title: Sex-related differential susceptibility to doxorubicin-induced cardiotoxicity in B6C3F1mice.
abstract: Sex is a risk factor for development of cardiotoxicity, induced by the anti-cancer drug, doxorubicin (DOX), in humans. To explore potential mechanisms underlying differential susceptibility to DOX between sexes, 8-week old male and female B6C3F1mice were dosed with 3mg/kg body weight DOX or an equivalent volume of saline via tail vein once a week for 6, 7, 8, and 9 consecutive weeks, resulting in 18, 21, 24, and 27mg/kg cumulative DOX doses, respectively. At necropsy, one week after each consecutive final dose, the extent of myocardial injury was greater in male mice compared to females as indicated by higher plasma concentrations of cardiac troponin T at all cumulative DOX doses with statistically significant differences between sexes at the 21 and 24mg/kg cumulative doses. A greater susceptibility to DOX in male mice was further confirmed by the presence of cytoplasmic vacuolization in cardiomyocytes, with left atrium being more vulnerable to DOX cardiotoxicity. The number of TUNEL-positive cardiomyocytes was mostly higher in DOX-treated male mice compared to female counterparts, showing a statistically significant sex-related difference only in left atrium at 21mg/kg cumulative dose. DOX-treated male mice also had an increased number of γ-H2A.X-positive (measure of DNA double-strand breaks) cardiomyocytes compared to female counterparts with a significant sex effect in the ventricle at 27mg/kg cumulative dose and right atrium at 21 and 27mg/kg cumulative doses. This newly established mouse model provides a means to identify biomarkers and access potential mechanisms underlying sex-related differences in DOX-induced cardiotoxicity.
authors.affiliation: Personalized Medicine Branch, Division of Systems Biology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, United States.
authors.forename: G Ronald
authors.initials: GR
authors.lastname: Jenkins
authors.affiliation: Department of Mathematics, Korea University, Sejong, Republic of Korea.
authors.forename: Taewon
authors.initials: T
authors.lastname: Lee
authors.affiliation: Personalized Medicine Branch, Division of Systems Biology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, United States.
authors.forename: Carrie L
authors.initials: CL
authors.lastname: Moland
authors.affiliation: Personalized Medicine Branch, Division of Systems Biology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, United States.
authors.forename: Vikrant
authors.initials: V
authors.lastname: Vijay
authors.affiliation: Toxicology and Pharmacology Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, The National Cancer Institute, Rockville, MD 20850-9734, United States.
authors.forename: Eugene H
authors.initials: EH
authors.lastname: Herman
authors.affiliation: Office of Scientific Coordination, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, United States.
authors.forename: Sherry M
authors.initials: SM
authors.lastname: Lewis
authors.affiliation: Toxicologic Pathology Associates, National Center for Toxicological Research, Jefferson, AR 72079, United States.
authors.forename: Kelly J
authors.initials: KJ
authors.lastname: Davis
authors.affiliation: Toxicologic Pathology Associates, National Center for Toxicological Research, Jefferson, AR 72079, United States.
authors.forename: Levan
authors.initials: L
authors.lastname: Muskhelishvili
authors.affiliation: Arkansas Heart Hospital, Little Rock, AR 72211, United States.
authors.forename: Susan
authors.initials: S
authors.lastname: Kerr
authors.affiliation: Personalized Medicine Branch, Division of Systems Biology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, United States.
authors.forename: James C
authors.initials: JC
authors.lastname: Fuscoe
authors.affiliation: Personalized Medicine Branch, Division of Systems Biology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, United States. Electronic address: varsha.desai@fda.hhs.gov.
authors.forename: Varsha G
authors.initials: VG
authors.lastname: Desai
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D001835:Body Weight / Q000187:drug effects; D004317:Doxorubicin / Q000633:toxicity*; D005260:Female; D006321:Heart / Q000187:drug effects*; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice; D009929:Organ Size / Q000187:drug effects; D012737:Sex Factors; D015430:Weight Gain / Q000187:drug effects
chemical_list: D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin
keywords: Apoptosis; Cardiotoxicity; DNA damage; Doxorubicin; Mouse model; Sex-based differences