title: Sex-specific dose-response analysis of genotoxicity in cyproterone acetate-treated F344 rats.
abstract: Cyproterone acetate (CPA), a synthetic hormonal drug, induces rat liver tumors in a sex-specific manner, with five-fold higher doses needed to induce liver tumors in male rats compared to females. In order to evaluate the potential of the in vivo alkaline Comet assay to predict the sex-specific carcinogenicity of CPA, CPA-induced direct DNA damage (DNA strand breaks and alkali-labile sites) were evaluated in the livers of both male and female F344 rats. In addition, secondary oxidative DNA damage was measured concurrently utilizing the human 8-oxoguanine-DNA-N-glycosylase (hOGG1) and EndonucleaseIII (EndoIII)-modified in vivo alkaline Comet assays and the reticulocyte micronucleus (MN) frequency was analyzed in peripheral blood. Groups of 5 seven-week-old male and female F344 rats received olive oil or 10, 25, 50 or 100 mg/kg bw CPA in olive oil by gavage at 0, 24, and 45 h and were sacrificed at 48 h. CPA-induced direct DNA damage in rat liver showed the same sex-specific pattern as its hepatotumorigenicity: a five-fold-higher dose of CPA was needed to induce a statistically significant increase in direct DNA damage in livers of males compared to females. However, peripheral blood MN frequency was weak in both sexes and CPA-induced oxidative DNA damage was generally greater in male than female rat livers. Taken together, our results demonstrate concordance in the sex-specificity of CPA in the in vivo alkaline Comet assay and cancer bioassay, while the induction of oxidative DNA damage by CPA was not directly correlated with its tumorigenicity.
authors.affiliation: Division of Genetic and Molecular Toxicology, US FDA/National Center for Toxicological Research, Jefferson, AR 72079, United States. Electronic address: Wei.Ding@fda.hhs.gov.
authors.forename: Wei
authors.initials: W
authors.lastname: Ding
authors.affiliation: Division of Genetic and Molecular Toxicology, US FDA/National Center for Toxicological Research, Jefferson, AR 72079, United States.
authors.forename: Michelle E
authors.initials: ME
authors.lastname: Bishop
authors.affiliation: Division of Genetic and Molecular Toxicology, US FDA/National Center for Toxicological Research, Jefferson, AR 72079, United States.
authors.forename: Mason G
authors.initials: MG
authors.lastname: Pearce
authors.affiliation: Toxicologic Pathology Associates, US FDA/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, US FDA/National Center for Toxicological Research, Jefferson, AR 72079, United States.
authors.forename: Gene A
authors.initials: GA
authors.lastname: White
authors.affiliation: Division of Genetic and Molecular Toxicology, US FDA/National Center for Toxicological Research, Jefferson, AR 72079, United States.
authors.forename: Lascelles E
authors.initials: LE
authors.lastname: Lyn-Cook
authors.affiliation: Division of Genetic and Molecular Toxicology, US FDA/National Center for Toxicological Research, Jefferson, AR 72079, United States.
authors.forename: Mugimane G
authors.initials: MG
authors.lastname: Manjanatha
mesh_terms: D000818:Animals; D020552:Comet Assay / Q000379:methods*; D017373:Cyproterone Acetate / Q000633:toxicity*; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008099:Liver / Q000187:drug effects*; D008297:Male; D042361:Mammary Glands, Human / Q000187:drug effects; D048629:Micronuclei, Chromosome-Defective / Q000187:drug effects; D015162:Micronucleus Tests / Q000379:methods*; D000069463:Olive Oil; D010084:Oxidation-Reduction / Q000187:drug effects; D010938:Plant Oils / Q000008:administration & dosage; D051381:Rats; D011916:Rats, Inbred F344; D012156:Reticulocytes / Q000187:drug effects; D012727:Sex Characteristics; D013737:Testis / Q000187:drug effects
chemical_list: D000069463:Olive Oil; D010938:Plant Oils; D017373:Cyproterone Acetate
keywords: Cyproterone acetate (CPA); DNA damage; In vivo Comet assay; Liver; Oxidative DNA damage; Sex-specific genotoxicity