Combination of 'omics' data to investigate the mechanism(s) of hydrazine-induced hepatotoxicity in rats and to identify potential biomarkers

被引:65
作者
Kleno, TG [1 ]
Kiehr, B [1 ]
Baunsgaard, D [1 ]
Sidelmann, UG [1 ]
机构
[1] Novo Nordisk AS, Dept Appl Trin, DK-2760 Malov, Denmark
关键词
hydrazine; proteomics; genomics; metabonomics; glucose metabolism; lipid metabolism; oxidative stress;
D O I
10.1080/13547500410001728408
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
To gain novel insight into the molecular mechanisms underlying hydrazine-induced hepatotoxicity, mRNAs, proteins and endogenous metabolites were identified that were altered in rats treated with hydrazine compared with untreated controls. These changes were resolved in a combined genomics, proteomics and metabonomics study. Sprague - Dawley rats were assigned to three treatment groups with 10 animals per group and given a single oral dose of vehicle, 30 or 90 mg kg(-1) hydrazine, respectively. RNA was extracted from rat liver 48 h post-dosing and transcribed into cDNA. The abundance of mRNA was investigated on cDNA microarrays containing 699 rat-specific genes involved in toxic responses. In addition, proteins from rat liver samples ( 48 and 120/168 h post-dosing) were resolved by two-dimensional differential gel electrophoresis and proteins with changed expression levels after hydrazine treatment were identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry peptide mass fingerprinting. To elucidate how regulation was reflected in biochemical pathways, endogenous metabolites were measured in serum samples collected 48 h post-dosing by 600-MHz H-1-NMR. In summary, a single dose of hydrazine caused gene, protein and metabolite changes, which can be related to glucose metabolism, lipid metabolism and oxidative stress. These findings support known effects of hydrazine toxicity and provide potential new biomarkers of hydrazine-induced toxicity.
引用
收藏
页码:116 / 138
页数:23
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