* New York State Department of Health, Wadsworth Center, and School of Public Health, University at Albany, Box 509, Albany, New York 12201-0509
Received February 23, 2004; accepted April 13, 2004
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ABSTRACT |
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Key Words: polychlorinated biphenyls (PCBs); dopamine; synaptosomes; dopamine transporter (DAT); vesicular monoamine transporter (VMAT).
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INTRODUCTION |
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One mechanism by which PCBs may mediate these changes is via inhibition of the plasma membrane DA transporter (DAT) (Mariussen et al., 2001a,b
; Rosin and Martin, 1981
), which is responsible for the re-uptake of extracellular DA. Interestingly, these, as well as other in vitro effects, including activation of protein kinases (Kodavanti et al., 1993
) and alteration in intracellular calcium (Wong and Pessah, 1996
), are only seen following exposure to non-coplanar PCB congeners. Thus, PCB-induced DAT inhibition, and the consequent elevations in extracellular DA, may activate presynaptic autoreceptors that, in turn, influence both the synthesis and further release of DA into either media or the extraneuronal space (Wolf and Roth, 1990
).
PCBs, including both individual congeners and commercial mixtures of congeners, also inhibit the vesicular monoamine transporter (VMAT) (Mariussen et al., 2001a), which packages nerve terminal cytosolic DA into synaptic vesicles (Nirenberg et al., 1996
). Inhibition of VMAT function increases free nerve terminal cytosolic DA (Teng et al., 1997
; Zetterstrom et al., 1988
). In turn, elevations in nerve terminal cytosolic DA may lead to end-product inhibition of tyrosine hydroxylase (TH) (Cerrito and Raiteri, 1980
; Kumer and Vrana, 1996
) and formation of reactive oxygen species (ROS) (Miller et al., 1996
) shown to reduce DA synthesis and content (Cooper et al., 1996
; Minami et al., 1992
).
Thus, there is considerable evidence that both non-coplanar PCB congeners and commercial mixtures of PCB congeners inhibit monoamine transporters which, in turn, play an important role in regulating DA function. Indeed, Gainetdinov and Caron (2003) demonstrated profound changes in DA function in DAT knockout mice. However, the relative contributions of PCB-induced inhibition of DAT and VMAT function in influencing tissue DA content have not been determined. In the experiments described below, we determined changes in media DA and DOPAC, recognized functional surrogates, respectively, for DAT and VMAT inhibition (Garris et al., 2003
; Lee et al., 2001
; Mazei et al., 2002
), in order to determine the consequences of PCB-induced inhibition of these transporters on synaptosomal DA content and compared these changes with those induced by known monoamine transporter inhibitors.
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MATERIALS AND METHODS |
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All PCBs were dissolved in dimethylformamide (DMF) to create 1000X concentrated stock solutions that were then used to prepare media containing PCBs at the concentrations used in this study (040 µM). An approximate molecular weight of 326.4 g/mol (Erickson, 1997) was used to calculate the estimated molarity of the A1254 solution.
Preparation of synaptosomes. The isolation of purified striatal synaptosomes is based on a modification of procedures described by Löscher and coworkers (1985). Briefly, 1012 week-old male Long-Evans rats (Taconic Farms, Germantown, NY), were stunned and decapitated and their brains were rapidly removed. The following procedures were performed at 4°C unless otherwise noted. A forebrain block, made by a coronal cut anterior to the optic chiasm, was isolated and the striata dissected free-hand. Striata from 68 rats were pooled in ice-cold 0.32 M sucrose prior to homogenization with a Potter-Elvehjem glass-Teflon tissue grinder (0.150.23 mm clearance). The resulting homogenate was centrifuged at 1000 x g for 10 min, and the supernatant collected and layered onto 1.2 M sucrose. Centrifugation at 50,000 x g, with an
2t setting of 1.6 x 1010 yielded an interface layer, which was collected, diluted, layered onto 0.8 M sucrose and centrifuged for a second time, using the same conditions as described above to yield the purified synaptosomal pellet. Synaptosomal pellets were re-suspended in a volume of oxygenated HEPES-buffered Hank's saline (HBHS) equivalent to the starting wet weight of the striatal tissue and kept on ice until use. All experiments were performed with the approval of the Wadsworth Center Institutional Animal Care and Use Committee.
