Toxicological Sciences 68, 451-457 (2002)
Copyright © 2002 by the Society of Toxicology
NEUROTOXICOLOGY |
Differential Effects of Polybrominated Diphenyl Ethers and Polychlorinated Biphenyls on [3H]Arachidonic Acid Release in Rat Cerebellar Granule Neurons
Cellular and Molecular Toxicology Branch, Neurotoxicology Division, MD 74B, NHEERL, ORD, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711
Received February 13, 2002; accepted April 22, 2002
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Polybrominated diphenyl ethers (PBDEs), which are widely used as flame-retardants, have been increasing in environmental and human tissue samples during the past 20–30 years, while other structurally related, persistent organic pollutants such as polychlorinated biphenyls (PCBs) and polychlorinated dibenzo-p-dioxins (on a TEQ basis), have decreased. PBDEs have been detected in human blood, adipose tissue, and breast milk, and developmental and long-term exposure to these contaminants may pose a human health risk, especially to children. Previously, we demonstrated that PCBs, which cause neurotoxic effects, including changes in learning and memory, stimulated the release of [3H]arachidonic acid ([3H]AA) by a cPLA2/iPLA2-dependent mechanism. PLA2(phospholipase A2) activity has been associated with learning and memory, and AA has been identified as a second messenger involved in synaptic plasticity. The objective of the present study was to test whether PBDE mixtures (DE-71 and DE-79), like other organohalogen mixtures, have a similar action on [3H]AA release in an in vitro neuronal culture model. Cerebellar granule cells at 7 days in culture were labeled with [3H]AA for 16–20 h and then exposed in vitro to PBDEs. DE-71, a mostly pentabromodiphenyl ether mixture, significantly stimulated [3H]AA release at concentrations as low as 10 µg/ml, while DE-79, a mostly octabromodiphenyl ether mixture, did not stimulate [3H]AA release, even at 50 µg/ml. The release of [3H]AA by DE-71 is time-dependent, and a significant increase was seen after only 5–10 min of exposure. The removal and chelation of calcium from the exposure buffer, using 0.3 mM EGTA, significantly attenuated the DE-71-stimulated [3H]AA release; however, only an 18% inhibition of the release was demonstrated for the calcium replete conditions at 30 µg/ml DE-71. Methyl arachidonylfluorophosphonate (5 µM), an inhibitor of cPLA2/iPLA2, completely attenuated the DE-71-stimulated [3H]AA release. Further studies focused on comparing the effects of DE-71 with PCB mixtures such as Aroclors 1016 and 1254. Both PCB mixtures stimulated [3H]AA release in a concentration-dependent manner; however, the effect for PCBs was about two times greater than that of the PBDEs on a weight basis, but was comparable on a molar basis. These results indicate that PBDEs stimulated the release of [3H]AA by activating PLA2, which is similar to the effect of other organohalogen mixtures.
Key Words: polybrominated diphenyl ethers; brominated flame retardants; arachidonic acid release; polychlorinated biphenyls; phospholipases; neurotoxicity.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Polybrominated diphenyl ethers (PBDEs) are produced and used in large quantities as flame retardants in electrical equipment, plastics, and building materials. The global production of PBDEs is in the range of 80 million pounds annually (WHO, 1994
); and, these compounds become ubiquitous contaminants in the environment because of their high production, lipophilic characteristics, and persistence (WHO, 1994). PBDEs have similar chemical structure and physicochemical properties (e.g., high lipophilicity and low reactivity) to other persistent pollutants such as polychlorinated biphenyls (PCBs) and dioxins (Fig. 1). PBDEs have been detected in human blood, adipose tissue, and breast milk; and, long-term exposure to these contaminants during development may pose a health risk (Hooper and McDonald, 2000; Ryan and Patry, 2000; She et al., 2002; Sjodin et al., 2001). Levels of PBDEs have been increasing in environmental and human samples (Hooper and McDonald, 2000; Noren and Meironyte, 2000) in the past 20–30 years, while other persistent organic pollutants such as PCBs and dioxins (on a TEQ basis) have decreased. Initial data indicate that tissue concentrations of PBDEs in humans in North America are much higher than those of Europeans (Betts, 2002). Recent reports indicated high levels of PBDEs in fish; PBDEs are as prevalent as PCBs in Lake Michigan and Virginia waters. Manchester-Neesvig et al.(2001) reported average concentrations of PBDEs in salmon of 80.1 ng/g wet weight, and these levels seem to be among the highest in the world for salmon in open waters. Hale et al. (2001a,b) found PBDEs in 87% of 334 fish from Virginia fresh water, and carp from one stream there contained 47.9 mg/kg of total PBDEs, the highest fillet burden reported in the world so far. If the trends in PBDE levels in human milk, fish, and the environment continue over the next 15–30 years, these chemicals will replace PCBs and DDT as the major environmentally persistent organic pollutants.
