title: Identification of urinary microRNA profiles in rats that may diagnose hepatotoxicity.
abstract: Circulating microRNAs (miRNAs) have emerged as novel noninvasive biomarkers for several diseases and other types of tissue injury. This study tested the hypothesis that changes in the levels of urinary miRNAs correlate with liver injury induced by hepatotoxicants. Sprague-Dawley rats were administered acetaminophen (APAP) or carbon tetrachloride (CCl(4)) and one nonhepatotoxicant (penicillin/PCN). Urine samples were collected over a 24 h period after a single oral dose of APAP (1250 mg/kg), CCl(4) (2000 mg/kg), or PCN (2400 mg/kg). APAP and CCl(4) induced liver injury based upon increased serum alanine and aspartate aminotransferase levels and histopathological findings, including liver necrosis. APAP and CCl(4) both significantly increased the urinary levels of 44 and 28 miRNAs, respectively. In addition, 10 of the increased miRNAs were in common between APAP and CCl(4). In contrast, PCN caused a slight decrease of a different nonoverlapping set of urinary miRNAs. Cluster analysis revealed a distinct urinary miRNA pattern from the hepatotoxicant-treated groups when compared with vehicle controls and PCN. Analysis of hepatic miRNA levels suggested that the liver was the source of the increased urinary miRNAs after APAP exposure; however, the results from CCl(4) were equivocal. Computational analysis was used to predict target genes of the 10 shared hepatotoxicant-induced miRNAs. Liver gene expression profiling using whole genome microarrays identified eight putative miRNA target genes that were significantly altered in the liver of APAP- and CCl(4)-treated animals. In conclusion, the patterns of urinary miRNA may hold promise as biomarkers of hepatotoxicant-induced liver injury.
authors: Division of Systems Biology, National Center for Toxicological Research, Food and Drug Administration, Jefferson, Arkansas 72079, USA.
authors: Xi
authors: X
authors: Yang
authors: James
authors: J
authors: Greenhaw
authors: Qiang
authors: Q
authors: Shi
authors: Zhenqiang
authors: Z
authors: Su
authors: Feng
authors: F
authors: Qian
authors: Kelly
authors: K
authors: Davis
authors: Donna L
authors: DL
authors: Mendrick
authors: William F
authors: WF
authors: Salminen
mesh_terms: D000082:Acetaminophen / Q000633:toxicity*; D000410:Alanine Transaminase / Q000097:blood; D000469:Alkaline Phosphatase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D015415:Biomarkers / Q000097:blood; D002251:Carbon Tetrachloride / Q000633:toxicity*; D056486:Chemical and Drug Induced Liver Injury / Q000175:diagnosis* / Q000209:etiology / Q000235:genetics / Q000473:pathology / Q000652:urine; D005819:Genetic Markers; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D035683:MicroRNAs / Q000652:urine*; D009336:Necrosis; D010406:Penicillins / Q000633:toxicity; D011237:Predictive Value of Tests; D051381:Rats; D017207:Rats, Sprague-Dawley; D018570:Risk Assessment; D013997:Time Factors; D018675:Toxicity Tests / Q000379:methods*; D016482:Urinalysis
chemical_list: D015415:Biomarkers; D005819:Genetic Markers; D035683:MicroRNAs; D010406:Penicillins; D000082:Acetaminophen; D002251:Carbon Tetrachloride; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D000469:Alkaline Phosphatase