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Research
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| Neutrophil Function after Exposure to Polychlorinated Biphenyls in vitro Patricia E. Ganey,1,2,3 Jay E. Sirois,1 Michael
Denison,3,4 J. Paul Robinson,5 and Robert A. Roth1,3
1Department of Pharmacology and Toxicology, 2Department
of Medicine, 3Institute for Environmental Toxicology, and 4Department
of Biochemistry, Michigan State University, East Lansing, MI 48824 USA;
5Purdue University Cytometry Laboratories and Department of Veterinary
Physiology and Pharmacology, Purdue University, West Lafayette, IN 47906
USA Abstract
Polychlorinated biphenyls (PCBs) are known to be immunotoxic, yet the effects on neutrophil (PMN) function are not well characterized. We incubated PMNs isolated from rat peritoneum with a mixture of PCB congeners, Aroclor 1242, in the absence or presence of either phorbol myristate acetate (PMA) to stimulate generation of superoxide anion (O2-) or N-formyl-methionyl-leucyl-phenylalanine (fMLP) to induce degranulation (measured as release of ß-glucuronidase) . Aroclor 1242 alone stimulated O2- production at a concentration of 10 µg/ml. Significant cytotoxicity was not observed under these conditions. This concentration of Aroclor 1242 also increased O2- generation in PMNs activated with 20 ng PMA/ml. In the presence of a concentration of PMA (2 ng/ml) that by itself did not stimulate production of O2-, 1 µg Aroclor 1242/ml caused significant generation of O2-, indicating synergy between Aroclor 1242 and PMA. Aroclor 1242 caused release of ß-glucuronidase from quiescent PMNs ; however, in PMNs stimulated with fMLP to undergo degranulation, Aroclor 1242 inhibited release of ß-glucuronidase. The effects of two PCB congeners, one that binds to the Ah receptor (3,3´,4,4´-tetrachlorobiphenyl) and one that has little affinity for this receptor (2,2´,4,4´-tetrachlorobiphenyl) were examined. 3,3´,4,4´-Tetrachlorobiphenyl had no effect on PMN function in vitro, whereas 2,2´,4,4´-tetrachlorobiphenyl had effects similar to those observed with Aroclor 1242. These results indicate that PCBs affect PMN function in vitro in a complex manner, stimulating or inhibiting function under different conditions. These effects are apparently not mediated through the Ah receptor. Key words: Ah receptor, degranulation, neutrophils, polychlorinated biphenyls, superoxide anion. Environ Health Perspect 101:430-434 (1993)
Address correspondence to P.E. Ganey, Department of Pharmacology and Toxicology, Life Sciences Building, Michigan State University, East Lansing, MI 48824 USA. This work was supported by grant ES04911 from NIEHS. R.A.R. was supported in part by a Burroughs Wellcome Toxicology Scholar Award. We thank Maria Colligan, Dianne Schwartz, and Eric Shobe for excellent technical assistance. Received 2 February 1993 ; acccepted 21 June 1993. |
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Introduction
Polychlorinated biphenyls (PCBs) are persistent environmental contaminants.
Exposure to PCBs is associated with a variety of biological effects including
induction of enzymes involved in xenobiotic metabolism, alterations in reproductive
function, hepatotoxicity, carcinogenicity, and dermal lesions. Thymic atrophy
is a consistent finding in PCB-treated animals, and alterations in immunity
after exposure to PCBs have been reported (1). For example, monkeys
fed Aroclor mixtures of PCBs for 11 months had lower anti-sheep red blood
cell titers and decreased concentrations of  -globulin compared
to controls (2). The splenic plaque-forming cell response to sheep
red blood cells was suppressed in mice exposed acutely to Aroclor mixtures
of PCBs (3) or to the coplanar PCB congener 3,3´,4,4´-tetrachlorobiphenyl
(1). In humans accidentally exposed to PCBs, decreases in the total
number of T-lymphocytes (4) and in the percentage of peripheral T-lymphocytes
(5), as well in the concentrations of IgM and IgA in serum (5),
were reported.