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In spite of widespread occurrence in the environment, extremely limited information is available on the toxicology of PBDEs. Based on limited toxicity data and structural similarities with PCBs, toxic endpoints likely to be the most sensitive for PBDEs are cancer, liver damage, thyroid hormone disruption, and neurobehavioral toxicity (McDonald, 2002
). Regarding neurobehavioral toxicity, recent studies demonstrated that PBDE exposure can cause aberrations in spontaneous behavior and reduced learning and memory in mice (Eriksson et al., 1999, 2001; Viberg et al., 2000, 2001); the effects are similar to those seen after exposure to DDT or PCBs (Eriksson, 1997). However, the mechanism by which these chemicals produce neurotoxic effects remains unclear.
Previously, we demonstrated that PCBs, which are structurally similar to PCBs and DDT and are known to cause neurotoxic effects, including changes in learning and memory in rats, perturbed intracellular signaling mechanisms (Kodavanti and Tilson, 2000), including stimulation of [3H]arachidonic acid ([3H]AA) release by a cPLA2/iPLA2-dependent mechanism (Kodavanti and Derr-Yellin, 1999) in an in vitro neuronal culture model. However, it is not known whether these mechanisms are related to the developmental neurotoxic effects observed in humans or nonhuman primates. Membrane phospholipids of the brain contain high concentrations of AA (arachidonic acid), and AA release is involved in synaptic plasticity, such as long-term potentiation and other cell-signaling systems (Farooqui et al., 1997b; Katsuki and Okuda, 1995). AA can be released by activation of phospholipases, predominantly by PLA2. AA itself affects the signaling pathway as a retrograde messenger, causing release of calcium from microsomal and mitochondrial stores (Huang and Chueh, 1996), alterations in neurotransmitter release and uptake (Roseth et al., 1998, Cunha and Ribeiro, 1999), and stimulation of protein kinase C (Luo and Vallano, 1995). PLA2 activity has been associated with learning and memory, and AA has been identified as a second messenger involved in synaptic plasticity (Wolf et al., 1995). The objectives of the present study are: to(1) test whether the available commercial PBDE mixtures, DE-71 (penta-mixture) and DE-79 (octa-mixture), have an action on [3H]AA release similar to that of PCBs and other organohalogens; (2) delineate the nature of PLA2 responsible for the release of [3H]AA by PBDEs; (3) and compare the effects of commercial PBDE and PCB mixtures on [3H]AA release. The selected PBDE mixtures DE-71 and DE-79 contain mostly penta- and octa-brominated diphenyl ether congeners, respectively. The composition of different commercial mixtures of PBDEs can be found in Sjodin (2000). The prominent congeners found in most human and biotic samples range from tetra to deca (2,2',4,4'-tetrabromodiphenyl ether, 2,2',4,4',5-pentabromodiphenyl ether, 2,2',4,4',5,5'-hexabromodiphenyl ether, 2,2',3,4,4',5',6-heptabromodiphenyl ether, and decabromodiphenyl ether; Noren and Meironyte, 2000; Ryan and Patry, 2000; Sjodin et al., 2001; She et al., 2002). DE-71 and DE-79 contain the prominent congeners found in biological samples and are representatives of lightly versus heavily brominated congeners. These two mixtures were tested to compare the effects of penta- versus octa-BDE mixtures.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Chemicals.
Radiolabeled [5, 6, 8, 9, 11, 12, 14, 15–3H(N)]arachidonic acid (210 Ci/mmol; >97% pure) was purchased from Dupont NEN Corporation (Boston, MA). PBDE mixtures (DE-71, Lot # 7550OK20A and DE-79, Lot # 8525DG01A) were a gift from Great Lakes Chemical Corporation (West Lafayette, IN) and PCB mixtures, Aroclor 1254 (Lots #124–191; >99% purity) was purchased from AccuStandard (New Haven, CT) and Aroclor 1016 (Lot #F216A) was purchased from Ultra Scientific (North Kingstown, RI). All compounds were dissolved in dimethyl sulfoxide (DMSO) and the final DMSO concentration in the assay buffer did not exceed 0.4% (v/v). DMSO at this concentration did not significantly affect [3H]AA release.