Exposure of synaptosomes and preparation for neurochemical analysis. Thirty µl aliquots of synaptosomes were then suspended in 750 µl of HBHS containing 1% horse serum and either 0.1% DMF or 0.1% DMF + PCBs (2.5, 5, 10, 20, or 40 µM), distributed into 96-well plates (130 µl/well) and incubated for 30 min in a humidified shaking water bath under an atmosphere of 95% O2/5% CO2 at 37°C. After exposure, the samples were transferred to microcentrifuge tubes and centrifuged for 5 min at 12,000 rpm to separate the synaptosomes from the medium. 100 µl of the resulting supernatant was removed and acidified by the addition of a volume of 0.4 N HClO4 equal to the volume of the supernatant, while the synaptosomal pellet was homogenized in 100 µl of 0.2 N HClO4. All samples were frozen at 80°C until analysis was performed, generally within 13 days.
Experiments were also performed to determine the effects of two DAT inhibitors, nomifensine (NOM) and GBR 12935 (GBR) (Garris et al., 2003; Lee et al., 2001
; Mazei et al., 2002
), both from Sigma (St. Louis, MO), and a VMAT inhibitor RO 41284 (Jones et al., 1998
) (a gift from Hoffman-La Roche, Nutley, NJ) on synaptosomal tissue and media DA and DOPAC concentrations. Aqueous stocks of these agents were serially diluted in media to the appropriate test concentrations and DMF was added to each solution to result in a final DMF concentration of 0.1%.
High performance liquid chromatographic analysis of DA and DOPAC. Quantification of synaptosomal and media DA and DOPAC concentrations was performed by high-performance liquid chromatography with electrochemical detection (HPLC-ECD) as described previously (Bemis and Seegal, 1999; Chishti et al., 1996
). Neurotransmitter concentrations were corrected for synaptosomal protein content determined by the bicinchoninic acid (BCA) method (Pierce, Rockford, IL). The protein concentration in each well was approximately 200 ng/ml. Total DOPAC concentrations (media + tissue) were reported since DOPAC is actively transported across the plasma membrane (Lamensdorf et al., 2000
) and summation of the changes in both compartments provides the best estimate of the ability of PCBs or RO 41284 to inhibit VMAT-mediated uptake of nerve terminal cytosolic DA.
Measurement of synaptosomal integrity. Synaptosomal plasma membrane integrity was estimated by measuring media lactate dehydrogenase (LDH) activity, since LDH release is a recognized measure of disruption of synaptosomal plasma membrane integrity (Berman et al., 1997). Briefly, following exposure of synaptosomes to PCBs, the medium was collected and the synaptosomes were disrupted ultrasonically to liberate intra-synaptosomal LDH. LDH release into media was expressed as a percentage of total LDH (media + intra-synaptosomal) to correct for the total number of synaptosomes. This method was performed with a modified Sigma Diagnostics LDH Assay® based on procedures described by Amador and coworkers (1963)
.
Statistical analyses. Neurochemical data (expressed as percent of DMF control) examining the effect of treatment of synaptosomes with increasing doses of PCB and media LDH activity (expressed as percent of total LDH activity) were analyzed using 1-way analysis of variance (ANOVA). Bonferroni-corrected post hoc t-tests allowed comparison of differences between treatment groups (mean ± SEM). Correlations between alterations in media DA or total DOPAC concentrations and synaptosomal DA concentrations were examined using linear regression analyses. Results are based on 23 replicate experiments with 56 wells per experiment.
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RESULTS |
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PCB congeners differed in their abilities to reduce synaptosomal DA concentrations (Fig. 1, Table 2). C95 was the most active congener (EC25 = 11 µM), followed by C91 (EC25 = 27 µM). The EC25 values of A1254 and C153 were similar to one another (37 and 40 µM, respectively). C103 was the least active of the non-coplanar PCBs tested with an EC25 significantly greater than 40 µM. Neither coplanar PCB congener altered tissue DA concentrations (data not shown).
