title: Early metabolomics changes in heart and plasma during chronic doxorubicin treatment in B6C3F1 mice.
abstract: The present study aimed to identify molecular markers of early stages of cardiotoxicity induced by a potent chemotherapeutic agent, doxorubicin (DOX). Male B6C3F1 mice were dosed with 3 mg kg(-1) DOX or saline via tail vein weekly for 2, 3, 4, 6 or 8 weeks (cumulative DOX doses of 6, 9, 12, 18 or 24 mg kg(-1) , respectively) and euthanized a week after the last dose. Mass spectrometry-based and nuclear magnetic resonance spectrometry-based metabolic profiling were employed to identify initial biomarkers of cardiotoxicity before myocardial injury and cardiac pathology, which were not noted until after the 18 and 24 mg kg(-1) cumulative doses, respectively. After a cumulative dose of 6 mg kg(-1) , 18 amino acids and four biogenic amines (acetylornithine, kynurenine, putrescine and serotonin) were significantly increased in cardiac tissue; 16 amino acids and two biogenic amines (acetylornithine and hydroxyproline) were significantly altered in plasma. In addition, 16 acylcarnitines were significantly increased in plasma and five were significantly decreased in cardiac tissue compared to saline-treated controls. Plasma lactate and succinate, involved in the Krebs cycle, were significantly altered after a cumulative dose of 6 mg kg(-1) . A few metabolites remained altered at higher cumulative DOX doses, which could partly indicate a transition from injury processes at 2 weeks to repair processes with additional injury happening concurrently before myocardial injury at 8 weeks. These altered metabolic profiles in mouse heart and plasma during the initial stages of injury progression due to DOX treatment may suggest these metabolites as candidate early biomarkers of cardiotoxicity. Published 2016. This article is a U.S. Government work and is in the public domain in the USA.
authors.affiliation: Division of Systems Biology, National Center for Toxicological Research, US FDA, Jefferson, Arkansas, 72079, USA. laura.schnackenberg@fda.hhs.gov.
authors.forename: Laura K
authors.initials: LK
authors.lastname: Schnackenberg
authors.affiliation: Division of Systems Biology, National Center for Toxicological Research, US FDA, Jefferson, Arkansas, 72079, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Pence
authors.affiliation: Division of Systems Biology, National Center for Toxicological Research, US FDA, Jefferson, Arkansas, 72079, USA.
authors.forename: Vikrant
authors.initials: V
authors.lastname: Vijay
authors.affiliation: Division of Systems Biology, National Center for Toxicological Research, US FDA, Jefferson, Arkansas, 72079, USA.
authors.forename: Carrie L
authors.initials: CL
authors.lastname: Moland
authors.affiliation: Division of Bioinformatics and Biostatistics, National Center for Toxicological Research, US FDA, Jefferson, Arkansas, 72079, USA.
authors.forename: Nysia
authors.initials: N
authors.lastname: George
authors.affiliation: Division of Systems Biology, National Center for Toxicological Research, US FDA, Jefferson, Arkansas, 72079, USA.
authors.forename: Zhijun
authors.initials: Z
authors.lastname: Cao
authors.affiliation: Division of Systems Biology, National Center for Toxicological Research, US FDA, Jefferson, Arkansas, 72079, USA.
authors.forename: Li-Rong
authors.initials: LR
authors.lastname: Yu
authors.affiliation: Division of Systems Biology, National Center for Toxicological Research, US FDA, Jefferson, Arkansas, 72079, USA.
authors.forename: James C
authors.initials: JC
authors.lastname: Fuscoe
authors.affiliation: Division of Systems Biology, National Center for Toxicological Research, US FDA, Jefferson, Arkansas, 72079, USA.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Beger
authors.affiliation: Division of Systems Biology, National Center for Toxicological Research, US FDA, Jefferson, Arkansas, 72079, USA.
authors.forename: Varsha G
authors.initials: VG
authors.lastname: Desai
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D001679:Biogenic Amines / Q000097:blood*; D015415:Biomarkers / Q000097:blood; D066126:Cardiotoxicity; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000633:toxicity*; D006321:Heart / Q000187:drug effects*; D007275:Injections, Intravenous; D008297:Male; D055442:Metabolome / Q000187:drug effects*; D008815:Mice, Inbred Strains; D009206:Myocardium / Q000378:metabolism*
chemical_list: D000903:Antibiotics, Antineoplastic; D001679:Biogenic Amines; D015415:Biomarkers; D004317:Doxorubicin
keywords: Biomarkers; Cardiotoxicity; Doxorubicin; Metabolomics