Animals.
Timed-pregnant female (16 days of gestation) Long-Evans rats were obtained from Charles River Laboratory (Raleigh, NC) and housed individually in animal facilities approved by the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC). Food and water were provided ad libitum. Temperature was maintained at 21 ± 2°C, relative humidity at 50 ± 10% with a 12-h light/dark cycle.
Cerebellar granule cell culture.
Primary cultures of rat cerebellar granule neurons were prepared from 6–8-day-old Long-Evans rat pups as outlined by Gallo et al. (1987) with modifications, Kodavanti et al.(1993). Cultures were grown in Dulbecco’s modified Eagle’s medium (DMEM) with 10% fetal bovine serum and 30 mM KCl in 12-well plates (Corning Costar), with a plating density of 1.5 x 106 cells/ml. Cytosine arabinoside was added 48 h after plating to prevent the proliferation of nonneuronal cells. Cultures were assayed for [3H]AA release at 7 days in vitro, when they are fully differentiated and exhibiting fasciculation of fibers that interconnect the cells (Fig. 2).
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[3H]Arachidonic acid (AA) release.
The [3H]AA release by cerebellar granule cells into the medium was determined according to the procedure modified from Lazarewicz et al. (1990) and Tithof et al. (1996). At 6 days in vitro, cell cultures were labeled for 16–20 h with 1 µCi [3H]AA per well. The cells were then washed once with modified Locke’s buffer and twice with modified Locke’s + 0.2% BSA. Preincubation was for 10 min in modified Locke’s + 0.2% BSA, with or without the addition of pharmacological agents. The incubation time was 20 min, except in time-course experiments. The cells were exposed for 20 min to PBDE mixtures (0–30 or –50 µg/ml) or PCB mixtures (0–30 µg/ml) in the presence or absence of pharmacological agents in modified Locke’s + 0.2% BSA (1 ml) with or without extracellular calcium (without Ca2+, 0.3 mM EGTA). All the media were removed immediately after exposure for counting in a scintillation counter, and 1 ml of 0.5 N NaOH was added to lyse the cells in order to measure total incorporation of [3H]AA.
Statistics.
All the data (mean ± SEM of 3–6 preparations, assayed in triplicate) were expressed as a percentage of total cellular radioactivity incorporation per well. The data were analyzed by a 2-way analysis of variance (ANOVA) with SigmaStat software, version 2.03 (SPSS Inc., Chicago, IL). In the case of significant interaction, step-down ANOVAs were used to test for main effects of PBDEs or pharmacological agents. Pair-wise comparisons between groups were made using Fishers LSD test. Since the data represented on a molar basis (Fig. 7C) could not be analyzed by ANOVA, we used the analysis of covariance to determine whether the linear regressions for Aroclor 1254 and DE-71 were parallel. If they were parallel, we then tested to see if the means of Aroclor 1254 and DE-71 were different (SAS, 1989). The accepted level of significance was p < 0.05.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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PBDE effects on [3H]AA release.
Cerebellar granule neurons, at 6 days in vitro, were labeled with [3H]AA (1 µCi) for 16–20 h and used for assays at 7 days in vitro. The toxicant exposure period lasted 20 min, with the exception of time-course study. The solvent (DMSO) used to prepare toxicant concentrations did not alter the basal levels of [3H]AA release (data not shown). Glutamate (50 µM), which is used as a positive control, significantly stimulated [3H]AA release (200% of control). Two PBDE mixtures with different congener compositions were tested on [3H]AA release by cerebellar granule neurons (Fig. 3
). ANOVA indicated a significant interaction of concentration by PBDE mixture (F5,36 = 4.784; p = 0.002). A post hoc test showed that the mostly penta-BDE mixture, DE-71, stimulated [3H]AA release in a concentration-dependent manner (Fig. 3). A significant effect was seen at a concentration as low as 10 µg/ml. On the other hand, a mostly octa-BDE mixture, DE-79, did not stimulate [3H]AA release, even at 50 µg/ml (Fig. 3). The lack of effect by DE-79 could be due to its low solubility when compared to DE-71. The release of [3H]AA by DE-71 is time-dependent (Fig. 4). ANOVA indicated a significant interaction of time and treatment (F4,30 = 27.365; p < 0.001). A post hoc test showed that significant increases in [3H]AA release were seen as early as after 5–10 min of DE-71 exposure, and increased with time (Fig. 4).
