Role of N-methyl-D-aspartate receptors in polychlorinated biphenyl mediated neurotoxicity.
Polychlorinated biphenyls (PCBs) are widespread persistent environmental pollutants. Chronic human and animal exposure to PCBs results in various harmful effects including neurotoxicity. This study investigates the effects of the PCB mixture Aroclor 1254 (A1254) and two PCB congeners (coplanar, non-ortho PCB 126, and non coplanar PCB 99) on the expression of N-methyl-D-aspartate receptors (NMDARs) and the subsequent toxic effects using a human SHS5-SY neuroblastoma cell line. NMDAR was measured using a radiolabeled phencyclidine receptor ligand [(3)H]-MK801, apoptosis was quantified using fluorogenic substrates specific for caspase-3 (DEVD-AFC) and cell death using lactate dehydrogenase (LDH) release. After treatment, a positive dose-response relationship of increasing NMDARS, increasing caspase-3 activity and cell death was observed in all PCB compounds. The non-coplanar PCB compounds were found to be significantly more toxic than the coplanar congener and the PCB mixture A1254. PCB-mediated cell death was attenuated with 10microM NMDAR antagonists: 1-amino-3,5-dimethyladamantane hydrochloride (memantine) and (+)-5-methyl-10,11-dihydro-5H-debenzocyclhepten-5,10-imine maleate ((+)-MK-801), thus demonstrating the importance of NMDAR in PCB neurotoxicity. Intracellular calcium [Ca(2+)](i) chelator BAPTA-AM (1microM) partially attenuated the neurotoxic effect of the PCBs suggesting a role of calcium homeostasis disruption in the neurotoxicity of PCBs. These results suggest that the neurotoxicity of PCBs can be mediated through activation of NMDARs.
Ndountse
Leopold Tchapda
LT
Community Health Sciences Program, University of Northern British Columbia, Prince George, BC, Canada V2N4Z9.
Chan
Hing Man
HM
D053148:Caspase 3 / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D004785:Environmental Pollutants / Q000378:metabolism / Q000633:toxicity*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008559:Memantine / Q000494:pharmacology*; D020258:Neurotoxicity Syndromes / Q000201:enzymology / Q000378:metabolism*; D011078:Polychlorinated Biphenyls / Q000378:metabolism / Q000633:toxicity*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism* / Q000502:physiology; D014407:Tumor Cells, Cultured
D004785:Environmental Pollutants; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D016291:Dizocilpine Maleate; D011078:Polychlorinated Biphenyls; D007770:L-Lactate Dehydrogenase; D053148:Caspase 3; D008559:Memantine