM+, which correspond, respectively, to pro/pre-B, immature B, and mature B lymphocytes (Hardy et al., 1991
). The choice of the 3 B-cell subpopulations defined by CD45R/B220 and IgM staining was made to allow for tracking of TCDD-mediated changes to subsets that encompassed all the developmental stages of the B lymphocyte (Hardy, et al., 1991
). Additionally, these subpopulations could be statistically analyzed, due to the reproducible gating between animals within each experiment. Gate coordinates for each B-lymphocyte subpopulation were set using vehicle-treated bone marrow, and were maintained for all animals analyzed in each experiment. Subpopulations of B cells were expressed as a percent of the total cells within the viable cell gate. The cells in the pro/pre-B, immature-B, and mature-B subpopulations were found to represent 93%97% of all cells in the viable cell gate staining for B220 in all groups with no correlation to treatment regimen (data not shown). No significant differences were observed between TCDD- and vehicle-treated animals for total numbers of mononuclear cells recovered from the bone marrow (data not shown).
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RESULTS |
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Experiments were also conducted to determine whether lower doses of TCDD would produce similar changes to the B-cell subpopulations as those observed at 30 µg/kg bw. Administration of TCDD at 15, 9 and 6 µg/kg bw also produced significant effects on the mature B-lymphocyte subset at day 2 following treatment (Fig. 5). No changes in this subpopulation were observed at doses of 3 and 0.3 µg/kg bw (Fig. 5
), and no changes were observed in either the pro/pre-B or immature B subpopulations at any of the doses tested.
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DISCUSSION |
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Time-dependent changes elicited by TCDD are characterized by an apparent increase in the mature subpopulation within 1 day following TCDD administration, followed by a gradual decrease by 9 days and a return to near vehicle control levels by 31 days (Fig. 4). Concurrent decreases in the less mature subpopulations at days 3, 6, and 9 were also observed (Fig. 4
). Additionally, at 9 days we also observed an increase in the earliest B-lymphocyte progenitor subpopulation (Fig. 4
). The marked increase in the mature B-cell subpopulation at 24 h following dosing suggests that TCDD may have a direct effect upon bone-marrow B lymphocytes, or upon bone-marrow stromal cells (i.e., non-hematopoietic), which produce growth factors and cytokines necessary for maturation. The rapid shift to the mature phenotype following TCDD administration might be due to an accelerated movement of the B-cell progenitors through the maturation cycle via modulation of cytokines involved in B-lymphocyte development. Several researchers have demonstrated that TCDD alters production of T lymphocyte-associated cytokines in the thymus (Lai et al., 1997
) and in the spleen (Kerkvliet et al., 1996
; Prell et al., 1995
), although no studies to date have shown alterations in bone marrow stromal B lymphocyte-associated cytokines.
In a previous study utilizing chimeric mice containing AHR+ and/or AHR- hematopoietic and/or stromal cell populations, we have shown that AHR must be present in both the hematopoietic and non-hematopoietic compartments for TCDD to affect the B-lymphocyte maturation profile (Thurmond, et al., 2000). Several studies have shown that AHR is found both in bone marrow stromal cells (Lavin et al., 1998
) and in splenic B lymphocytes (Blank, et al., 1987
; Sulentic et al., 1998
; Tucker, et al., 1986
). However, Yamaguchi et al. (1997) were unable to detect AHR in sorted CD45/B220+ primary bone-marrow cells from C57BL/6 mice. Their inability to detect the AHR could be due to the receptor's presence in only a small subpopulation of the B220+ cells. Several researchers have shown that the AHR can be down-regulated in various tissues (Dohr et al., 1997
; Eltom et al., 1998
; Giannone et al., 1995
; Reick et al., 1994
; Reiners et al., 1997
), and Crawford et al. (1997) demonstrated that the AHR was upregulated in leukocytes following their activation. Given these findings, it is possible that the receptor's presence in the B cell may vary with stage of development, and that this variation in expression may result in altered control of the production of, or sensitivity to, regulatory cytokines.
An alternate explanation to a TCDD-induced rapid shift to a mature B-cell phenotype is that TCDD treatment mediates, directly or indirectly, a developmental arrest of the mature B-cell subpopulation, defined here by the B220hi/IgM+ phenotype. This arrest may prevent their release into the peripheral circulation and result in the increase in their relative number in bone marrow. Expression and engagement of the B-cell receptor (BCR) during this point in development determines both positive and negative selection processes, as well as release from bone marrow. These processes are mediated and modulated by several signal-transduction pathways (for review see King et al., 1998, (1998)), the proteins of which (e.g., nuclear factor-B and CD19) may be affected by inappropriate activation of the AHR (Masten and Shiverick, 1995
; Tian et al., 1999
).
In particular CD19, a B cell-specific protein tyrosine phosphatase, is thought to modulate BCR-induced responses (Fearon and Carter, 1995). A major binding site for B cell-specific activator protein (BSAP) is located in the promoter region of the gene encoding CD19 (Busslinger and Urbanek, 1995
). Previous results have indicated that the TCDD-activated AHR complex binds to the BSAP site on the CD19 gene producing a decreased CD19 mRNA expression in human B-lymphoblast cell lines (Masten and Shiverick, 1995
). Thus, it is possible that TCDD may alter CD19 expression and subsequent modulation of selection processes. TCDD may also directly elicit an arrest in cell cycle at this developmental stage. Several reports indicate that the AHR may be involved in cell cycle regulation (Dohr and Abel, 1997
; Ma and Whitlock, 1996
; Puga et al., 2000
; Weiss et al., 1996
). Recent data have suggested that TCDD does induce inhibition of thymic development through altered cell cycle regulation (Kolluri et al., 1999
). Additional research is needed to determine whether TCDD may have a similar effect on B lymphopoiesis as well as to determine the effect of TCDD on expression of CD19.