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Further experiments concentrated on characterizing [3H]AA release by DE-71. As seen with PCB exposure, we initially examined the role of calcium, as shown in Figure 5
. ANOVA indicated a significant effect of DE-71concentration (F3,36 = 75.997; p < 0.001) and EGTA treatment (F1,36 = 5.85; p = 0.021). Removal of extracellular calcium and chelation of Ca2+ with 0.3 mM EGTA significantly decreased the DE-71-stimulated [3H]AA release; however, only an 18% inhibition of the release was demonstrated for the calcium replete conditions at 30 µg/ml DE-71 (Fig. 5). Although these results suggest the role of calcium in DE-71 stimulated [3H]AA release, it is obvious that the major component of DE-71-stimulated [3H]AA release consists of a calcium-independent mechanism. A similar observation was made previously with PCBs in cerebellar granule neurons (Kodavanti and Derr-Yellin, 1999) and in rat neutrophils (Tithof et al., 1998).
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Additional experiments were conducted to demonstrate that PLA2 is responsible for DE-71-stimulated [3H]AA release. Previous studies on PCBs using a variety of PLA2 inhibitors suggested that cytosolic PLA2 (cPLA2) might play a key role in PCB-mediated [3H]AA release (Kodavanti and Derr-Yelllin, 1999
). We have now tested the effects of methyl arachidonyl fluorophosphonate (MAFP) on DE-71-stimulated [3H]AA release. MAFP inhibits both cPLA2, which is calcium-dependent, and iPLA2, which is a calcium-independent form. ANOVA indicated a significant interaction of DE-71 concentration and MAFP treatment (F 3,16 = 5.724; p = 0.007). A post hoc test showed that MAFP at 5 µM significantly attenuated DE-71 stimulated [3H]AA release (Fig. 6).
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Comparative effects of PCBs and PBDEs on [3H]AA release.
Since PBDEs are structurally similar to PCBs (Fig. 1
), we tested the effects of these two groups of chemicals on [3H]AA release in order to understand the relative potency of PBDEs. The selected PCB mixtures used were Aroclor 1016 and Aroclor 1254. Figure 7A shows the concentration-dependent effects of DE-71 and Aroclor 1254 (on a weight basis), which are mostly penta-halogenated mixtures. ANOVA indicated a significant interaction of treatment and concentration (F4,25 = 4.228; p = 0.009). These two penta-halogenated mixtures significantly stimulated [3H]AA release starting at 10 µg/ml (Fig. 7A). On a weight basis, the effect was much greater with Aroclor 1254 (589% of control at 10 µg/ml) when compared to DE-71 (275% of control at 10 µg/ml). A similar trend was observed for the time-course of [3H]AA release following exposure to 10 µg/ml of DE-71, Aroclor 1254, or Aroclor 1016. ANOVA indicated a significant interaction of treatment and time (F12,40 = 16.116; p < 0.001). DE-71 and both PCB mixtures stimulated [3H]AA release in a time-dependent manner (Fig. 7B). The effect of PCB mixtures was much greater when compared to PBDEs on a weight basis (µg/ml). PCB mixtures also initiated the response much earlier than PBDEs (Fig. 7B). When the concentrations (µg/ml) were transformed to a molar basis (µM) based on the average/approximate molecular weights of Aroclor 1254 (M.W. 326.77 pentachloro mixture) and DE-71 (M.W. 565.05 pentabromo mixture), the difference in the potency decreased considerably (Fig. 7C). Analysis of covariance indicated that the effects of Aroclor 1254 and DE-71 were linear and parallel. Further analysis indicated that the mean effects of Aroclor 1254 and DE-71 were not significantly different (F1,8 = 2.7; p = 0.12). The slope of the log concentration of Aroclor 1254 and DE-71 was significantly different from 0 µM (F1,18 = 43.4; p < 0.001). Although there are some minor quantitative differences, the effects of PBDEs are qualitatively similar to those of PCBs. |
DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Results from the present study demonstrate for the first time that PBDEs cause stimulation of [3H]AA release in rat cerebellar granule neurons. This finding is consistent with previous studies on structurally related chemicals such as PCBs in neutrophils (Brown and Ganey, 1995
; Tithof et al., 1996, 1998), renal tubular cells (Sanchez et al., 1997, 2000), and cerebellar granule neurons (Kodavanti and Derr-Yellin, 1999). A similar effect was observed with organohalogen pesticides in rat neutrophils as well (Tithof et al., 2000). Membrane phospholipids of the brain are rich in AA, and AA release is involved in synaptic plasticity, such as long-term potentiation and other cell-signaling systems (Farooqui et al., 1997b; Katsuki and Okuda, 1995). AA has been shown to modulate ion channels and to regulate the activity of many enzyme proteins, such as protein kinase A, protein kinase C, and diacylglycerol kinase (Farooqui et al., 1997a). In addition, AA has been implicated in pathophysiological processes including neurodegeneration (Farooqui et al., 1997a; Ross et al., 1998). Thus, AA has been implicated in both physiological (synaptic plasticity) and pathophysiological (neurodegenerative) functions (Katsuki and Okuda, 1995). Results from this study indicate that DE-71 (penta-brominated mixture), but not DE-79 (octa-brominated mixture), significantly stimulated [3H]AA release at low concentrations (10 µg/ml). The effects of PBDEs on [3H]AA release in cerebellar neurons suggest that altered intracellular signaling of AA might be involved in the neurotoxicity associated with exposure to PBDEs.