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PCBs Differ in Their Abilities to Elevate Total DOPAC Concentrations
Statistically significant elevations in total DOPAC were observed following exposure to C91 and C95: 40 µM concentrations of these congeners resulted in maximal elevations of DOPAC to 118 and 128% of control, respectively. C103, C153, A1254, and the coplanar congeners C77 and C126 did not significantly alter DOPAC concentrations (Fig. 3; Table 2).
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DISCUSSION |
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The mechanisms responsible for the decreases in tissue DA, however, are not fully understood. In a previous study, where we observed significant reductions in tissue DA concentrations in striatal slices exposed ex vivo to PCBs (Bemis and Seegal, 1999), we suggested that elevations in media DA concentrations, due to inhibition of DAT function (Mazei et al., 2002
), are responsible for the reductions in striatal DA content. This hypothesis, that PCBs influence tissue DA concentrations by inhibiting DAT function, was supported not only by findings of Rosin and Martin (1981)
but also by recent findings from Mariussen and Fonnum (2001b)
. Both groups demonstrated that either Aroclor mixtures or non-coplanar PCB congeners significantly and competitively inhibited uptake of labeled DA into whole brain synaptosomes. The data presented here, however, suggest that, at least for those congeners which result in the greatest reductions in tissue DA content, elevations in media DA play a less important role in reducing synaptosomal DA concentrations than do elevations in nerve terminal cytosolic DA due to PCB-mediated inhibition of the VMAT. This hypothesis is based on three findings.
First, there is only a weak statistical relationship between PCB-induced elevations in media DA and reductions in synaptosomal DA concentrations. This lack of a statistically significant relationship suggests that PCB-induced inhibition of DA uptake and the subsequent reductions in the amount of DA available for re-packaging into storage vesicles has only a minor effect on synaptosomal DA content.
Second, the elevations in media DA concentrations following exposure to NOM and GBR, associated with a 25% reduction in synaptosomal DA, are much greater than the elevations in media DA following exposure to PCBs (Table 2). These discrepancies in the levels of media DA associated with similar reductions in synaptosomal DA suggest that, except perhaps for A1254, PCBs do not elevate media DA to levels sufficient to significantly influence synaptosomal DA content and that other mechanisms must be evoked to explain the reductions in synaptosomal DA.
Finally, we have previously demonstrated that A1254 significantly elevated extra-neuronal DA (indicative of PCB-induced DAT inhibition) without significantly altering rat striatal DA concentrations (Seegal et al., 2002). These latter results, obtained using in vivo microdialysis, support our contention that DAT inhibition, resulting in elevations in extra-neuronal DA concentrations, at least in the short term, plays at best only a minor role in influencing striatal DA levels in vivo.
The data for PCB-induced VMAT inhibition (and subsequent elevations in nerve terminal cytosolic DA) in reducing synaptosomal DA concentrations are considerably stronger. The greatest reductions in DA were observed following exposure to either C95 or C91, both of which significantly elevated total DOPAC concentrations (Fig. 4), indicative of an elevation in free nerve terminal cytosolic DA (Teng et al., 1997). In turn, elevations in nerve terminal cytosolic DA may ultimately influence synaptosomal DA by a number of mechanisms, including reductions in de novo DA synthesis by end-product inhibition or activation of presynaptic receptors, and enhanced metabolism of nerve terminal cytosolic DA to quinones and/or sulfated metabolites (Kumer and Vrana, 1996
).
This hypothesis, that PCBs reduce synaptosomal DA concentrations by elevating nerve terminal cytosolic DA, is supported by two additional pieces of evidence. First, the concentration of RO 41284 associated with a 25% reduction in synaptosomal DA concentration, elevated total DOPAC to a level nearly identical to that seen following exposure to either C91 or C95, the two congeners that reduced synaptosomal DA to the greatest extent (Table 2). Second, the correlation between PCB-induced elevations in total DOPAC and reductions in synaptosomal DA is statistically highly significant, suggesting that PCB-induced elevations in free nerve terminal cytosolic DA are responsible for the decreases in synaptosomal DA concentrations.
