Synergistic effects of iron and aluminum on stress-related gene expression in primary human neural cells.
Disturbances in metal-ion transport, homeostasis, overload and metal ion-mediated catalysis are implicated in neurodegenerative conditions such as Alzheimer's disease (AD). The mechanisms of metal-ion induced disruption of genetic function, termed genotoxicity, are not well understood. In these experiments we examined the effects of non-apoptotic concentrations of magnesium-, iron- and aluminum-sulfate on gene expression patterns in untransformed human neural (HN) cells in primary culture using high density DNA array profiling and Western immunoassay. Two week old HN cells were exposed to low micromolar magnesium, iron, or aluminum for 7 days, representing trace metal exposure over one-third of their lifespan. While total RNA yield and abundance were not significantly altered, both iron and aluminum were found to induce HSP27, COX-2, betaAPP and DAXX gene expression. Similarly up-regulated gene expression for these stress-sensing, pro-inflammatory and pro-apoptotic elements have been observed in AD brain. The combination of iron and aluminum together was found to be particularly effective in up-regulating these genes, and was preceded by the evolution of reactive oxygen intermediates as measured by 2',7'-dichlorofluorescein diacetate assay. These data indicate that physiologically relevant amounts of iron and aluminum are capable of inducing Fenton chemistry-triggered gene expression programs that may support downstream pathogenic responses and brain cell dysfunction.
Alexandrov
Peter N
PN
Russian Academy of Medical Sciences, Moscow 113152, Russia.
Zhao
Yuhai
Y
Pogue
Aileen I
AI
Tarr
Matthew A
MA
Kruck
Theo P A
TP
Percy
Maire E
ME
Cui
Jian-Guo
JG
Lukiw
Walter J
WJ
D048868:Adaptor Proteins, Signal Transducing; D000534:Alum Compounds / Q000633:toxicity*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D015153:Blotting, Western; D002352:Carrier Proteins / Q000235:genetics*; D002460:Cell Line; D056970:Co-Repressor Proteins; D051546:Cyclooxygenase 2 / Q000235:genetics*; D016172:DNA Fingerprinting; D004357:Drug Synergism; D015870:Gene Expression / Q000187:drug effects*; D055551:HSP27 Heat-Shock Proteins; D006360:Heat-Shock Proteins / Q000235:genetics*; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D007501:Iron / Q000633:toxicity*; D008278:Magnesium Sulfate / Q000633:toxicity; D018832:Molecular Chaperones; D009363:Neoplasm Proteins / Q000235:genetics*; D009474:Neurons / Q000187:drug effects*; D009687:Nuclear Proteins / Q000235:genetics*; D012313:RNA / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; D000534:Alum Compounds; D016564:Amyloid beta-Protein Precursor; D002352:Carrier Proteins; D056970:Co-Repressor Proteins; C106985:DAXX protein, human; D055551:HSP27 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; D047908:Intracellular Signaling Peptides and Proteins; D018832:Molecular Chaperones; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; C041524:aluminum sulfate; D012313:RNA; D008278:Magnesium Sulfate; D007501:Iron; D051546:Cyclooxygenase 2