Further experiments focused on the mechanism by which PBDE mixture caused [3H]AA release. Liberation of AA from membrane phospholipids mainly occurs by two pathways: through the activation of phospholipase A2 (PLA2) or by activation of phospholipase C (PLC). Although phospholipase D (PLD) is considered an alternative pathway, the involvement of PLD in the generation of AA has not been confirmed in the nervous system (Katsuki and Okuda, 1995). Previous studies from our laboratory indicated that ortho-substituted PCBs (noncoplanar PCBs), which are structurally similar to PBDEs, stimulated [3H]AA release in cerebellar neurons by activation of PLA2, which is both calcium-dependent and -independent (Kodavanti and Derr-Yellin, 1999). These studies also indicated that the major factor of PCB-stimulated [3H]AA release consists of a calcium-independent mechanism. A similar activation of calcium-dependent and -independent PLA2 has also been demonstrated for PCBs (Brown and Ganey, 1995; Tithof et al., 1996) as well as organochlorine pesticides in rat neutrophils (Tithof et al., 2000). Therefore in the present study, we examined the role of calcium and tested the effects of a PLA2 inhibitor on DE-71-stimulated [3H]AA release. Results from the present study indicated that DE-71-induced [3H]AA release also requires the presence of calcium. In addition, MAFP, which inhibits both Ca2+-dependent and -independent cytosolic phospholipase A2 (cPLA2/iPLA2 (Basavarajappa et al., 1998; Lio et al., 1996) attenuated DE-71stimulated release of [3H]AA completely, suggesting the involvement of cPLA2/iPLA2. We have demonstrated that structurally related chemicals such as PCBs increased intracellular free calcium (Kodavanti and Tilson, 1997), which is dependent upon the presence of extracellular calcium (Mundy et al., 1999) and have demonstrated that removal of extracellular Ca2+ caused a slight, but significant, decrease in PCB-stimulated [3H]AA release (Kodavanti and Derr-Yellin, 1999). We have also shown that polychlorinated diphenyl ethers (PCDEs) have similar effects on intracellular second messengers as noncoplanar PCBs (Kodavanti et al., 1996), demonstrating the role of noncoplanarity. PBDEs are also noncoplanar in nature as PCDEs and noncoplanar PCBs. Both calcium-independent and -dependent cPLA2 are present in the rat cerebellum (Molloy et al., 1998) and one or both are probably involved in the stimulation of [3H]AA release in rat cerebellar granule cells by PCBs, PBDEs, and other organohalogens.