Although effects of PCBs on cell-mediated and humoral immunity have been
investigated, little is known about the effects of PCBs on polymorphonuclear
leukocytes (PMNs), which contribute to nonspecific immunity. One study reported
that 3,3´,4,4´-tetrachlorobiphenyl decreased generation of leukotriene
B4 from human PMNs stimulated with sodium fluoride (6).
Because sodium fluoride activates G-proteins, which results in metabolism
of arachidonic acid and subsequent formation of leukotrienes, the authors
speculated that the interaction of sodium fluoride and PCBs with PMNs induced
synthesis of a set of inhibitory G-proteins that reduced leukotriene formation.
Interestingly, in the same study, exposure to 3,3´,4,4´-tetrachlorobiphenyl
increased leukotriene B4 release from opsonized zymosan-stimulated
PMNs and from PMNs pretreated with sodium fluoride, suggesting that PCBs
enhance the generation of leukotrienes once production has been initiated.
Thus, one function of PMNs is either inhibited or augmented, depending on
the experimental conditions. To extrapolate this observation to possible
consequences if this happened in vivo, suppression of PMN function
by PCBs could lead to increased susceptibility to infection. Alternatively,
activation of PMNs has been implicated in tissue injury in a variety of
disease models.
To begin to explore possible alterations in PMN function caused by PCBs,
the effect of in vitro exposure to Aroclor 1242, a complex mixture
of PCB congeners, on PMN function was evaluated. Some biological effects
of PCBs, for example, induction of hepatic aryl hydrocarbon hydroxylase
activity (7), are mediated through binding to the Ah receptor, a
cytosolic receptor that binds to PCBs. The resultant receptor-ligand complex
translocates to the nucleus and alters gene expression to initiate toxic
and other biologic effects. Binding to the Ah receptor and biological activity
depend on the structure of individual congeners, such that coplanar PCB
congeners (e.g., 3,3´,4,4´-tetrachlorobiphenyl) have the greatest
affinity for the receptor (7). To test the potential role of binding
to the Ah receptor in initiating alterations in PMN function produced by
Aroclor 1242, we examined the effects of two PCB congeners, one which binds
with high affinity to the Ah receptor and one that has little affinity for
the receptor (8).
Materials and Methods
Aroclor 1242, 2,2´,4,4´-tetrachlorobiphenyl (>99% pure),
and 3,3´,4,4´-tetrachlorobiphenyl (>99% pure) were purchased
from ChemService (West Chester, Pennsylvania). Phorbol myristate acetate
(PMA) was purchased from LC Services (Woburn, Massachusetts), and superoxide
dismutase (SOD) was obtained from Diagnostic Data, Inc. (Mountainview, California).
We obtained [3H]-2,3,7,8-tetrachlorodibenzo-p-dioxin ([3H]TCDD)
and 2,3,7,8-tetrachlorodibenzofuran, used in determining the presence of
Ah receptors in rat PMNs, from Stephen Safe (Texas A & M University).
All other chemicals were of the highest grade commercially available.
We isolated glycogen-elicited PMNs from the peritoneum of male Sprague-Dawley,
retired breeder rats [CD-Crl:CD (SD)BR VAF/Plus; Charles River Laboratories,
Portage, Michigan], as described previously (9). Briefly, 30-40 ml
of 1% glycogen in sterile saline was injected into the peritoneum of rats
anesthetized with diethylether. Four hours later the rats were anesthetized
again with diethylether and were killed by decapitation. We rinsed the peritoneum
with 30 ml of 0.1 M phosphate-buffered saline (PBS) containing 1 U/ml heparin.
The rinse solution was filtered through gauze and centrifuged for 7 min
at 500g. We lysed contaminating red blood cells in 15 ml of 0.15
M NH4Cl, and then centrifuged the PMNs for 7 min at 300g.
Cells were washed once with PBS, then resuspended in Hanks' balanced salt
solution (HBSS). The final concentration of PMNs in the assays was 2 x 106
cells/ml. The percentage of PMNs in the cell preparation was routinely >95%,
and viability (i.e., ability to exclude trypan blue dye) was >95%.
