期刊
NEUROTOXICOLOGY
卷 28, 期 3, 页码 478-489出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.neuro.2006.10.005
关键词
manganese; inflammatory factors; human astrocytes; microarray; gene expression
资金
- NHLBI NIH HHS [R01 HL065568-06, HL 65568, R01 HL065568] Funding Source: Medline
- NIEHS NIH HHS [P42 ES010349] Funding Source: Medline
- NINDS NIH HHS [NS 31492, P01 NS031492-13, P01 NS031492] Funding Source: Medline
Exposure of adult humans to manganese (Mn) has long been known to cause neurotoxicity. Recent evidence also suggests that exposure of children to Mn is associated with developmental neurotoxicity. Astrocytes are critical for the proper functioning of the nervous system, and they play active roles in neurogenesis, synaptogenesis and synaptic neurotransmission. In this report, to help elucidate the molecular events underlying Mn neurotoxicity, we systematically identified the molecular targets of Mn in primary human astrocytes at a genome-wide level, by using microarray gene expression profiling and computational data analysis algorithms. We found that Mn altered the expression of diverse genes ranging from those encoding cytokines and transporters to signal transducers and transcriptional regulators. Particularly, 28 genes encoding proinflammatory chemokines, cytokines and related functions were up-regulated, whereas 15 genes encoding functions involved in DNA replication and repair and cell cycle checkpoint control were down-regulated. Consistent with the increased expression of proinflammatory factors, analysis of common regulators revealed that 16 targets known to be positively affected by the interferon-gamma signaling pathway were up-regulated by Mn2+. In addition, 68 genes were found to be similarly up- or down-regulated by both Mn2+ and hypoxia. These results from genomic analysis are further supported by data from real-time RT-PCR, Western blotting, flow cytometric and toxicological analyses. Together, these analyses show that Mn2+ selectively affects cell cycle progression, the expression of hypoxia-responsive genes, and the expression of proinflammatory factors in primary human astrocytes. These results provide important insights into the molecular mechanisms underlying Mn neurotoxicity. (c) 2006 Elsevier Inc. All rights reserved.
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