These results from this study indicate that PBDEs stimulated [3H]AA release by activating the PLA2 pathway in neuronal cells, as do other organohalogen mixtures in neurons and neutrophils. Although the efficacy of PBDEs seems to be lower when compared to PCBs on a weight basis, they are almost equally potent on a molar basis. For example, mostly the pentachlorinated mixture of PCBs (Aroclor 1254) at 10 µg/ml stimulated [3H]AA release during a 20-min incubation by 589–735% of control, while a similar mixture of PBDEs (DE-71) stimulated only 275–336% of control. These results indicate that PCBs are 2.2 times more potent than PBDEs on a weight basis. However, the approximate average molecular weight of Aroclor 1254 is 1.7 times less than DE-71. Hence, the difference in efficacy between PCBs and PBDEs decreased considerably on a molar basis as compared to weight basis. Additional studies with specific congeners are needed to address this differential efficacy/potency between PBDEs and PCBs. Although there are minor quantitative differences in the effects of PBDEs and PCBs, the effects were qualitatively similar. Since PBDEs are as ubiquitous as PCBs in human tissues (Ryan and Patry, 2000) and the levels of PBDEs are rapidly rising in North Americans (Betts, 2002), PBDEs might pose a greater health risk in the future. Considering the structural similarity of PBDEs with PCBs (Fig. 1) and the known health effects of PCBs, these two groups of chemicals may be working together, through the same mechanisms, to cause developmental neurotoxicity. Due to continued use of PBDEs in consumer products and the bioaccumulative nature of the PBDE congeners, toxicological consequence of exposure to PBDEs should be evaluated.
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ACKNOWLEDGMENTS |
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The authors thank Great Lakes Chemical Corporation and Dr. Kevin Crofton of U.S. EPA for providing a sample of PBDE mixtures, Mr. Jerry Highfill for statistical help, Mr. Steve Little of U.S. EPA for help with graphics, Dr. Gabriele Ludewig of the University of Kentucky and Ms. Janet Diliberto and Dr. Tim Shafer of U.S. EPA for their helpful comments on the earlier version of this manuscript.
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NOTES |
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1 To whom correspondence should be addressed. Fax: (919) 541-4849. E-mail: kodavanti.prasada{at}epa.gov.
2 Present address: Cancer Research Institute, Wells Research Center, Room 432, 1044 West Walnut Street, Indianapolis, IN 46202-5254.
This manuscript has been reviewed by the National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, and approved for publication. Approval does not signify that the contents necessarily reflect the views and policies of the Agency, nor does mention of trade names or commercial products constitute endorsement or recommendation for use. Some of the data included in this report were presented at the Society of Toxicology annual meeting, March 2001, at San Francisco, CA.
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REFERENCES |
|---|
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Basavarajappa, B. S., Cooper, T. B., and Hungund, B. L. (1998). Effects of chronic ethanol exposure on mouse brain arachidonic acid-specific phospholipase A2. Biochem. Pharmacol. 55, 515–521.[Web of Science][Medline]
Betts, K. S. (2002). Rapidly rising PBDE levels in North America. Environ. Sci. Technol. 36, 50–52A.
Brown, A. P. and Ganey, P.E. (1995). Neutrophil degranulation and superoxide production induced by polychlorinated biphenyls are calcium-dependent. Toxicol. Appl. Pharmacol. 131, 198–205.[Web of Science][Medline]
Cunha, R. A., and Ribeiro, J. A. (1999). Facilitation of GABA release by arachidonic acid in rat hippocampal synaptosomes. Eur. J. Neurosci. 11, 2171–2174.[Web of Science][Medline]
Eriksson, P. (1997). Developmental neurotoxicity of environmental agents in the neonate. Neurotoxicology 18, 719–726.[Web of Science][Medline]
Eriksson, P., Jakobsson, E., and Fredriksson, A. (2001). Brominated flame retardants: A novel class of developmental neurotoxicants in our environment? Environ. Health Perspect. 109, 903–908.[Web of Science][Medline]
Eriksson, P., Viberg, H., Jakobsson, E., Orn, U., and Fredriksson, A. (1999). PBDE,2,2',4,4',5-pentabromodiphenyl ether, causes permanent neurotoxic effects during a defined period of neonatal brain development. Organohal. Comp. 40, 333–336.
Farooqui, A. A., Rosenberger, T. A., and Horrocks, L. A. (1997a). Arachidonic acid, neurotrauma and neurodegenerative diseases, in Fatty Acids: Biochemistry and Behavior (Mostofsky, D. I. and Yehuda, S., Eds.), pp. 277–295. Humana Press, Totowa, NJ.
