Combination of 'omics' data to investigate the mechanism(s) of hydrazine-induced hepatotoxicity in rats and to identify potential biomarkers.
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 1H-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.
Klenø
T G
TG
Department of Applied Trinomics, Novo Nordisk A/S, Måløv, Denmark. tgkl@novonordisk.com
Kiehr
B
B
Baunsgaard
D
D
Sidelmann
U G
UG
D000818:Animals; D015415:Biomarkers; D056486:Chemical and Drug Induced Liver Injury; D015180:Electrophoresis, Gel, Two-Dimensional; D020869:Gene Expression Profiling; D023281:Genomics; D005947:Glucose / Q000378:metabolism; D006834:Hydrazines / Q000009:adverse effects*; D050356:Lipid Metabolism; D008099:Liver / Q000737:chemistry; D008107:Liver Diseases / Q000235:genetics / Q000378:metabolism; D008297:Male; D008660:Metabolism / Q000235:genetics; D018384:Oxidative Stress; D011506:Proteins / Q000032:analysis; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
D015415:Biomarkers; D006834:Hydrazines; D011506:Proteins; D012333:RNA, Messenger; C029424:hydrazine; D005947:Glucose