PMNs were stimulated with either N-formyl-methionyl-leucyl-phenylanine
(fMLP) in the presence of cytochalasin B (5 µg/ml) or with PMA. Concentrations
of fMLP and PMA were chosen based on previous studies in which these concentrations
were shown to stimulate degranulation (9) or superoxide anion production
(10), respectively.
For measurement of superoxide anion (O2-) generation,
Aroclor 1242 was dissolved in methanol, 3,3´,4,4´-tetrachlorobiphenyl
was dissolved in dimethylformamide, and 2,2´,4,4´-tetrachlorobiphenyl
was dissolved in 50% acetone/50% dimethylsulfoxide. We added 1 µl
of the stock solutions to 1 ml of HBSS containing the suspended PMNs to
achieve the desired final concentrations. Control PMNs received an equivalent
volume of the appropriate vehicle. Preliminary studies indicated that none
of the vehicles affected O2- production at the concentrations
used.
We incubated PMNs at 37°C with PCBs for 30 min. PMA was
then added, and samples were incubated for an additional 10 min. We measured
O2- generated during this 40-min period spectrophotometrically
as the SOD-sensitive reduction of ferricytochrome C (11). For every
sample, two tubes were incubated: one to which SOD (85 U/ml) was added before
incubation and one to which SOD was added after incubation. We used the
difference in absorbance (550 nm) of the cell-free supernatant fluids from
these two tubes to estimate the amount of cytochrome C reduced, using an
extinction coefficient of 18.5 cm-1mM-1.
To study the degranulation response, PMNs were incubated with PCBs at
37°C in the presence of cytochalasin B for 10 min. We then
added fMLP and incubated the cells for another 10 min. The activity of ß-glucuronidase
in the cell-free supernatant fluids was measured as the release of phenolphthalein
from its glucuronide at pH 4.5 during incubation at 37oC (12).
We determined total ß-glucuronidase activity in PMNs lysed with 1%
Triton X-100 and sonication, and values are presented as the percentage
of total ß-glucuronidase released into the buffer. The presence of
PCBs did not interfere with determination of the activity of ß-glucuronidase.
We estimated cytotoxicity from release of the cytosolic enzyme lactate
dehydrogenase (LDH). PMNs were incubated with PCBs in the absence or presence
of PMA as described above for measurement of generation of O2-.
We determined the activity of LDH in the cell-free supernatant fluids according
to the method of Bergmeyer and Bernt (13). A separate aliquot of
PMNs was lysed with Triton X-100 and sonication, and total LDH activity
was determined in the cell-free supernatant fluids from these lysates. Cytotoxicity
is expressed as the percentage of total LDH activity released into the buffer.
The presence of PCBs did not interfere with determination of the activity
of LDH.
Specific binding of [3H]TCDD to cytosol from rat peritoneal
PMNs was determined using the hydroxylapatite binding assay (14).
Receptor concentrations are presented as femtomoles of [3H]TCDD
specifically bound per milligram of protein.
Results are presented as means + SEM. For all results presented,
n represents the number of repetitions of an experiment, and each
experiment used cells from different rats. Data were analyzed by analysis
of variance. We transformed data that did not safisfy the criterion of homogeneity
before further statistical analysis. Individual means were compared using
the Student-Newman-Keuls' test. For all studies, the criterion for significance
was p <0.05.
Results
Quiescent PMNs produced no O2-, and incubation
with Aroclor 1242 up to 1 µg/ml did not stimulate generation of O2-
(Fig. 1). When PMNs were exposed to Aroclor 1242 at a concentration of 10
µg/ml for 30 min, a significant amount of O2-
was produced.
Figure 1. Superoxide
anion generation by PMNs exposed to Aroclor 1242. Glycogen-elicited peritoneal
PMNs (2 x 106/ml) were incubated for 30 min in the presence of
Aroclor 1242 (at the concentrations indicated) or an equivalent volume of
vehicle (methanol), followed by an additional 10-min incubation with PMA.
O2- produced over this 40-min period was determined
as described in Materials and Methods (n = 4-6). aSignificantly
different from respective value with 0 µg Aroclor 1242/ml; bsignificantly
different from respective value with 0 ng PMA/ml.
