title: Development of doxorubicin-induced chronic cardiotoxicity in the B6C3F1 mouse model.
abstract: Serum levels of cardiac troponins serve as biomarkers of myocardial injury. However, troponins are released into the serum only after damage to cardiac tissue has occurred. Here, we report development of a mouse model of doxorubicin (DOX)-induced chronic cardiotoxicity to aid in the identification of predictive biomarkers of early events of cardiac tissue injury. Male B6C3F(1) mice were administered intravenous DOX at 3mg/kg body weight, or an equivalent volume of saline, once a week for 4, 6, 8, 10, 12, and 14weeks, resulting in cumulative DOX doses of 12, 18, 24, 30, 36, and 42mg/kg, respectively. Mice were sacrificed a week following the last dose. A significant reduction in body weight gain was observed in mice following exposure to a weekly DOX dose for 1week and longer compared to saline-treated controls. DOX treatment also resulted in declines in red blood cell count, hemoglobin level, and hematocrit compared to saline-treated controls after the 2nd weekly dose until the 8th and 9th doses, followed by a modest recovery. All DOX-treated mice had significant elevations in cardiac troponin T concentrations in plasma compared to saline-treated controls, indicating cardiac tissue injury. Also, a dose-related increase in the severity of cardiac lesions was seen in mice exposed to 24mg/kg DOX and higher cumulative doses. Mice treated with cumulative DOX doses of 30mg/kg and higher showed a significant decline in heart rate, suggesting drug-induced cardiac dysfunction. Altogether, these findings demonstrate the development of DOX-induced chronic cardiotoxicity in B6C3F(1) mice.
authors.affiliation: Personalized Medicine Branch, Division of Systems Biology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, USA. varsha.desai@fda.hhs.gov
authors.forename: Varsha G
authors.initials: VG
authors.lastname: Desai
authors.forename: Eugene H
authors.initials: EH
authors.lastname: Herman
authors.forename: Carrie L
authors.initials: CL
authors.lastname: Moland
authors.forename: William S
authors.initials: WS
authors.lastname: Branham
authors.forename: Sherry M
authors.initials: SM
authors.lastname: Lewis
authors.forename: Kelly J
authors.initials: KJ
authors.lastname: Davis
authors.forename: Nysia I
authors.initials: NI
authors.lastname: George
authors.forename: Taewon
authors.initials: T
authors.lastname: Lee
authors.forename: Susan
authors.initials: S
authors.lastname: Kerr
authors.forename: James C
authors.initials: JC
authors.lastname: Fuscoe
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects / Q000502:physiology; D054715:Cardiotoxins / Q000633:toxicity*; D002908:Chronic Disease; D003433:Crosses, Genetic; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000633:toxicity*; D006321:Heart / Q000187:drug effects / Q000502:physiology; D006331:Heart Diseases / Q000097:blood / Q000139:chemically induced* / Q000473:pathology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D009929:Organ Size / Q000187:drug effects / Q000502:physiology; D013045:Species Specificity
chemical_list: D054715:Cardiotoxins; D004317:Doxorubicin