title: Sex-related differences in mast cell activity and doxorubicin toxicity: a study in spontaneously hypertensive rats.
abstract: Clinically, girls appear to be more sensitive than boys to the cardiotoxic effects of doxorubicin, whereas the opposite may be true for adults. To identify and characterize potential sex-related differences, adult male and female spontaneously hypertensive rats (SHR; some ovariectomized [OVX]) received 1 mg/kg of doxorubicin or saline iv weekly for 9, 10, or 12 weeks. Weight gain was slower in treated males. Serum concentrations of cholesterol and triglycerides increased and those of albumin decreased in both sexes, but changes were more pronounced in treated males. Treated males had significantly more severe cardiomyopathy scores and higher serum levels of cTnT than females. The increased cardiotoxicity was accompanied by higher numbers of cardiac mast cells (MCs) and percentage of cardiac MCs undergoing degranulation. Doxorubicin-treated OVX animals had significantly increased numbers of cardiac MCs, more severe myocardial lesions, and elevated serum concentrations of cTnT compared to doxorubicin-treated normal female SHR. The severity of cardiac lesions in the OVX female was similar to that observed in doxorubicin-treated males. This study demonstrated the presence of sex-related differences in the cardiotoxic effects elicited by doxorubicin and identified variations in the level of cardiac MC activity as a factor which could possibly contribute to the male-female dissimilarity.
authors.affiliation: 1Division of Drug Safety Research, Center for Drug Evaluation and Research Food and Drug Administration, Silver Spring, Maryland, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.forename: Alan
authors.initials: A
authors.lastname: Knapton
authors.forename: Steven E
authors.initials: SE
authors.lastname: Lipshultz
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Cochran
authors.forename: Hajime
authors.initials: H
authors.lastname: Hiraragi
authors.forename: Eugene H
authors.initials: EH
authors.lastname: Herman
mesh_terms: D000818:Animals; D001774:Blood Chemical Analysis; D009202:Cardiomyopathies / Q000097:blood / Q000139:chemically induced* / Q000473:pathology; D004317:Doxorubicin / Q000633:toxicity*; D005260:Female; D006321:Heart / Q000187:drug effects; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D007674:Kidney Diseases / Q000097:blood / Q000139:chemically induced* / Q000473:pathology; D008297:Male; D008407:Mast Cells / Q000166:cytology* / Q000187:drug effects*; D010052:Ovariectomy; D051381:Rats; D011918:Rats, Inbred SHR; D012737:Sex Factors
chemical_list: D004317:Doxorubicin
keywords: cardiac mast cells; cardiomyopathy; doxorubicin; nephropathy; ovariectomy; renal mast cells.; spontaneously hypertensive rats