Incubation of PMNs with 20 ng PMA/ ml, but not 2 ng PMA/ml, caused significant
generation of O2- compared to quiescent PMNs. A significant
increase in O2- generation was observed at 1 and 10
µg/ml Aroclor 1242 when PMNs were treated with 2 ng PMA/ml. In PMNs
activated with 20 ng PMA/ml, effects of Aroclor 1242 were similar to those
seen in the absence of PMA: increased production of O2-
was observed only at 10 µg Aroclor 1242/ml.
About 7% of the total ß-glucuronidase activity appeared in the
medium above quiescent PMNs (Fig. 2). Incubation with Aroclor 1242 at concentrations
of 1 µg/ml and higher increased release of ß-glucuronidase from
PMNs.
Figure 2. Release
of ß-glucuronidase from PMNs exposed to Aroclor 1242. Glycogen-elicited
peritoneal PMNs (2 x 106/ml) were incubated for 10 min in the
presence of Aroclor 1242 (at the concentrations indicated) or an equivalent
volume of vehicle, followed by an additional 10-min incubation with fMLP.
Cytochalasin B (5 µg/ml) was present in all samples. Activity of ß-glucuronidase
released into the medium was determined as described in Materials and Methods.
Total ß-glucuronidase activity was 1.36 + 0.11 U/106
PMNs (n = 3-5). aSignificantly different from respective
value with 0 µg Aroclor 1242/ml; bsignificantly different
from respective value with 0 nM fMLP.
In the absence of Aroclor 1242, a concentration-related increase in the
percentage of ß-glucuronidase released by control PMNs was observed
with fMLP stimulation (Fig. 2). Exposure to Aroclor 1242 did not affect
release of ß-glucuronidase from PMNs stimulated with 1 nM fMLP. In
PMNs stimulated with higher concentrations of fMLP, Aroclor 1242 (10 µg/ml)
inhibited degranulation in response to fMLP.
LDH release was increased when PMNs were incubated with 10 µg Aroclor
1242/ml (Fig. 3). These values reached statistical significance only when
PMNs were co-incubated with PMA.
Figure 3. Release
of lactate dehydrogenase (LDH) from PMNs exposed to Aroclor 1242. PMNs were
incubated as described in the legend to Figure 1, and LDH activity released
by the PMNs was determined as described in Materials and Methods. Total
LDH activity was 85 + 34 U/103 PMNs (n = 4-6).
aSignificantly different from respective value with 0 µg
Aroclor 1242/ml.
Because some effects of PCBs are mediated through the Ah receptor, it
was of interest to determine the presence and concentration of the Ah receptor
in rat PMNs. In cytosol from glycogen-elicited PMNs, 14.2 + 2.5 fmol
[3H]TCDD/mg protein were specifically bound. This value is consistent
with that reported for mouse peritoneal PMNs (18-25 fmol/mg protein) (15).
Exposure to 3,3´,4,4´-tetrachlorobiphenyl did not affect
generation of O2- in the absence or in the presence
of PMA (Fig. 4A). Release of ß-glucuronidase from PMNs was also unaffected
by incubation with 3,3´,4,4´-tetrachlorobiphenyl (Fig. 4B).
This lack of effect was observed in both the absence and the presence of
fMLP. LDH release by PMNs was unaffected by exposure to 3,3´,4,4´-tetrachlorobiphenyl
(Fig. 5).
Figure 4. Superoxide
anion generation (A) and release of ß-glucuronidase (B) by PMNs exposed
to 3,3´,4,4´-tetrachlorobiphenyl. Experiments were performed
as described in the legends to Figure 1 and 2. The vehicle used for controls
was dimethylformamide. Total ß-glucuronidase activity was 1.10 +
0.07 U/106 PMNs (n = 5). bSignificantly different
from respective value without PMN stimulus.
Figure 5. Release
of lactate dehydrogenase (LDH) from PMNs exposed to 3,3´,4,4´-tetrachlorobiphenyl.
PMNs were incubated as described in the legend to Figure 1, and LDH activity
released by the PMNs was determined as described in Materials and Methods.
Total LDH activity was 54 + 4 U/103 PMNs (n = 5).
aSignificantly different from respective value with 0 µg
3,3´,4,4´-tetrachlorobiphenyl/ml.