Farooqui, A. A., Yang, H.-C., Rosenberger, T. A., and Horrocks, L. A. (1997b). Phospholipase A2 and its role in brain tissue. J. Neurochem. 69, 889–901.[Web of Science][Medline]
Gallo, V., Kingsbury, A., Balazs, R., and Jorgensen, O. S. (1987). The role of depolarization in the survival and differentiation of cerebellar granule cells in culture. J. Neurosci. 7, 2203–2213.[Abstract]
Hale, R. C., La Guardia, M. J., Harvey, E. P., Gaylor, M. O., Mainor, T. M., and Duff, W. H. (2001a). Flame retardants: Persistent pollutants in land-applied sludges. Nature 412, 140–141.[Medline]
Hale, R. C., La Guardia, M. J., Harvey, E. P., Mainor, T. M., Duff, W. H., and Gaylor, M. O. (2001b). Polybrominated diphenyl ether flame retardants in Virginia freshwater fishes (USA). Environ. Sci. Technol. 35, 4585–4591.[Medline]
Hooper, K., and McDonald, T. A. (2000). The PBDEs: An emerging environmental challenge and another reason for breast-milk monitoring programs. Environ. Health Perspect. 108, 387–392.[Web of Science][Medline]
Huang, W.-C., and Chueh, S.-H. (1996). Calcium mobilization from the intracellular mitochondrial and nonmitochondrial stores of the rat cerebellum. Brain Res. 718, 151–158.[Web of Science][Medline]
Katsuki, H., and Okuda, S. (1995). Arachidonic acid as a neurotoxic and neurotrophic substance. Prog. Neurobiol. 46, 607–636.[Web of Science][Medline]
Kodavanti, P. R. S., and Derr-Yellin, E. C. (1999). Activation of calcium-dependent and independent phospholipase A2 by non-coplanar polychlorinated biphenyls in rat cerebellar granule neurons. Organohal. Comp. 42, 449–453.
Kodavanti, P. R. S., Shin, D. S., Tilson, H. A., and Harry, G. J. (1993). Comparative effects of two polychlorinated biphenyl congeners on calcium homeostasis in rat cerebellar granule cells. Toxicol. Appl. Pharmacol. 123, 97–106.[Web of Science][Medline]
Kodavanti, P. R. S., and Tilson, H. A. (1997). Structure-activity relationships of potentially neurotoxic PCB congeners in the rat. Neurotoxicology 18, 425–441.[Web of Science][Medline]
Kodavanti, P. R. S., and Tilson, H. A. (2000). Neurochemical effects of environmental chemicals: In vitro and in vivo correlations on second messenger pathways. Ann. N.Y. Acad. Sci. 919, 97–105.[Medline]
Kodavanti, P. R. S., Ward, T. R., McKinney, J. D., Waller, C. L., and Tilson, H. A. (1996). Increased [3H]phorbol ester binding in rat cerebellar granule cells and inhibition of 45Ca2+ sequestration in rat cerebellum by polychlorinated diphenyl ether congeners and analogs: Structure-activity relationships. Toxicol. Appl. Pharmacol. 138, 251–261.[Web of Science][Medline]
Lazarewicz, J. W., Wroblewski, J. W., and Costa, E. (1990). N-Methyl-D-aspartate-sensitive glutamate receptors induce calcium-mediated arachidonic acid release in primary cultures of cerebellar granule cells. J. Neurochem. 55, 1875–1881.[Web of Science][Medline]
Lio, Y. C., Reynolds, L. J., Balsinde, J., and Dennis, E. A. (1996). Irreversible inhibition of Ca(2+)-independent phospholipase A2 by methyl arachidonylfluorophosphonate. Biochim. Biophys. Acta 1302, 55–60.[Medline]
Luo, Y., and Vallano, M. L. (1995). Arachidonic acid, but not sodium nitroprusside, stimulates presynaptic protein kinase C and phosphorylation of GAP-43 in rat hippocampal slices and synaptosomes. J. Neurochem. 64, 1808–1818.[Web of Science][Medline]
Manchester-Neesvig, J. B., Valters, K., and Sonzogni, W. C. (2001). Comparison of polybrominated diphenyl ethers (PBDEs) and polychlorinated biphenyls (PCBs) in Lake Michigan salmonids. Environ. Sci. Technol. 35, 1072–1077.[Medline]
McDonald, T. A. (2002). A perspective on the potential health risks of PBDEs. Chemosphere 46, 745–755.[Medline]
Molloy, G. Y., Rattray, M., and Williams, R. J. (1998). Genes encoding multiple forms of phospholipase A2 are expressed in rat brain. Neurosci. Lett. 258, 139–142.[Web of Science][Medline]
Mundy, W. R., Shafer, T. J., Tilson, H. A., and Kodavanti, P. R. S. (1999). Extracellular calcium is required for the polychlorinated biphenyl-induced increase of intracellular free calcium levels in cerebellar granule cell culture. Toxicology 136, 27–39.[Web of Science][Medline]
Noren, K., and Meironyte, D. (2000). Certain organochlorine and organobromine contaminants in Swedish human milk in the perspective of the past 20–30 years. Chemosphere 40, 1111–1123.[Medline]
Roseth, S., Fykse, E. M., and Fonnum, F. (1998). The effect of arachidonic acid and free fatty acids on vesicular uptake of glutamate and 
-aminobutyric acid. Eur. J. Pharmacol. 34, 281–288.