The PCB congeners examined here, and the majority of those reported by Fonnum and coworkers, may inhibit DA uptake at both monoamine transporter sites. However, we suggest that VMAT inhibition (and the resulting elevation in nerve terminal cytosolic DA, seen here as elevations in total DOPAC) is most likely responsible for the reductions in synaptosomal DA following exposure to C95 and C91. Elevations in nerve terminal cytosolic DA are less likely to be responsible for the reductions in DA following exposure to A1254 where inhibition of DAT function appears to be the primary mechanism responsible for the relatively modest decreases in synaptosomal DA. However, the remaining PCB congeners, which were unremarkable in their ability to alter either DAT or VMAT function, may involve low-level inhibition of both transporters.
Additional mechanisms may also contribute to the observed reductions in synaptosomal DA including ROS formation, due to metabolism of increased nerve terminal cytosolic DA concentrations, alterations in intrasynaptosomal calcium concentrations (Wong et al., 1997) as well as nonspecific PCB-induced structural modifications of cytoplasmic membranes. Indeed, Kim et al. (2001)
demonstrated structural changes, including increased membrane fluidity, in Ralstonia eutropha H850 membranes following long term exposure to the non-coplanar congener 2,5,2',5'-tetrachlorobiphenyl. It is unlikely, however, that PCB-induced changes in transcription contribute to the reductions in synaptosomal DA because of the rapidity with which changes in synaptosomal DA occur.
Finally, an examination of the data in Table 1 provides a cautionary note concerning the relationship between monoamine transporter inhibition and alterations in synaptosomal DA concentrations. These data, particularly for the C95 and C103 values that are shaded, demonstrate that measurement of PCB-induced inhibition of uptake of labeled DA may fail to predict the reductions in synaptosomal DA induced by some PCBs. For example, although A1254 and C95 have similar DAT IC50 values, they differ significantly in their ability to elevate media DA concentrations. On the other hand, the IC50 for C103 VMAT inhibition is similar to that for C91, despite the relatively small increase in total DOPAC seen with C103. These discrepancies may reflect the fact that PCBs, unlike highly specific pharmacological transporter inhibitors, may influence both transporters.
In addition to reducing synaptosomal DA concentrations, PCB-induced inhibition of VMAT, resulting in elevated levels of free nerve terminal cytosolic DA, may also reduce neuronal viability. In this study, however, we found no evidence of loss of membrane integrity. Nevertheless, elevated concentrations of free nerve terminal cytosolic DA (shown here as an increase in total DOPAC concentrations) have been shown to act as an endogenous neurotoxin (Berman and Hastings, 1997; Montine et al., 2000
) that induces oxidative stress, impairs protein and membrane functions, and modifies DNA/RNA (Berman and Hastings, 1999
; LaVoie and Hastings, 1999
). Thus, PCB-mediated alterations in intracellular DA storage may exacerbate the neurodegeneration occurring in normal conditions (e.g., aging), as well as interacting with other environmental risk factors (e.g., rotenone) and genetic predispositions associated with certain disease states, e.g., Parkinson's disease (De Iuliis et al., 2002
).
In summary, the evidence presented here strongly suggests that PCB induced elevations in free nerve terminal cytosolic DA, rather than increases in either media or extra-neuronal DA, play the greatest role in reducing tissue DA concentrations and perhaps, in the long term, leading to changes in behavior and/or initiating or enhancing neurodegenerative processes associated with Parkinsonism.
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ACKNOWLEDGMENTS |
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NOTES |
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1 To whom correspondence should be addressed at Wadsworth Center, New York State Department of Health, Empire State Plaza, Box 509, Albany, NY 12201-0509. Fax: (518) 486-1505. E-mail: seegal{at}wadsworth.org.
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