In the absence of PMA, 2,2´,4,4´-tetrachlorobiphenyl did
not stimulate production of O2- (Fig. 6A). In the
presence of PMA, concentrations of 2,2´,4,4´-tetrachlorobiphenyl
of 1 and 10 µg/ml increased generation of O2-.
Figure 6. Superoxide
anion generation (A) and release of ß-glucuronidase (B) by PMNs exposed
to 2,2´,4,4´-tetrachlorobiphenyl. Experiments were performed
as described in the legends to Figures 1 and 2. The vehicle used for controls
was 50% acetone/50% dimethylsulfoxide. Total ß-glucuronidase activity
was 1.35 + 0.16 U/106 PMNs. (A) n = 5; (B) n
= 4. aSignificantly different from respective value with 0 µg
2,2´,4,4´-tetrachlorobiphenyl/ml; bsignificantly
different from respective value without PMN stimulus.
In the absence of fMLP, 2,2´,4,4´-tetrachlorobiphenyl did
not significantly affect release of ß-glucuronidase from PMNs (Fig.
6B). Beta-glucuronidase release from PMNs exposed to 2,2´,4,4´-tetrachlorobiphenyl
was not affected by addition of fMLP at a concentration of 1 nM. When PMNs
were activated with higher concentrations of fMLP, exposure to 2,2´,4,4´-tetrachlorobiphenyl
(1 or 10 µg/ml) inhibited the fMLP-stimulated release of ß-glucuronidase.
Exposure to 10 µg 2,2´,4,4´-tetrachlorobiphenyl/ml
increased release of LDH, and this was only statistically significant when
PMNs were also exposed to PMA (Fig. 7).
Figure 7. Release
of lactate dehydrogenase (LDH) from PMNs exposed to 2,2´,4,4´-tetrachlorobiphenyl.
PMNs were incubated as described in the legend to Figure 1, and LDH activity
released by the PMNs was determined as described in Materials and Methods.
Total LDH activity was 58 + 7 U/103 PMNs (n = 5).
aSignificantly different from respective value with 0 µg
2,2´,4,4´-tetrachlorobiphenyl/ml.
Discussion
In the present study, the function of rat PMNs was affected by exposure
to PCBs in vitro. Aroclor 1242 stimulated O2-
generation in a dose-related manner (Fig. 1). Production of O2-
by PMA-activated PMNs was also altered. Two concentrations of PMA were used
in these studies: one that does not cause significant production of O2-
(2 ng/ml), and one that does (20 ng/ml). The purpose of using the smaller
concentration of PMA was to allow detection of synergy between PCBs and
a known activator of PMNs. Such a synergistic effect was observed with Aroclor
1242: the concentration-response curve to Aroclor 1242 shifted to the left
in the presence of 2 ng PMA/ml. This effect on O2-
production occurred in the absence of significant cytotoxicity to the PMNs,
decreasing the likelihood that the increased generation of oxygen free-radicals
occurred in response to cell injury. The mechanism by which PCBs enhance
O2- generation by PMNs is unknown. PCBs might increase
O2- generation through effects on protein kinase C
(PKC). Activation of PKC is associated with generation of O2-
in PMNs stimulated with PMA (16), and PCBs have been reported to
activate PKC directly (17-19). Alternatively, PCBs may increase
the rate of generation of O2-.
Several reports suggest that PCBs have effects on immunity. For example,
exposure to PCBs in vivo caused suppression of humoral immunity in
mice and monkeys (1-3,20). In mice this effect was
related to the chlorine content of PCB mixtures: those mixtures with a higher
percentage of chlorine were more potent immunosuppressants (3). Many
of the biological effects of PCBs and other halogenated aromatic hydrocarbons
correlate with binding affinity for the Ah receptor (8), with TCDD
having the highest affinity for the receptor. Accordingly, several of the
immunotoxic effects of PCBs appear to be mediated through the Ah receptor.
