Mechanisms underlying the developmental neurotoxic effect of PBDE-47 and the enhanced toxicity associated with its combination with PCB153 in rats.
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.
He
Ping
P
Department of Environmental Health, MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, People's Republic of China.
Wang
Ai-guo
AG
Xia
Tao
T
Gao
Ping
P
Niu
Qiang
Q
Guo
Li-juan
LJ
Chen
Xue-min
XM
D000818:Animals; D000831:Animals, Newborn; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D045304:Cytochromes c / Q000235:genetics / Q000378:metabolism; D064550:Death-Associated Protein Kinases; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D005260:Female; D055768:Halogenated Diphenyl Ethers / Q000633:toxicity*; D006624:Hippocampus / Q000473:pathology; D018782:Maze Learning / Q000187:drug effects; D046529:Microscopy, Electron, Transmission / Q000379:methods; D020258:Neurotoxicity Syndromes / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology*; D011078:Polychlorinated Biphenyls / Q000633:toxicity*; D011247:Pregnancy; D017966:Pyramidal Cells / Q000648:ultrastructure; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; D004338:Drug Combinations; D055768:Halogenated Diphenyl Ethers; D012333:RNA, Messenger; D051636:X-Linked Inhibitor of Apoptosis Protein; C511295:2,2',4,4'-tetrabromodiphenyl ether; D045304:Cytochromes c; D011078:Polychlorinated Biphenyls; D064550:Death-Associated Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020169:Caspases; C014024:2,4,5,2',4',5'-hexachlorobiphenyl