Ross, B. M., Moszczynska, A., Erlich, J., and Kish, S. J. (1998). Low activity of key phospholipid catabolic and anabolic enzymes in human substantia nigra: Possible implications for Parkinson’s disease. Neuroscience 83, 791–798.[Web of Science][Medline]
Ryan, J. J., and Patry, B. (2000). Determination of brominated diphenyl ethers (BDEs) and levels in Canadian human milks. Organohal. Comp. 47, 57–60.
Sanchez, E., Fernandez-Santiago, M., Lopez-Aparicio, P., Recio, M. N., and Perez-Albarsanz, M. A. (2000). Selective fatty acid release from intracellular phospholipids caused by PCBs in rat renal tubular cell cultures. Chem. Biol. Interact. 125, 117–131.[Web of Science][Medline]
Sanchez, E., Lopez-Aparicio, P., Recio, M.. N., and Perez-Albarsanz, M. A. (1997). Effect of Aroclor 1248 and two pure PCB congeners upon the release of arachidonic acid from the intracellular phospholipids of rat renal tubular cell cultures. Pestic. Biochem. Physiol. 59, 25–34.
SAS. (1989). SAS/STAT users guide, vol. 2, GLM-VARCOMP, version 6, 4th ed, SAS institute, Cary, NC.
She, J., Petreas, M., Winkler, J., Visita, P., McKinney, M., and Kopec, D. (2002). PBDEs in the San Francisco Bay area: Measurements in harbor seal blubber and human breast adipose tissue. Chemosphere 46, 697–707.[Medline]
Sjodin, A. (2000). Occupational and dietary exposure to organohalogen substances, with special emphasis on polybrominated diphenyl ethers. Doctoral dissertation, Stockholm University.
Sjodin, A., Patterson, D. G., Jr., and Bergman, A. (2001). Brominated flame retardants in serum from U.S. blood donors. Environ. Sci. Technol. 35, 3830–3833.[Medline]
Tithof, P. K., Olivero, J., Ruehle, K., and Ganey, P. E. (2000). Activation of neutrophil calcium-dependent and -independent phospholipases A2 by organochlorine compounds. Toxicol. Sci. 53, 40–47.
Tithof, P. K., Peters-Golden, M., and Ganey, P. E. (1998). Distinct phospholipases A2 regulate the release of arachidonic acid for eicosanoid production and superoxide anion generation in neutrophils. J. Immunol. 160, 953–960.
Tithof, P. K., Schiamberg, E., Peters-Golden, M., and Ganey, P. E. (1996). Phospholipase A2 is involved in the mechanism of activation of neutrophils by polychlorinated biphenyls. Environ.. Health Perspect. 104, 52–58.[Web of Science][Medline]
Viberg, H., Fredriksson, A., Jakobsson, E., Ohrn, U., and Eriksson, P. (2000). Developmental neurotoxic effects of 2,2',4,4',5-pentabromodiphenyl ether (PBDE 99) in the neonatal mouse. Toxicologist 54, 290 (Abstract).
Viberg, H., Fredriksson, A., Jakobsson, E., Ohrn, U., and Eriksson, P. (2001). Brominated flame retardant: uptake, retention and developmental neurotoxic effects of decabromo-diphenyl ether (PBDE 209) in the neonatal mouse. Toxicologist 60, 217 (Abstract).
Wolf, M. J., Izumi, Y., Zorumski, C. F., and Gross, R. W. (1995). Long-term potentiation requires activation of calcium-dependent phospholipase A2. FEBS Lett. 377, 358–362.[Web of Science][Medline]
WHO (1994). Environmental Health Criteria 162: Brominated Diphenyl Ethers, Prepared by Dr. G. J. Van Esch, International programme on chemical safety. World Health Organization, Geneva, Switzerland.
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