Treatment of mice with a coplanar congener (3,3´,4,4´-tetrachlorobiphenyl)
that binds to the Ah receptor with high affinity resulted in inhibition
of the primary direct splenic antibody response, whereas treatment with
a congener with lower affinity for the Ah receptor (2,2´,5,5´-tetrachlorobiphenyl)
did not alter this response (1). In addition, 3,3´,4,4´-tetrachlorobiphenyl
was immunotoxic in C57BL/6J mice, which are sensitive to TCDD and have high
affinity Ah receptors, but not in DBA/2J mice, which have defective Ah receptors.
These results suggest that the Ah receptor may play a role in producing
immunotoxic effects.
This hypothesis is supported by the observation that TCDD itself is immunotoxic.
Cell-mediated immunity was suppressed by TCDD in a dose-related manner (21).
Treatment of mice with TCDD resulted in decreased generation of cytotoxic
T-lymphocytes (22) and suppression of differentiation of B-cells
(23). In addition, decreased resistance to Salmonella infections
has been reported (24). Alterations in PMN function have also been
reported after exposure of mice to TCDD (15). B6C3F1 mice
are TCDD sensitive and have high-affinity Ah receptors. Acute exposure of
B6C3F1 mice to TCDD resulted in inhibition of PMA-stimulated,
PMN-mediated cytolysis of tumor cells (15). In contrast, function
was not altered in PMNs from TCDD-treated DBA/2N mice.
Unlike effects on PMNs observed after TCDD exposure of mice in vivo
(15), our results suggest that effects observed after exposure
of rat PMNs to PCBs in vitro are not Ah receptor-mediated. 2,2´,4,4´-Tetrachlorobiphenyl
has little affinity for the Ah receptor and produces a phenobarbital-like
induction of drug-metabolizing enzymes, whereas 3,3´,4,4´-tetrachlorobiphenyl
binds to the Ah receptor with high affinity and causes induction of drug-metabolizing
enzymes similar to that seen with TCDD (8). Effects on PMN function
similar to those seen with Aroclor 1242 were observed when PMNs were exposed
to 2,2´,4,4´-tetrachlorobiphenyl (Fig. 6A), but 3,3´,4,4´-tetrachlorobiphenyl
did not alter O2- production by PMNs (Fig. 4A). The
difference between results presented here and those observed in mouse PMNs
after exposure in vivo may be due to the difference in exposure regimens
(i.e., in vivo versus in vitro) or the choice of species.
In addition, although [3H]TCDD bound specifically to cytosol
from rat PMNs, indicating the presence of Ah receptors that bind ligand,
it is not known whether these receptors are functional.
It is unlikely that 2,2´,4,4´-tetrachlorobiphenyl in the
Aroclor mixture accounted entirely for the effects observed with Aroclor
1242 because 2,2´,4,4´-tetrachlorobiphenyl was no more potent
than the mixture. It is probable that alterations in PMN function after
exposure to Aroclor 1242 are at least partly due to non-coplanar PCB congeners
present in the mixture and also to additive, cooperative, or synergistic
effects of congeners.
Although exposure to PCBs enhanced the respiratory burst of PMNs in
vitro, the effects on degranulation were more complex. In unstimulated
PMNs and in PMNs treated with a subthreshold concentration of fMLP, exposure
to Aroclor 1242 caused release of ß-glucuronidase from the cells.
However, Aroclor 1242 attenuated fMLP-induced enzyme release. fMLP binds
to a specific receptor to stimulate degranulation, and one possible explanation
for the effects seen with Aroclor 1242 is that it acts as a weak or partial
agonist at the fMLP receptor. Alternatively, the Aroclor 1242-induced stimulation
of degranulation in quiescent PMNs and the inhibition of fMLP-induced activation
may occur by two different mechanisms. These effects occurred only at a
concentration of Aroclor 1242 at which cytotoxicity was observed, and it
cannot be ruled out that cytotoxicity to the PMNs contributed to inhibition
of degranulation.
As with effects on generation of O2-, effects of
PCBs on degranulation do not appear to be mediated through the Ah receptor,
because 3,3´,4,4´-tetrachlorobiphenyl was ineffective but 2,2´,4,4´-tetrachlorobiphenyl
produced effects similar to Aroclor 1242. 2,2´,4,4´-Tetrachlorobiphenyl
may contribute to the effects observed with Aroclor 1242, as 2,2´,4,4´-tetrachlorobiphenyl
was more potent than Aroclor 1242 in inhibiting degranulation. The possibility
that other congeners in the mixture or additive or synergistic effects among
congeners contribute to the responses in PMNs cannot be ruled out.