A block in further maturation at the mature B-cell stage may also explain the subsequent changes to the more immature subpopulations. It is possible, for example, that feedback mechanisms, based on the numbers of cells in the mature subpopulation, regulate the numbers of precursors moving into the immature stage. This is supported by the decrease in pro/pre-B and immature B subpopulations at days 3, 6, and 9 (Fig. 4), as well as by the significant decrease in total B220+ cells in the viable gate at these time points. These decreases also correlate with the observed increase in the earliest B-cell progenitor phenotype (B220+/CD24/AA4.1+) at that time (Fig. 4
). Additionally, the pro/pre-B subset has been shown to be positive for the developmental TdT and RAG-1 (reviewed in Hardy et al., 1998), and the decrease in this subset at days 6 and 9 is consistent with previous work from our laboratories showing that these 2 markers are reduced between days 6 and 12 following treatment with TCDD (Silverstone et al., 1994
). The present data imply that these changes in TdT and RAG-1 are not primary effects of TCDD but secondary to earlier effects on other subpopulations in bone marrow. We have also shown that TCDD treatment produces an elevation in the pluripotent bone marrow hematopoietic progenitors delineated by expression of Sca-1 and c-kit antigens on lineage negative cells at one day following exposure (Murante and Gasiewicz, 2000
). The subsequent recovery of all 3 B-cell subpopulations to near vehicle-treated levels by day 31 following TCDD treatment indicates that single-dose administration apparently does not have irreversible long-term effects on B lymphocytes, at least in young adult animals.
The dose-response results (Fig. 5) show that doses as low as 6 µg/kg bw TCDD can have an effect in vivo on maturation of small B lymphocytes at 2 days following dosing. The only B-cell subset consistently affected by TCDD treatment was the mature subpopulation that was significantly elevated at all doses down to 6 µg/kg bw. This alteration of only the mature subpopulation at the lower TCDD doses further supports a primary, although possibly indirect, effect of TCDD on cells at this developmental stage.
The results from the present study support our findings from research assessing the role of AHR on B-cell maturation in null allele (AHR/) mice (Thurmond, et al., 2000). In that investigation we observed that vehicle-treated AHR/ animals had elevated numbers of both pro/pre B and immature B cells with no change in the mature subpopulation versus the wild type control animals. Treatment of these animals with TCDD produced no change in the B-lymphocyte profile indicating the dependence on the presence of the AHR. Our present data show that in wild type animals the activation of the AHR by TCDD produces elevated numbers of mature cells while there is a subsequent decrease in the less mature subpopulations (Fig. 4
). These contrasting B-cell profiles suggest that AHR may play an active role in mediating normal murine B lymphopoiesis, possibly representing one pathway of B cell-maturation regulation in response to an, as yet unidentified, endogenous ligand.
The data from this study lends support for the findings of other researchers who showed that a functional deficit exists in those B lymphocytes recovered from TCDD-treated animals (Blank et al., 1987; Luster et al., 1985
; Tucker et al., 1986
; Vecchi et al., 1980
). Our data may also help to explain the changes in human lymphocytes reported in some studies following in vitro treatment with TCDD (Kerkvliet, 1995
; Lang et al., 1998
; Spencer et al., 1999
), and in human in vivo studies subsequent to occupational and accidental TCDD exposure (Jung et al., 1998
; Kerkvliet, 1995
; Nagayama et al., 1998
). It should be noted, however, that because the functionality of the B lymphocytes was not assessed in our study, no definitive conclusions can be drawn as to the relationship of the B-cell changes we observed to those reported by these researchers.
In conclusion, our study has established for the first time that the effect of TCDD on bone marrow B-lymphocyte maturation occurs rapidly and initially produces its greatest change on the mature subpopulation. The alterations in the maturation profiles are time-dependent, with greatest depletion of those cells in the less mature and mature subpopulations occurring at 6 and 9 days post-dosing. These data suggest that the initial TCDD-induced cellular change is primarily on those cells entering, and/or within, the mature subpopulation, and the resulting alteration in the B-cell progenitors is a reaction to the effect on these cells. Additional studies are planned to further define the precise B-cell maturation stage at which the TCDD-induced change is initiated, and the cell target(s) mediating this change.
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ACKNOWLEDGMENTS |
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NOTES |
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1 To whom correspondence should be addressed at the University of Rochester, Department of Environmental Medicine, 575 Elmwood Ave., Box EHSC, Rochester, NY 14642. Fax: (716) 2572591. E-mail: tom_gasiewicz{at}urmc.rochester.edu.
2 It should be noted that while this publication was in preparation, Tudor et al. (2000) reported that, contrary to the findings of Li and colleagues, they have identified a cell subset that is negative for CD45R and positive for CD24, which they consider to be the earliest B-cell progenitor. This finding will need to be addressed in subsequent research.
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