Differential effects of polybrominated diphenyl ethers and polychlorinated biphenyls on [3H]arachidonic acid release in rat cerebellar granule neurons.
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 [(3)H]arachidonic acid ([(3)H]AA) by a cPLA(2)/iPLA(2)-dependent mechanism. PLA(2)(phospholipase A(2)) 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 [(3)H]AA release in an in vitro neuronal culture model. Cerebellar granule cells at 7 days in culture were labeled with [(3)H]AA for 16-20 h and then exposed in vitro to PBDEs. DE-71, a mostly pentabromodiphenyl ether mixture, significantly stimulated [(3)H]AA release at concentrations as low as 10 microg/ml, while DE-79, a mostly octabromodiphenyl ether mixture, did not stimulate [(3)H]AA release, even at 50 microg/ml. The release of [(3)H]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 [(3)H]AA release; however, only an 18% inhibition of the release was demonstrated for the calcium replete conditions at 30 microg/ml DE-71. Methyl arachidonylfluorophosphonate (5 microM), an inhibitor of cPLA(2)/iPLA(2), completely attenuated the DE-71-stimulated [(3)H]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 [(3)H]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 [(3)H]AA by activating PLA(2), which is similar to the effect of other organohalogen mixtures.
Kodavanti
Prasada Rao S
PR
Cellular and Molecular Toxicology Branch, Neurotoxicology Division, MD 74B, NHEERL, ORD, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA. kodavanti.prasada@epa.gov
Derr-Yellin
Ethel C
EC
D000818:Animals; D000831:Animals, Newborn; D016718:Arachidonic Acid / Q000378:metabolism*; D001095:Arachidonic Acids / Q000494:pharmacology; D002118:Calcium / Q000494:pharmacology; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology; D004305:Dose-Response Relationship, Drug; D004336:Drug Antagonism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005411:Flame Retardants / Q000633:toxicity*; D055768:Halogenated Diphenyl Ethers; D006842:Hydrocarbons, Brominated / Q000633:toxicity*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D063065:Organophosphonates / Q000494:pharmacology; D010647:Phenyl Ethers / Q000633:toxicity*; D010741:Phospholipases A / Q000037:antagonists & inhibitors; D011075:Polybrominated Biphenyls; D011078:Polychlorinated Biphenyls / Q000633:toxicity*; D051381:Rats; D020318:Rats, Long-Evans; D013997:Time Factors; D014316:Tritium
D001095:Arachidonic Acids; D004791:Enzyme Inhibitors; D005411:Flame Retardants; D055768:Halogenated Diphenyl Ethers; D006842:Hydrocarbons, Brominated; D063065:Organophosphonates; D010647:Phenyl Ethers; D011075:Polybrominated Biphenyls; C104810:methyl arachidonylfluorophosphonate; D014316:Tritium; D016718:Arachidonic Acid; C086401:pentabromodiphenyl ether; D011078:Polychlorinated Biphenyls; D010741:Phospholipases A; D002118:Calcium