cytochrome-c-t and 2-4-5-2--4--5--hexachlorobiphenyl

Polybrominated diphenyl ethers (PBDEs) are used in large quantities as flame-retardant additives, especially in electrical appliances and textiles. Because of their structural similarity, PBDEs are thought to have toxicities similar to those of polychlorinated biphenyls (PCBs), which are well-known persistent compounds. Both 2,2',4,4'-tetrabromodiphenyl ether (PBDE-47) and 2,2',4,4',5, 5'-hexachlorobiphenyl (PCB153) can coexist in the environment and human tissues as dominant congeners of PBDEs and PCBs, respectively. To explore the mechanisms of the neurotoxic effect of PBDE-47 and the interaction in combination with PCB153, cell viability, lactate dehydrogenase (LDH) leakage, intracellular Ca2+ concentration ([Ca2+]i), apoptosis and expression levels of death associated protein kinase (DAPK), caspase3, caspase12 and cytochrome c mRNA and proteins were measured in SH-SY5Y cells treated with PBDE-47 (0, 1, 5, 10 micromol/L) and/or PCB153 (5 micromol/L) for 24 h. Compared to controls, the cell viabilities were clearly decreased (P<0.05), and LDH leakage, [Ca2+]i and apoptosis were significantly increased (P<0.05). Furthermore, expression levels of DAPK and caspase3 mRNA, caspase12, as well as cytochrome c mRNA and proteins were markedly increased (P<0.05), while pro-caspase3 proteins were significantly decreased (P<0.05). A positive correlation between [Ca2+]i and percentage of apoptotic cells (r=0.86, P<0.05) and an interaction between PBDE-47 and PCB153 (P<0.05) were observed. We conclude that PBDE-47 can induce SH-SY5Y cell apoptosis via three classic apoptosis pathways and interact with PCB153 to enhance neurotoxicity.

Topics: Apoptosis; Apoptosis Regulatory Proteins; Calcium; Calcium-Calmodulin-Dependent Protein Kinases; Caspase 12; Caspase 3; Cell Line; Cell Survival; Cells, Cultured; Cytochromes c; Death-Associated Protein Kinases; Dose-Response Relationship, Drug; Drug Synergism; Halogenated Diphenyl Ethers; Humans; L-Lactate Dehydrogenase; Neurons; Polybrominated Biphenyls; Polychlorinated Biphenyls

To explore the mechanisms underlying the developmental neurotoxic effect of PBDE-47 and its interaction with PCB153, expression levels of mRNA and proteins of the x-chromosome-linked inhibitor of apoptosis protein (XIAP), death associated protein kinase (DAPK), caspase3, caspase12 and cytochrome C in the hippocampus of 2-month-old rats exposed to a single oral dose of PBDE-47 and/or PCB153 on post natal day (PND) 10 were examined. Four levels of PBDE-47 (0, 1, 5, 10 mg/kg) and two levels of PCB153 (0 and 5mg/kg) were added to corn oil in a 4 x 2 factorial completely randomized design study. Meanwhile, the ultrastructures of neurons in the hippocampal CA1 region were observed and the learning and memory capacities were measured in these rats. The results suggested that the mRNA and protein expression levels of all examined genes (with the exception of cytochrome C mRNA in female rats) were significantly changed at some doses (P<0.05); additionally, the total distance swam by rats to reach an escape platform was significantly increased and the ratio of distance taken in the platform quadrant to total distance was notably decreased in all treated groups in the water maze experiment (P<0.05) compared to the control. Numerous alterations were observed in the ultrastructure of neurons in PBDE-47 alone or combination of PBDE-47 and PCB153 groups. Furthermore, an interaction was found between PBDE-47 and PCB153 in lengthening the total distance taken to the platform and decreasing the platform quadrant ratios in the water maze experiment, as well as in the inducing of caspase3, caspase12 and cytochrome C mRNA and protein expression (with exception of cytochrome C mRNA in female rats) in the hippocampus. We conclude that PBDE-47 may induce developmental neurotoxicity in rats via three classic apoptosis pathways, and it may interact with PCB153 to enhance developmental neurotoxicity.

Topics: Animals; Animals, Newborn; Apoptosis Regulatory Proteins; Calcium-Calmodulin-Dependent Protein Kinases; Caspases; Cytochromes c; Death-Associated Protein Kinases; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Combinations; Female; Halogenated Diphenyl Ethers; Hippocampus; Maze Learning; Microscopy, Electron, Transmission; Neurotoxicity Syndromes; Polychlorinated Biphenyls; Pregnancy; Pyramidal Cells; Rats; Rats, Sprague-Dawley; RNA, Messenger; X-Linked Inhibitor of Apoptosis Protein