In summary, exposure to PCBs in vitro alters PMN function in a
complex manner. Aroclor 1242 enhances generation of O2-
in quiescent and activated PMNs and stimulates degranulation in quiescent
cells, but it attenuates fMLP-induced degranulation. 2,2´,4,4´-Tetrachlorobiphenyl
produces the same pattern of effects as Aroclor 1242, but the coplanar congener
3,3´,4,4´-tetrachlorobiphenyl does not affect PMN function in
vitro. These results suggest that the observed effects of PCBs on rat
PMN function in vitro are not Ah receptor dependent.
Similar changes in PMN function after exposure to PCBs in vivo could
contribute to altered response to infection. Recent findings with bacterial
endotoxin-induced toxicity support this hypothesis. PMNs play a central
role in tissue injury due to endotoxin in liver (25) and lung (26),
and treatment with PCBs (2,27) or TCDD (28) increases
sensitivity to endotoxin. It is not known whether the increased sensitivity
to endotoxin is mediated through PMNs, but the possibility remains that
alterations in PMN function caused by PCBs in vivo could affect the
response to subsequent exposure to pathogens.
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References
1. Silkworth JB, Grabstein EM. Polychlorinated biphenyl
immunotoxicity: dependence on isomer planarity and the Ah gene complex.
Toxicol Appl Pharmacol 65:109-115(1982).
2. Thomas PT, Hinsdill RD. Effect of polychlorinated biphenyls
on the immune responses of rhesus monkeys and mice. Toxicol Appl Pharmacol
44:41-51(1978).
3. Davis D, Safe S. Dose-response immunotoxicities of commercial
polychlorinated biphenyls (PCBs) and their interaction with 2,3,7,8-tetrachlorodibenzo-p-dioxin.
Toxicol Lett 48:35-43 (1989).
4. Elo O, Vuojolahti P, Janhunen H, Rantanen J. Recent
PCB accidents in Finland. Environ Health Perspect 60:315-319(1985).
5. Chang K-J, Hsieh K-H, Lee T-P, Tang S-Y, Tung T-C. Immunologic
evaluation of patients with polychlorinated biphenyl poisoning: determination
of lymphocyte subpopulations. Toxicol Appl Pharmacol 61:58-63(1981).
6. Raulf M, Konig W. Modulation of leukotriene generation
from human polymorphonuclear granulocytes by polychlorinated biphenyls (PCB).
Immunology 73:485-490(1991).
7. Safe S, Bandiera S, Sawyer T, Robertson L, Safe L, Parkinson
A, Thomas PE, Ryan DE, Reik LM, Levin W, Denomme MA, Fujita T. PCBs: structure-function
relationships and mechanism of action. Environ Health Perspect 60:47-56(1985).
8. Safe S, Bandiera S, Sawyer T, Zmudzka B, Mason G, Romkes
M, Fujita T. Effects of structure on binding to the 2,3,7,8-TCDD receptor
protein and AHH induction--halogenated biphenyls. Environ Health Perspect
61:21-33(1985).
9. Hewett JA, Roth RA. Dieldrin activates rat neutrophils
in vitro. Toxicol Appl Pharmacol 96:269-278(1991).
10. Roth RA, Ball TM. Technical grade but not recrystallized
alpha-naphthylthiourea potentiates superoxide release by rat neutrophils
stimulated in vitro by phorbol myristate acetate. Fundam Appl Toxicol
7:324-328(1986).
11. Babior BM, Kipnes RS, Curnutte JT. Biological defense
mechanisms. The production by leukocytes of superoxide, a potential bactericidal
agent. J Clin Invest 52:741-744(1973).
12. Fishman WH, Springer B, Brunetti R. Application of
an improved glucuronidase assay method to the study of human blood ß-glucuronidase.
J Biol Chem 173:449-456(1948).
13. Bergmeyer HV, Bernt E. Lactate dehydrogenase UV assay
with pyruvate and NADH. In: Methods of enzymatic analysis (Bergmeyer HV,
ed). New York:Academic Press, 1974; 524-579.
