Ding Wei, Bishop Michelle E, Pearce Mason G, Davis Kelly J, White Gene A, Lyn-Cook Lascelles E, Manjanatha Mugimane G
Division of Genetic and Molecular Toxicology, US FDA/National Center for Toxicological Research, Jefferson, AR 72079, United States.
Division of Genetic and Molecular Toxicology, US FDA/National Center for Toxicological Research, Jefferson, AR 72079, United States.
Mutat Res Genet Toxicol Environ Mutagen. 2014 Nov 1;774:1-7. doi: 10.1016/j.mrgentox.2014.08.005. Epub 2014 Sep 3.
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.
醋酸环丙孕酮（CPA）是一种合成激素药物，它以性别特异性的方式诱发大鼠肝脏肿瘤，与雌性大鼠相比，雄性大鼠诱发肝脏肿瘤所需的剂量高出五倍。为了评估体内碱性彗星试验预测CPA性别特异性致癌性的潜力，在雄性和雌性F344大鼠的肝脏中评估了CPA诱导的直接DNA损伤（DNA链断裂和碱不稳定位点）。此外，同时利用人8-氧鸟嘌呤-DNA-N-糖基化酶（hOGG1）和核酸内切酶III（EndoIII）改良的体内碱性彗星试验测量继发性氧化DNA损伤，并分析外周血中的网织红细胞微核（MN）频率。将5组7周龄的雄性和雌性F344大鼠在0、24和45小时通过灌胃给予橄榄油或10、25、50或100mg/kg体重的CPA溶于橄榄油中，并在48小时处死。CPA诱导的大鼠肝脏直接DNA损伤表现出与其肝致瘤性相同的性别特异性模式：与雌性相比，雄性肝脏中诱导直接DNA损伤出现统计学显著增加所需的CPA剂量高出五倍。然而，两性的外周血MN频率都较低，并且CPA诱导的氧化DNA损伤在雄性大鼠肝脏中通常比雌性大鼠更大。综上所述，我们的结果表明，在体内碱性彗星试验和癌症生物测定中，CPA的性别特异性具有一致性，而CPA诱导的氧化DNA损伤与其致瘤性没有直接相关性。
