title: Integrated histopathological and urinary metabonomic investigation of the pathogenesis of microcystin-LR toxicosis.
abstract: Patterns of change of endogenous metabolites may closely reflect systemic and organ-specific toxic changes. The authors examined the metabolic effects of the cyanobacterial (blue-green algal) toxin microcystin-LR by (1)H-nuclear magnetic resonance (NMR) analysis of urinary endogenous metabolites. Rats were treated with a single sublethal dose, either 20 or 80 µg/kg intraperitoneally, and sacrificed at 2 or 7 days post dosing. Changes in the high-dose, 2-day sacrifice group included centrilobular hepatic necrosis and congestion, accompanied in some animals by regeneration and neovascularization. By 7 days, animals had recovered, the necrotizing process had ended, and the centrilobular areas had been replaced by regenerative, usually hypertrophic hepatocytes. There was considerable interanimal variation in the histologic process and severity, which correlated with the changes in patterns of endogenous metabolites in the urine, thus providing additional validation of the biomarker and biochemical changes. Similarity of the shape of the metabolic trajectories suggests that the mechanisms of toxic effects and recovery are similar among the individual animals, albeit that the magnitude and timing are different for the individual animals. Initial decreases in urinary citrate, 2-oxoglutarate, succinate, and hippurate concentrations were accompanied by a temporary increase in betaine and taurine, then creatine from 24 to 48 hours. Further changes were an increase in guanidinoacetate, dimethylglycine, urocanic acid, and bile acids. As a tool, urine can be repeatedly and noninvasively sampled and metabonomics utilized to study the onset and recovery after toxicity, thus identifying time points of maximal effect. This can help to employ histopathological examination in a guided and effective fashion.
authors.affiliation: Discovery Toxicology, Bristol-Myers Squibb Co, Princeton, NJ 08543, USA. glenn.cantor@bms.com
authors.forename: G H
authors.initials: GH
authors.lastname: Cantor
authors.forename: O
authors.initials: O
authors.lastname: Beckonert
authors.forename: M E
authors.initials: ME
authors.lastname: Bollard
authors.forename: H C
authors.initials: HC
authors.lastname: Keun
authors.forename: T M D
authors.initials: TM
authors.lastname: Ebbels
authors.forename: H
authors.initials: H
authors.lastname: Antti
authors.forename: J A
authors.initials: JA
authors.lastname: Wijsman
authors.forename: R H
authors.initials: RH
authors.lastname: Bible
authors.forename: A P
authors.initials: AP
authors.lastname: Breau
authors.forename: G L
authors.initials: GL
authors.lastname: Cockerell
authors.forename: E
authors.initials: E
authors.lastname: Holmes
authors.forename: J C
authors.initials: JC
authors.lastname: Lindon
authors.forename: J K
authors.initials: JK
authors.lastname: Nicholson
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000652:urine; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000633:toxicity*; D007274:Injections, Intraperitoneal; D007668:Kidney / Q000187:drug effects* / Q000473:pathology; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008387:Marine Toxins; D055432:Metabolomics / Q000379:methods*; D052998:Microcystins / Q000378:metabolism / Q000633:toxicity*; D046931:Microcystis / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014560:Urocanic Acid / Q000652:urine
chemical_list: D001647:Bile Acids and Salts; D004791:Enzyme Inhibitors; D008387:Marine Toxins; D052998:Microcystins; C057862:cyanoginosin LR; D014560:Urocanic Acid