14. Helferich WG, Denison MS. Ultraviolet photoproducts
of tryptophan can act as dioxin agonists. Mol Pharmacol 40:674-678(1991).
15. Ackerman MF, Gasiewicz TA, Lamm KR, Germolec DR, Luster
MI. Selective inhibition of polymorphonuclear neutrophil activity by 2,3,7,8-tetrachlorodibenzo-p-dioxin.
Toxicol Appl Pharmacol 101:470-480(1989).
16. Heyworth PG, Badwey JA. Protein phosphorylation associated
with the stimulation of neutrophils. Modulation of superoxide production
by protein kinase C and calcium. J Bioenerg Biomembr 22(1):1-26(1990).
17. Bombick DW, Jankun J, Tullis K, Matsumura F. 2,3,7,8-Tetrachlorodibenzo-p-dioxin
causes increases in expression of c-erb-A and levels of protein-tyrosine
kinases in selected tissues of responsive mouse strains. Proc Natl Acad
Sci USA 85:4128-4132(1988).
18. Bombick DW, Madhukar BV, Brewster DW, Matsumura F.
TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) causes increases in protein
kinases particularly protein kinase C in the hepatic plasma membrane of
the rat and the guinea pig. Biochem Biophys Res Commun 127(1):296-302(1985).
19. Carrier F, Owens RA, Nebert DW, Puga A. Dioxin-dependent
activation of murine Cyp1a-1 gene transcription requires protein
kinase C-dependent phosphorylation. Mol Cell Biol 12(4):1856-1863(1992).
20. Tryphonas H, Luster MI, Schiffman G, Dawson LL, Hodgen
M, Germolec D, Hayward S, Bryce F, Loo JCK, Mandy F, Arnold DL. Effect of
chronic exposure of PCB (Aroclor 1254) on specific and nonspecific immune
parameters in the Rhesus (Macaca mulatta) monkey. Fundam Appl Toxicol
16:773-786 (1991).
21. Vos JG, Van Loveren H, Schuurman H-J. Immunotoxicity
of dioxin: immune function and host resistance in laboratory animals and
humans. In: Biological basis for risk assessment of dioxins and related
compounds (Gallo MA, Scheuplein RJ, Van Der Heijden KA, eds), Banbury Report
35. Cold Spring Harbor, NY:Cold Spring Harbor Laboratory Press, 1991;79-93.
22. Clark DA, Gauldie J, Szewczuk MR, Sweeney G. Enhanced
suppressor cell activity as a mechanism of immunosuppression by 2,3,7,8-tetrachlorodibenzo-p-dioxin
(41275). Proc Soc Exp Biol Med 168:290-299(1981).
23. Tucker AN, Vore SJ, Luster MI. Suppression of B cell
differentiation by 2,3,7,8-tetrachlorodibenzo-p-dioxin. Mol Pharmacol
29:372-377(1986).
24. Thigpen JE, Faith RE, McConnell EE, Moore JA. Increased
susceptibility to bacterial infection as a sequela of exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin.
Infect Immun 12: 1319-1324(1975).
25. Hewett JA, Schultze AE, VanCise S, Roth RA. Neutrophil
depletion protects against liver injury from bacterial endotoxin. Lab Invest
66(3):347-361(1992).
26. Brigham KL, Meyrick B. Interactions of granulocytes
with the lungs. Circ Res 54(6):623- 635(1984).
27. Shedlofsky SI, Hoglen NC, Rodman LE, Honchel R, Robinson
FR, Swim AT, McClain CJ, Robertson LW. 3,3´,4,4´-Tetrabromobiphenyl
sensitizes rats to the hepatotoxic effects of endotoxin by a mechanism that
involves more than tumor necrosis factor. Hepatology 14:1201-1208(1991).
28. Rosenthal GJ, Lebetkin E, Thigpen JE, Wilson R, Tucker
AN, Luster MI. Characteristics of 2,3,7,8-tetrachlorodibenzo-p-dioxin
induced endotoxin hypersensitivity: association with hepatotoxicity. Toxicology
56:239-251(1989).
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